EA006876B1 - Композиция, содержащая нестероидное противовоспалительное средство (nsaid) и ингибитор киназы egfr, для лечения или ингибирования полипов в ободочной кишке и рака ободочной и прямой кишки - Google Patents
Композиция, содержащая нестероидное противовоспалительное средство (nsaid) и ингибитор киназы egfr, для лечения или ингибирования полипов в ободочной кишке и рака ободочной и прямой кишки Download PDFInfo
- Publication number
- EA006876B1 EA006876B1 EA200200246A EA200200246A EA006876B1 EA 006876 B1 EA006876 B1 EA 006876B1 EA 200200246 A EA200200246 A EA 200200246A EA 200200246 A EA200200246 A EA 200200246A EA 006876 B1 EA006876 B1 EA 006876B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- carbon atoms
- alkyl
- carbon
- phenyl
- atoms
- Prior art date
Links
- 229940043355 kinase inhibitor Drugs 0.000 title claims abstract description 70
- 239000003757 phosphotransferase inhibitor Substances 0.000 title claims abstract description 70
- 206010009944 Colon cancer Diseases 0.000 title claims abstract description 17
- 208000001333 Colorectal Neoplasms Diseases 0.000 title claims abstract description 9
- 238000011282 treatment Methods 0.000 title claims description 15
- 239000000203 mixture Substances 0.000 title claims description 12
- 230000005764 inhibitory process Effects 0.000 title claims description 8
- 208000035984 Colonic Polyps Diseases 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 32
- 241000124008 Mammalia Species 0.000 claims abstract description 9
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 1977
- -1 phenoprofen Chemical compound 0.000 claims description 543
- 125000000217 alkyl group Chemical group 0.000 claims description 241
- 229910052799 carbon Inorganic materials 0.000 claims description 152
- 229910052739 hydrogen Inorganic materials 0.000 claims description 130
- 239000001257 hydrogen Substances 0.000 claims description 130
- 125000003342 alkenyl group Chemical group 0.000 claims description 127
- 125000000304 alkynyl group Chemical group 0.000 claims description 122
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 122
- 150000002431 hydrogen Chemical class 0.000 claims description 108
- 125000003545 alkoxy group Chemical group 0.000 claims description 97
- 150000001721 carbon Chemical group 0.000 claims description 92
- 150000003254 radicals Chemical class 0.000 claims description 90
- 229910052757 nitrogen Inorganic materials 0.000 claims description 88
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 87
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 86
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 85
- 125000001424 substituent group Chemical group 0.000 claims description 82
- 125000003282 alkyl amino group Chemical group 0.000 claims description 80
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 80
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 80
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 78
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 77
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 72
- 229910052736 halogen Inorganic materials 0.000 claims description 70
- 150000002367 halogens Chemical group 0.000 claims description 68
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 65
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 64
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 64
- 125000004414 alkyl thio group Chemical group 0.000 claims description 60
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 60
- 150000001875 compounds Chemical class 0.000 claims description 59
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 58
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 56
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 56
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 55
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 53
- 125000004429 atom Chemical group 0.000 claims description 47
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 47
- 125000004076 pyridyl group Chemical group 0.000 claims description 46
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 46
- 229920006395 saturated elastomer Polymers 0.000 claims description 44
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 44
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 42
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 40
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 40
- 125000000623 heterocyclic group Chemical group 0.000 claims description 40
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 36
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 36
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 35
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 34
- 125000004423 acyloxy group Chemical group 0.000 claims description 34
