ES2256552T3 - Compuestos policiclicos que tienen actividad anti-tumoral. - Google Patents
Compuestos policiclicos que tienen actividad anti-tumoral.Info
- Publication number
- ES2256552T3 ES2256552T3 ES02779413T ES02779413T ES2256552T3 ES 2256552 T3 ES2256552 T3 ES 2256552T3 ES 02779413 T ES02779413 T ES 02779413T ES 02779413 T ES02779413 T ES 02779413T ES 2256552 T3 ES2256552 T3 ES 2256552T3
- Authority
- ES
- Spain
- Prior art keywords
- diaza
- benzo
- fluoren
- ethylamino
- dimethylamino
- 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 description 142
- 230000000259 anti-tumor effect Effects 0.000 title description 11
- -1 hydroxy, mercapto Chemical class 0.000 claims abstract description 82
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 53
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 43
- 239000001257 hydrogen Substances 0.000 claims abstract description 43
- 125000003367 polycyclic group Chemical group 0.000 claims abstract description 39
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 31
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 29
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 21
- 150000002367 halogens Chemical class 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 16
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 12
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000000000 cycloalkoxy group Chemical group 0.000 claims abstract description 7
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims abstract description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 6
- 125000006715 (C1-C5) alkylthio group Chemical group 0.000 claims abstract description 5
- 125000006557 (C2-C5) alkylene group Chemical group 0.000 claims abstract description 5
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims abstract description 3
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 127
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 18
- PXHZSTZHFFHHGQ-UHFFFAOYSA-N 9-[2-(dimethylamino)ethylamino]-5-hydroxy-8,14-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),2(7),3,5,8,12(17),13,15-octaen-11-one Chemical compound C12=CC=NC=C2C(=O)C2=C1C1=CC=C(O)C=C1N=C2NCCN(C)C PXHZSTZHFFHHGQ-UHFFFAOYSA-N 0.000 claims description 12
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 10
- QIHMHPKNXLROSQ-UHFFFAOYSA-N 6-(2-dimethylamino-ethylamino)-3-hydroxy-4-methyl-5,9-diaza-benzo[c]fluoren-7-one Chemical compound C1=NC=C2C(=O)C3=C(NCCN(C)C)NC4=C(C)C(=O)C=CC4=C3C2=C1 QIHMHPKNXLROSQ-UHFFFAOYSA-N 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- PKHAOBNORGOIKL-UHFFFAOYSA-N C12=CC=NC=C2C(=O)C2=C1C1=CC=C(OC)C=C1N=C2NCCN(C)C Chemical compound C12=CC=NC=C2C(=O)C2=C1C1=CC=C(OC)C=C1N=C2NCCN(C)C PKHAOBNORGOIKL-UHFFFAOYSA-N 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- WADHTZYYSJTDEE-UHFFFAOYSA-N C12=CC=NC=C2C(=O)C2=C1C1=CC=CC=C1N=C2NCCN(C)C Chemical compound C12=CC=NC=C2C(=O)C2=C1C1=CC=CC=C1N=C2NCCN(C)C WADHTZYYSJTDEE-UHFFFAOYSA-N 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- GBTRMNJQEKCYRN-UHFFFAOYSA-N fluoren-2-one Chemical compound C1=CC=CC2=CC3=CC(=O)C=CC3=C21 GBTRMNJQEKCYRN-UHFFFAOYSA-N 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- CFWDZUYNCBBQEE-UHFFFAOYSA-N 3h-phenanthren-2-one Chemical compound C1=CC=C2C=CC3=CC(=O)CC=C3C2=C1 CFWDZUYNCBBQEE-UHFFFAOYSA-N 0.000 claims description 5