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 32
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 claims description 32
- 229960000894 sulindac Drugs 0.000 claims description 32
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 30
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 30
- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims description 29
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 28
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- 125000005843 halogen group Chemical group 0.000 claims description 24
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 24
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 24
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 23
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 23
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 23
- 229910052794 bromium Inorganic materials 0.000 claims description 23
- 229910052801 chlorine Inorganic materials 0.000 claims description 23
- 239000000460 chlorine Substances 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 21
- 125000000033 alkoxyamino group Chemical group 0.000 claims description 20
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 20
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 20
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 19
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 239000011737 fluorine Substances 0.000 claims description 19
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 19
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 17
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 16
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 16
- 108091000080 Phosphotransferase Proteins 0.000 claims description 16
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 16
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 125000004043 oxo group Chemical group O=* 0.000 claims description 16
- 102000020233 phosphotransferase Human genes 0.000 claims description 16
- 150000003536 tetrazoles Chemical class 0.000 claims description 16
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 claims description 15
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- 229930192474 thiophene Natural products 0.000 claims description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 13
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 12
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 12
- 210000001072 colon Anatomy 0.000 claims description 12
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 claims description 12
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 12
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 11
- 208000029742 colonic neoplasm Diseases 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 8
- 125000003418 alkyl amino alkoxy group Chemical group 0.000 claims description 7
- RJMIEHBSYVWVIN-LLVKDONJSA-N (2r)-2-[4-(3-oxo-1h-isoindol-2-yl)phenyl]propanoic acid Chemical compound C1=CC([C@H](C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-LLVKDONJSA-N 0.000 claims description 6
- MDKGKXOCJGEUJW-VIFPVBQESA-N (2s)-2-[4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-VIFPVBQESA-N 0.000 claims description 6
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 6
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims description 6
- 229960003184 carprofen Drugs 0.000 claims description 6
- 229960002390 flurbiprofen Drugs 0.000 claims description 6
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 claims description 6
- 229960001680 ibuprofen Drugs 0.000 claims description 6
- 229960004187 indoprofen Drugs 0.000 claims description 6
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 6
- 229960000991 ketoprofen Drugs 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 229960002009 naproxen Drugs 0.000 claims description 6
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 6
- 229960004492 suprofen Drugs 0.000 claims description 6
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims description 5
- 229960000590 celecoxib Drugs 0.000 claims description 5
- 125000004984 dialkylaminoalkoxy group Chemical group 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 claims description 4
- MWGVSJNZBRLKBE-UHFFFAOYSA-N ClC=1C=C(C=CC1F)NC1=C(C=NC2=CC(=C(C=C12)C(C(=O)N)=CCN(C)C)OCC)C#N Chemical group ClC=1C=C(C=CC1F)NC1=C(C=NC2=CC(=C(C=C12)C(C(=O)N)=CCN(C)C)OCC)C#N MWGVSJNZBRLKBE-UHFFFAOYSA-N 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 4
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- MITFXPHMIHQXPI-UHFFFAOYSA-N Oraflex Chemical compound N=1C2=CC(C(C(O)=O)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 MITFXPHMIHQXPI-UHFFFAOYSA-N 0.000 claims 10
- 125000006319 alkynyl amino group Chemical group 0.000 claims 5
- 229960005430 benoxaprofen Drugs 0.000 claims 5
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 claims 5
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 claims 5
- 229960005293 etodolac Drugs 0.000 claims 5
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 claims 4
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 claims 4
- 229960000371 rofecoxib Drugs 0.000 claims 4
- 230000002759 chromosomal effect Effects 0.000 claims 2
- 101150034825 DODA gene Proteins 0.000 claims 1
- 241001024304 Mino Species 0.000 claims 1
- 239000008186 active pharmaceutical agent Substances 0.000 claims 1
- 125000005137 alkenylsulfonyl group Chemical group 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 235000005583 doda Nutrition 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims 1
- HKUFIYBZNQSHQS-UHFFFAOYSA-N n-octadecyloctadecan-1-amine Chemical compound CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC HKUFIYBZNQSHQS-UHFFFAOYSA-N 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 abstract description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 abstract description 2
- 208000037062 Polyps Diseases 0.000 description 26
- 238000012360 testing method Methods 0.000 description 23
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 13
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- 230000000144 pharmacologic effect Effects 0.000 description 10
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 8
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- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
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- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 6
- WDXARTMCIRVMAE-UHFFFAOYSA-N quinoline-2-carbonitrile Chemical class C1=CC=CC2=NC(C#N)=CC=C21 WDXARTMCIRVMAE-UHFFFAOYSA-N 0.000 description 6
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- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 5
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- 229910052740 iodine Inorganic materials 0.000 description 5
- 150000007522 mineralic acids Chemical class 0.000 description 5
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- 108090000623 proteins and genes Proteins 0.000 description 5
- ITGIYLMMAABTHC-ONEGZZNKSA-N (e)-4-(dimethylazaniumyl)but-2-enoate Chemical compound CN(C)C\C=C\C(O)=O ITGIYLMMAABTHC-ONEGZZNKSA-N 0.000 description 4
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 4
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 4
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 4
- WNZQDUSMALZDQF-UHFFFAOYSA-N 2-benzofuran-1(3H)-one Chemical compound C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 description 4
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 4
- NQRDPXAROIKHDQ-UHFFFAOYSA-N 4-[4-(3-bromoanilino)quinazolin-6-yl]but-2-ynamide Chemical compound C12=CC(CC#CC(=O)N)=CC=C2N=CN=C1NC1=CC=CC(Br)=C1 NQRDPXAROIKHDQ-UHFFFAOYSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 4
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- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
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- 230000000737 periodic effect Effects 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 229940080469 phosphocellulose Drugs 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- OHZYAOYVLLHTGW-UHFFFAOYSA-N pyrido[3,2-c]pyridazine Chemical compound C1=CN=NC2=CC=CN=C21 OHZYAOYVLLHTGW-UHFFFAOYSA-N 0.000 description 1
- TYLGVQVJCVFREB-UHFFFAOYSA-N pyrido[3,4-b]pyrazine Chemical compound C1=NC=CC2=NC=CN=C21 TYLGVQVJCVFREB-UHFFFAOYSA-N 0.000 description 1
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical class NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 150000004944 pyrrolopyrimidines Chemical class 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 150000003252 quinoxalines Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000021014 regulation of cell growth Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
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- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- 229940046009 vitamin E Drugs 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US37326199A | 1999-08-12 | 1999-08-12 | |
| PCT/US2000/021021 WO2001012227A1 (en) | 1999-08-12 | 2000-08-02 | Nsaid and efgr kinase inhibitor containing composition for the treatment or inhibition of colonic polyps and colorectal cancer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA200200246A1 EA200200246A1 (ru) | 2002-08-29 |
| EA006876B1 true EA006876B1 (ru) | 2006-04-28 |
Family
ID=23471660
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA200200246A EA006876B1 (ru) | 1999-08-12 | 2000-08-02 | Композиция, содержащая нестероидное противовоспалительное средство (nsaid) и ингибитор киназы egfr, для лечения или ингибирования полипов в ободочной кишке и рака ободочной и прямой кишки |