- MKNPIDKTSOAVQT-UHFFFAOYSA-N 5-hydroxy-6-methyl-9-(2-pyrrolidin-1-ylethylamino)-8,15-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1,3,5,7,9,12(17),13,15-octaen-11-one Chemical compound Cc1c(O)ccc2c3-c4cnccc4C(=O)c3c(NCCN3CCCC3)nc12 MKNPIDKTSOAVQT-UHFFFAOYSA-N 0.000 claims description 5
- DMCBLWAXHOEHOT-UHFFFAOYSA-N 5-hydroxy-9-(2-pyrrolidin-1-ylethylamino)-8,14-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),2(7),3,5,8,12(17),13,15-octaen-11-one Chemical compound N=1C2=CC(O)=CC=C2C=2C3=CC=NC=C3C(=O)C=2C=1NCCN1CCCC1 DMCBLWAXHOEHOT-UHFFFAOYSA-N 0.000 claims description 5
- OLBLLCOUWPLERR-UHFFFAOYSA-N 5-hydroxy-9-(2-pyrrolidin-1-ylethylamino)-8,15-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),2(7),3,5,8,12(17),13,15-octaen-11-one Chemical compound Oc1ccc2c3-c4cnccc4C(=O)c3c(NCCN3CCCC3)nc2c1 OLBLLCOUWPLERR-UHFFFAOYSA-N 0.000 claims description 5
- WLDGJSAXDBUUGM-UHFFFAOYSA-N 9-[2-(dimethylamino)ethylamino]-5-hydroxy-14-methyl-8,15-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),2(7),3,5,8,12(17),13,15-octaen-11-one Chemical compound CN(C)CCNc1nc2cc(O)ccc2c2-c3cnc(C)cc3C(=O)c12 WLDGJSAXDBUUGM-UHFFFAOYSA-N 0.000 claims description 5
- VUHFFVOGZLPTFE-UHFFFAOYSA-N 9-[2-(dimethylamino)ethylamino]-5-hydroxy-6-methyl-8,15-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1,3,5,7,9,12(17),13,15-octaen-11-one Chemical compound CN(C)CCNc1nc2c(C)c(O)ccc2c2-c3cnccc3C(=O)c12 VUHFFVOGZLPTFE-UHFFFAOYSA-N 0.000 claims description 5
- QEYROBKXHYYYGU-UHFFFAOYSA-N 9-[2-(dimethylamino)ethylamino]-5-hydroxy-8,15-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),2(7),3,5,8,12(17),13,15-octaen-11-one Chemical compound CN(C)CCNc1nc2cc(O)ccc2c2-c3cnccc3C(=O)c12 QEYROBKXHYYYGU-UHFFFAOYSA-N 0.000 claims description 5
- JMHLIFKVFONERU-UHFFFAOYSA-N C12=CC=NC=C2C(=O)C2=C1C1=CC=C(Cl)C=C1N=C2NCCN(C)C Chemical compound C12=CC=NC=C2C(=O)C2=C1C1=CC=C(Cl)C=C1N=C2NCCN(C)C JMHLIFKVFONERU-UHFFFAOYSA-N 0.000 claims description 5
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- YKVCBPVRDBFOKE-UHFFFAOYSA-N 6-(2-dimethylamino-ethoxy)-3-hydroxy-5,9-diaza-benzo[c]fluoren-7-one Chemical compound C1=NC=C2C(=O)C3=C(OCCN(C)C)NC4=CC(=O)C=CC4=C3C2=C1 YKVCBPVRDBFOKE-UHFFFAOYSA-N 0.000 claims description 4
- VWYGWDLRIGOTGD-UHFFFAOYSA-N 6-(2-dimethylamino-ethylamino)-3-ethoxy-5,9-diaza-benzo[c]fluoren-7-one Chemical compound C12=CC=NC=C2C(=O)C2=C1C1=CC=C(OCC)C=C1N=C2NCCN(C)C VWYGWDLRIGOTGD-UHFFFAOYSA-N 0.000 claims description 4
- FWLFCEYQROSVEQ-UHFFFAOYSA-N 9-[2-(dimethylamino)ethylamino]-3,5-dimethoxy-8,14-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),2(7),3,5,8,12(17),13,15-octaen-11-one Chemical compound C12=CC=NC=C2C(=O)C2=C1C1=C(OC)C=C(OC)C=C1N=C2NCCN(C)C FWLFCEYQROSVEQ-UHFFFAOYSA-N 0.000 claims description 4
- YNLUJSRODFBOPG-UHFFFAOYSA-N C12=CN=C(C)C=C2C(=O)C2=C1C1=CC=C(OC)C=C1N=C2NCCN(C)C Chemical compound C12=CN=C(C)C=C2C(=O)C2=C1C1=CC=C(OC)C=C1N=C2NCCN(C)C YNLUJSRODFBOPG-UHFFFAOYSA-N 0.000 claims description 4
- QKGRZKSBMSULAN-UHFFFAOYSA-N C12=CN=CC=C2C(=O)C2=C1C1=CC=C(OC)C=C1N=C2NCCN(C)C Chemical compound C12=CN=CC=C2C(=O)C2=C1C1=CC=C(OC)C=C1N=C2NCCN(C)C QKGRZKSBMSULAN-UHFFFAOYSA-N 0.000 claims description 4
- URUMTOXJTMRQMH-UHFFFAOYSA-N C1=NC(NCC(C)(C)CN(C)C)=C2C(C3=CC=C(C(=C3N=C3NCCN(C)C)C)OC)=C3C(=O)C2=C1 Chemical compound C1=NC(NCC(C)(C)CN(C)C)=C2C(C3=CC=C(C(=C3N=C3NCCN(C)C)C)OC)=C3C(=O)C2=C1 URUMTOXJTMRQMH-UHFFFAOYSA-N 0.000 claims description 4
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- UUVANKPOSJGIQF-UHFFFAOYSA-N 16-[[3-(dimethylamino)-2,2-dimethylpropyl]amino]-9-[2-(dimethylamino)ethylamino]-5-methoxy-8,15-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),2(7),3,5,8,12(17),13,15-octaen-11-one Chemical compound C1=NC(NCC(C)(C)CN(C)C)=C2C(C3=CC=C(C=C3N=C3NCCN(C)C)OC)=C3C(=O)C2=C1 UUVANKPOSJGIQF-UHFFFAOYSA-N 0.000 claims description 3
- BEYPNRRNAGSTKG-UHFFFAOYSA-N 3-methoxy-4-methyl-6-(2-pyrrolidin-1-yl-ethylamino)-5,10-diaza-benzo[c]fluoren-7-one Chemical compound N=1C2=C(C)C(OC)=CC=C2C=2C3=CN=CC=C3C(=O)C=2C=1NCCN1CCCC1 BEYPNRRNAGSTKG-UHFFFAOYSA-N 0.000 claims description 3
- QUQJWYLBPFXQIV-UHFFFAOYSA-N 5-hydroxy-9-(2-morpholin-4-ylethylamino)-8,14-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),2(7),3,5,8,12(17),13,15-octaen-11-one Chemical compound N=1C2=CC(O)=CC=C2C=2C3=CC=NC=C3C(=O)C=2C=1NCCN1CCOCC1 QUQJWYLBPFXQIV-UHFFFAOYSA-N 0.000 claims description 3
- HPXVFGITVDFZNH-UHFFFAOYSA-N 6,11-bis-(2-dimethylamino-ethylamino)-3-methoxy-5,10-diaza-benzo[c]fluoren-7-one Chemical compound C1=NC(NCCN(C)C)=C2C(C3=CC=C(C=C3N=C3NCCN(C)C)OC)=C3C(=O)C2=C1 HPXVFGITVDFZNH-UHFFFAOYSA-N 0.000 claims description 3
- JBMUOGFBQWYCIJ-UHFFFAOYSA-N 9-[2-(dimethylamino)ethyl-methylamino]-5-hydroxy-8,14-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),2(7),3,5,8,12(17),13,15-octaen-11-one Chemical compound C12=CC=NC=C2C(=O)C2=C1C1=CC=C(O)C=C1N=C2N(C)CCN(C)C JBMUOGFBQWYCIJ-UHFFFAOYSA-N 0.000 claims description 3
- YODFATPDRUCQLG-UHFFFAOYSA-N C12=CC=NC=C2C(=O)C2=C1C1=CC=C(OC)C=C1N=C2NCCNC Chemical compound C12=CC=NC=C2C(=O)C2=C1C1=CC=C(OC)C=C1N=C2NCCNC YODFATPDRUCQLG-UHFFFAOYSA-N 0.000 claims description 3
- LEKZHQZGEALBBX-UHFFFAOYSA-N N=1C2=CC(OC)=CC=C2C=2C3=CC=NC=C3C(=O)C=2C=1N1CCN(C)CC1 Chemical compound N=1C2=CC(OC)=CC=C2C=2C3=CC=NC=C3C(=O)C=2C=1N1CCN(C)CC1 LEKZHQZGEALBBX-UHFFFAOYSA-N 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 238000002483 medication Methods 0.000 claims description 3
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 2
- 125000005605 benzo group Chemical group 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 230000002062 proliferating effect Effects 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