Country Status (24)
| Country | Link |
|---|---|
| EP (1) | EP1202746B1 (enExample) |
| JP (1) | JP2003507342A (enExample) |
| KR (1) | KR20020018201A (enExample) |
| CN (1) | CN1229142C (enExample) |
| AR (1) | AR029763A1 (enExample) |
| AT (1) | ATE341341T1 (enExample) |
| AU (1) | AU783116B2 (enExample) |
| BR (1) | BR0013219A (enExample) |
| CA (1) | CA2380904C (enExample) |
| CZ (1) | CZ2002474A3 (enExample) |
| DE (1) | DE60031127T2 (enExample) |
| DK (1) | DK1202746T3 (enExample) |
| EA (1) | EA006876B1 (enExample) |
| ES (1) | ES2272305T3 (enExample) |
| HK (1) | HK1042244A1 (enExample) |
| HU (1) | HUP0203162A3 (enExample) |
| IL (1) | IL147913A0 (enExample) |
| MX (1) | MXPA02001448A (enExample) |
| NO (1) | NO20020663L (enExample) |
| NZ (1) | NZ517120A (enExample) |
| PL (1) | PL353267A1 (enExample) |
| PT (1) | PT1202746E (enExample) |
| WO (1) | WO2001012227A1 (enExample) |
| ZA (1) | ZA200201156B (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2606114C2 (ru) * | 2011-06-01 | 2017-01-10 | Джейнус Байотерапьютикс, Инк. | Новые модуляторы иммунной системы |
Families Citing this family (36)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040127470A1 (en) * | 1998-12-23 | 2004-07-01 | Pharmacia Corporation | Methods and compositions for the prevention or treatment of neoplasia comprising a Cox-2 inhibitor in combination with an epidermal growth factor receptor antagonist |
| BR0109165A (pt) * | 2000-03-13 | 2003-04-22 | American Cyanamid Co | Método de tratamento de pólipos colÈnicos |
| US6384051B1 (en) | 2000-03-13 | 2002-05-07 | American Cyanamid Company | Method of treating or inhibiting colonic polyps |
| EP1412367A4 (en) | 2001-06-21 | 2006-05-03 | Ariad Pharma Inc | NEW CHINOLINE AND ITS USE |
| EP1409481B1 (en) | 2001-07-16 | 2006-10-04 | Astrazeneca AB | Quinoline derivatives and their use as tyrosine kinase inhibitors |
| DE60224299T2 (de) * | 2001-10-25 | 2008-12-11 | Novartis Ag | Kombinationsmedikationen mit einem selektiven cyclooxygenase-2-inhibitor |
| US6924285B2 (en) | 2002-03-30 | 2005-08-02 | Boehringer Ingelheim Pharma Gmbh & Co. | Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them |
| EP1542989B1 (en) | 2002-07-31 | 2007-04-18 | Critical Outcome Technologies, Inc. | Protein tyrosine kinase inhibitors |
| EP1551824B1 (en) | 2002-10-09 | 2007-12-12 | Critical Outcome Technologies, Inc. | Protein tyrosine kinase inhibitors |
| CA2506066A1 (en) * | 2002-11-15 | 2004-06-03 | Genomic Health, Inc. | Gene expression profiling of egfr positive cancer |
| US8309562B2 (en) | 2003-07-03 | 2012-11-13 | Myrexis, Inc. | Compounds and therapeutical use thereof |
| KR101218213B1 (ko) | 2003-07-03 | 2013-01-04 | 시토비아 인크. | 카스파제의 활성인자 및 세포자멸사의 유도인자로서의4-아릴아미노-퀴나졸린 |
| GB0326459D0 (en) | 2003-11-13 | 2003-12-17 | Astrazeneca Ab | Quinazoline derivatives |
| TW200529846A (en) | 2004-02-20 | 2005-09-16 | Wyeth Corp | 3-quinolinecarbonitrile protein kinase inhibitors |
| EP2168968B1 (en) | 2004-04-02 | 2017-08-23 | OSI Pharmaceuticals, LLC | 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors |
| NZ551027A (en) | 2004-04-08 | 2011-01-28 | Targegen Inc | Benzotriazine inhibitors of kinases |
| EP1746999B1 (en) | 2004-05-06 | 2011-11-16 | Warner-Lambert Company LLC | 4-phenylamino-quinazolin-6-yl-amides |
| EP1758601A1 (en) | 2004-06-03 | 2007-03-07 | F.Hoffmann-La Roche Ag | Treatment with cisplatin and an egfr-inhibitor |
| US8258145B2 (en) | 2005-01-03 | 2012-09-04 | Myrexis, Inc. | Method of treating brain cancer |
| CA2592900A1 (en) | 2005-01-03 | 2006-07-13 | Myriad Genetics Inc. | Nitrogen containing bicyclic compounds and therapeutical use thereof |
| MY167260A (en) | 2005-11-01 | 2018-08-14 | Targegen Inc | Bi-aryl meta-pyrimidine inhibitors of kinases |
| US8575164B2 (en) | 2005-12-19 | 2013-11-05 | OSI Pharmaceuticals, LLC | Combination cancer therapy |
| EP1921070A1 (de) | 2006-11-10 | 2008-05-14 | Boehringer Ingelheim Pharma GmbH & Co. KG | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstelllung |
| US8138191B2 (en) | 2007-01-11 | 2012-03-20 | Critical Outcome Technologies Inc. | Inhibitor compounds and cancer treatment methods |
| AU2008212999A1 (en) | 2007-02-06 | 2008-08-14 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof |
| WO2009079797A1 (en) | 2007-12-26 | 2009-07-02 | Critical Outcome Technologies, Inc. | Compounds and method for treatment of cancer |
| EP2245026B1 (de) | 2008-02-07 | 2012-08-01 | Boehringer Ingelheim International GmbH | Spirocyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
| AU2009247782C1 (en) | 2008-05-13 | 2013-09-19 | Astrazeneca Ab | Fumarate salt of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (N-methylcarbamoylmethyl) piperidin- 4-yl] oxy } quinazoline |