- 239000000843 powder Substances 0.000 description 67
- 239000000203 mixture Substances 0.000 description 66
- 238000005160 1H NMR spectroscopy Methods 0.000 description 62
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 59
- 239000002253 acid Substances 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 34
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 33
- 239000007787 solid Substances 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- 238000005481 NMR spectroscopy Methods 0.000 description 30
- 239000000243 solution Substances 0.000 description 24
- 150000002148 esters Chemical class 0.000 description 23
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 21
- MIICHPXXYGNQBM-UHFFFAOYSA-N 6-chloro-3-methoxy-5,9-diaza-benzo[c]fluoren-7-one Chemical compound C12=CC=NC=C2C(=O)C2=C1C1=CC=C(OC)C=C1N=C2Cl MIICHPXXYGNQBM-UHFFFAOYSA-N 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 14
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 13
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 125000004494 ethyl ester group Chemical group 0.000 description 12
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 description 12
- HTDBMJVEKVGYQM-UHFFFAOYSA-N 6-chloro-3-hydroxy-5,9-diaza-benzo[c]fluoren-7-one Chemical compound C1=NC=C2C(=O)C3=C(Cl)NC4=CC(=O)C=CC4=C3C2=C1 HTDBMJVEKVGYQM-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- SALKPUCIOGVGQC-UHFFFAOYSA-N 6-chloro-3-methoxy-5,10-diaza-benzo[c]fluoren-7-one Chemical compound C12=CN=CC=C2C(=O)C2=C1C1=CC=C(OC)C=C1N=C2Cl SALKPUCIOGVGQC-UHFFFAOYSA-N 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- QIGSUPYDEMBLHS-UHFFFAOYSA-N 6-chloro-3-methoxy-5,11-diaza-benzo[c]fluoren-7-one Chemical compound C12=NC=CC=C2C(=O)C2=C1C1=CC=C(OC)C=C1N=C2Cl QIGSUPYDEMBLHS-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 6
- NXVASHZYOSPBKV-UHFFFAOYSA-N 9-chloro-5-methoxy-8,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),2(7),3,5,8,12(17),13,15-octaen-11-one Chemical compound C12=CC=CN=C2C(=O)C2=C1C1=CC=C(OC)C=C1N=C2Cl NXVASHZYOSPBKV-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- RCJVRSBWZCNNQT-UHFFFAOYSA-N dichloridooxygen Chemical compound ClOCl RCJVRSBWZCNNQT-UHFFFAOYSA-N 0.000 description 1
- DPYNYVNPEYKKRI-UHFFFAOYSA-N dichloromethane;methanol;2,2,2-trifluoroacetic acid Chemical compound OC.ClCCl.OC(=O)C(F)(F)F DPYNYVNPEYKKRI-UHFFFAOYSA-N 0.000 description 1
- GLYLMXARZJNUEY-UHFFFAOYSA-N dichloromethane;methanol;hydrate Chemical compound O.OC.ClCCl GLYLMXARZJNUEY-UHFFFAOYSA-N 0.000 description 1
- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
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- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- FQYYIPZPELSLDK-UHFFFAOYSA-N ethyl pyridine-2-carboxylate Chemical compound CCOC(=O)C1=CC=CC=N1 FQYYIPZPELSLDK-UHFFFAOYSA-N 0.000 description 1
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- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- UZFAGXNQUOXUBW-UHFFFAOYSA-N indeno[2,1-c]quinolin-7-one Chemical compound C1=NC2=CC=CC=C2C2=C1C(=O)C1=CC=CC=C12 UZFAGXNQUOXUBW-UHFFFAOYSA-N 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- ULDIVZQLPBUHAG-UHFFFAOYSA-N n',n',2,2-tetramethylpropane-1,3-diamine Chemical compound CN(C)CC(C)(C)CN ULDIVZQLPBUHAG-UHFFFAOYSA-N 0.000 description 1
- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- KFIGICHILYTCJF-UHFFFAOYSA-N n'-methylethane-1,2-diamine Chemical compound CNCCN KFIGICHILYTCJF-UHFFFAOYSA-N 0.000 description 1
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 1
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- KPTCZURLWZSRKB-UHFFFAOYSA-N o-prop-2-enylhydroxylamine Chemical compound NOCC=C KPTCZURLWZSRKB-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 150000003254 radicals Chemical group 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- VILMUCRZVVVJCA-UHFFFAOYSA-M sodium glycolate Chemical compound [Na+].OCC([O-])=O VILMUCRZVVVJCA-UHFFFAOYSA-M 0.000 description 1
- 229940056729 sodium sulfate anhydrous Drugs 0.000 description 1
- VSIVTUIKYVGDCX-UHFFFAOYSA-M sodium;4-[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].COC1=CC([N+]([O-])=O)=CC=C1[N+]1=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=NN1C1=CC=C([N+]([O-])=O)C=C1 VSIVTUIKYVGDCX-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940071117 starch glycolate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 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
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- PTVRCUVHYMGECC-UHFFFAOYSA-N tert-butyl 2-(aminomethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1CN PTVRCUVHYMGECC-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
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- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01123908 | 2001-10-05 | ||
| EP01123908 | 2001-10-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2256552T3 true ES2256552T3 (es) | 2006-07-16 |
Family
ID=8178868
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES02779413T Expired - Lifetime ES2256552T3 (es) | 2001-10-05 | 2002-09-25 | Compuestos policiclicos que tienen actividad anti-tumoral. |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US6680326B2 (OSRAM) |
| EP (1) | EP1436293B1 (OSRAM) |
| JP (1) | JP4369229B2 (OSRAM) |
| KR (1) | KR100676114B1 (OSRAM) |
| CN (1) | CN1284781C (OSRAM) |
| AR (1) | AR037327A1 (OSRAM) |
| AT (1) | ATE316971T1 (OSRAM) |
| AU (1) | AU2002342752B2 (OSRAM) |
| BR (1) | BR0213122A (OSRAM) |
| CA (1) | CA2461572C (OSRAM) |
| DE (1) | DE60209029T2 (OSRAM) |
| ES (1) | ES2256552T3 (OSRAM) |
| MX (1) | MXPA04003173A (OSRAM) |
| PL (1) | PL370530A1 (OSRAM) |
| RU (1) | RU2315050C2 (OSRAM) |
| WO (1) | WO2003031444A1 (OSRAM) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6946472B2 (en) * | 2002-04-30 | 2005-09-20 | Hoffman-La Roche Inc. | Polycyclic compounds exhibiting anti-tumor activities |