| ES2396613T3 (es) | 2008-05-19 | 2013-02-22 | OSI Pharmaceuticals, LLC | Imidazopirazinas e imidazotriazinas sustituidas |
| CA2733153C (en) | 2008-08-08 | 2016-11-08 | Boehringer Ingelheim International Gmbh | Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them |
| PL387312A1 (pl) | 2009-02-19 | 2010-08-30 | Farma-Projekt Spółka Z Ograniczoną Odpowiedzialnością | Zastosowanie sulindaku i/lub jego metabolitu we wspomagającym leczeniu raka jelita grubego u ludzi |
| US20120064072A1 (en) | 2009-03-18 | 2012-03-15 | Maryland Franklin | Combination Cancer Therapy Comprising Administration of an EGFR Inhibitor and an IGF-1R Inhibitor |
| US8513415B2 (en) | 2009-04-20 | 2013-08-20 | OSI Pharmaceuticals, LLC | Preparation of C-pyrazine-methylamines |
| CA2794952C (en) | 2010-04-01 | 2018-05-15 | Critical Outcome Technologies Inc. | Compounds and method for treatment of hiv |
| AU2010363329A1 (en) | 2010-11-07 | 2013-05-09 | Targegen, Inc. | Compositions and methods for treating myelofibrosis |
| WO2012129145A1 (en) | 2011-03-18 | 2012-09-27 | OSI Pharmaceuticals, LLC | Nscle combination therapy |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001521926A (ja) * | 1997-11-04 | 2001-11-13 | ファイザー・プロダクツ・インク | 治療上活性の化合物におけるカテコールのインダゾール生物学的等価物置換 |
| EP1039910A1 (en) * | 1997-11-06 | 2000-10-04 | American Cyanamid Company | Use of quinazoline derivatives as tyrosine kinase inhibitors for treating colonic polyps |
-
2000
- 2000-08-02 IL IL14791300A patent/IL147913A0/xx unknown
- 2000-08-02 MX MXPA02001448A patent/MXPA02001448A/es active IP Right Grant
- 2000-08-02 AT AT00950930T patent/ATE341341T1/de not_active IP Right Cessation
- 2000-08-02 EP EP00950930A patent/EP1202746B1/en not_active Expired - Lifetime
- 2000-08-02 PT PT00950930T patent/PT1202746E/pt unknown
- 2000-08-02 DE DE60031127T patent/DE60031127T2/de not_active Expired - Lifetime
- 2000-08-02 AU AU63959/00A patent/AU783116B2/en not_active Ceased
- 2000-08-02 BR BR0013219-5A patent/BR0013219A/pt not_active IP Right Cessation
- 2000-08-02 JP JP2001516570A patent/JP2003507342A/ja active Pending
- 2000-08-02 CN CNB008117977A patent/CN1229142C/zh not_active Expired - Fee Related
- 2000-08-02 NZ NZ517120A patent/NZ517120A/en unknown
- 2000-08-02 HU HU0203162A patent/HUP0203162A3/hu unknown
- 2000-08-02 DK DK00950930T patent/DK1202746T3/da active
- 2000-08-02 HK HK02104004.4A patent/HK1042244A1/zh unknown
- 2000-08-02 KR KR1020027001817A patent/KR20020018201A/ko not_active Ceased
- 2000-08-02 ES ES00950930T patent/ES2272305T3/es not_active Expired - Lifetime
- 2000-08-02 CA CA002380904A patent/CA2380904C/en not_active Expired - Fee Related
- 2000-08-02 EA EA200200246A patent/EA006876B1/ru not_active IP Right Cessation
- 2000-08-02 PL PL00353267A patent/PL353267A1/xx not_active Application Discontinuation
- 2000-08-02 WO PCT/US2000/021021 patent/WO2001012227A1/en not_active Ceased
- 2000-08-02 CZ CZ2002474A patent/CZ2002474A3/cs unknown
- 2000-08-11 AR ARP000104159A patent/AR029763A1/es not_active Application Discontinuation
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2002
- 2002-02-11 ZA ZA200201156A patent/ZA200201156B/en unknown
- 2002-02-11 NO NO20020663A patent/NO20020663L/no not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2606114C2 (ru) * | 2011-06-01 | 2017-01-10 | Джейнус Байотерапьютикс, Инк. | Новые модуляторы иммунной системы |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2272305T3 (es) | 2007-05-01 |
| CZ2002474A3 (cs) | 2003-02-12 |
| AR029763A1 (es) | 2003-07-16 |
| PT1202746E (pt) | 2007-01-31 |
| NO20020663D0 (no) | 2002-02-11 |
| EP1202746B1 (en) | 2006-10-04 |
| AU6395900A (en) | 2001-03-13 |
| HUP0203162A2 (hu) | 2003-01-28 |
| HK1042244A1 (zh) | 2002-08-09 |
| NO20020663L (no) | 2002-04-09 |
| CA2380904C (en) | 2009-02-10 |
| IL147913A0 (en) | 2002-08-14 |
| EP1202746A1 (en) | 2002-05-08 |
| WO2001012227A1 (en) | 2001-02-22 |
| AU783116B2 (en) | 2005-09-29 |
| CA2380904A1 (en) | 2001-02-22 |
| HUP0203162A3 (en) | 2006-07-28 |
| ZA200201156B (en) | 2003-05-12 |
| EA200200246A1 (ru) | 2002-08-29 |
| ATE341341T1 (de) | 2006-10-15 |
| KR20020018201A (ko) | 2002-03-07 |
| DK1202746T3 (da) | 2007-01-02 |
| PL353267A1 (en) | 2003-11-03 |
| CN1229142C (zh) | 2005-11-30 |
| BR0013219A (pt) | 2002-04-23 |
| DE60031127D1 (de) | 2006-11-16 |
| NZ517120A (en) | 2004-10-29 |
| CN1370080A (zh) | 2002-09-18 |
| JP2003507342A (ja) | 2003-02-25 |
| DE60031127T2 (de) | 2007-02-01 |
| MXPA02001448A (es) | 2002-07-02 |
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Legal Events
| Date | Code | Title | Description |
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| MM4A | Lapse of a eurasian patent due to non-payment of renewal fees within the time limit in the following designated state(s) |
Designated state(s): AM AZ BY KZ KG MD TJ TM |