| US20060189893A1 (en) * | 2005-01-06 | 2006-08-24 | Diamics, Inc. | Systems and methods for detecting abnormal cells |
| US20060161076A1 (en) * | 2005-01-06 | 2006-07-20 | Diamics, Inc. | Systems and methods for collection of cell clusters |
| CN103204781B (zh) * | 2013-03-14 | 2015-04-01 | 武汉大学 | 2,7–二取代芴酮衍生物及其制备方法与应用 |
| CN110448555B (zh) * | 2019-09-10 | 2020-10-23 | 河南省人民医院 | 多环化合物在制备抗肿瘤药物中的应用及抗肿瘤药物 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW440562B (en) * | 1994-05-20 | 2001-06-16 | Taiho Pharmaceutical Co Ltd | Condensed-indan derivative and pharmaceutically acceptable salts thereof |
| WO1998045272A1 (en) | 1997-04-07 | 1998-10-15 | Latrobe University | Topoisomerase inhibitors |
| FR2801309B1 (fr) * | 1999-11-18 | 2002-01-04 | Adir | Nouveaux composes analogues de la camptothecine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
-
2002
- 2002-09-25 CA CA2461572A patent/CA2461572C/en not_active Expired - Fee Related
- 2002-09-25 EP EP02779413A patent/EP1436293B1/en not_active Expired - Lifetime
- 2002-09-25 US US10/254,951 patent/US6680326B2/en not_active Expired - Fee Related
- 2002-09-25 AU AU2002342752A patent/AU2002342752B2/en not_active Ceased
- 2002-09-25 AT AT02779413T patent/ATE316971T1/de active
- 2002-09-25 WO PCT/EP2002/010722 patent/WO2003031444A1/en not_active Ceased
- 2002-09-25 BR BR0213122-6A patent/BR0213122A/pt not_active IP Right Cessation
- 2002-09-25 ES ES02779413T patent/ES2256552T3/es not_active Expired - Lifetime
- 2002-09-25 JP JP2003534427A patent/JP4369229B2/ja not_active Expired - Fee Related
- 2002-09-25 CN CNB028197712A patent/CN1284781C/zh not_active Expired - Fee Related
- 2002-09-25 MX MXPA04003173A patent/MXPA04003173A/es active IP Right Grant
- 2002-09-25 PL PL02370530A patent/PL370530A1/xx not_active Application Discontinuation
- 2002-09-25 RU RU2004114245/04A patent/RU2315050C2/ru not_active IP Right Cessation
- 2002-09-25 DE DE60209029T patent/DE60209029T2/de not_active Expired - Lifetime
- 2002-09-25 KR KR1020047004899A patent/KR100676114B1/ko not_active Expired - Fee Related
- 2002-10-02 AR ARP020103723A patent/AR037327A1/es unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003031444A1 (en) | 2003-04-17 |
| PL370530A1 (en) | 2005-05-30 |
| DE60209029T2 (de) | 2006-09-28 |
| EP1436293B1 (en) | 2006-02-01 |
| US20030073691A1 (en) | 2003-04-17 |
| US6680326B2 (en) | 2004-01-20 |
| MXPA04003173A (es) | 2004-07-27 |
| EP1436293A1 (en) | 2004-07-14 |
| CN1284781C (zh) | 2006-11-15 |
| CA2461572C (en) | 2011-02-15 |
| AU2002342752B2 (en) | 2007-11-15 |
| JP2005504846A (ja) | 2005-02-17 |
| KR100676114B1 (ko) | 2007-02-02 |
| CA2461572A1 (en) | 2003-04-17 |
| CN1610681A (zh) | 2005-04-27 |
| JP4369229B2 (ja) | 2009-11-18 |
| BR0213122A (pt) | 2004-09-21 |
| ATE316971T1 (de) | 2006-02-15 |
| KR20040048926A (ko) | 2004-06-10 |
| RU2004114245A (ru) | 2005-06-27 |
| RU2315050C2 (ru) | 2008-01-20 |
| AR037327A1 (es) | 2004-11-03 |
| DE60209029D1 (de) | 2006-04-13 |
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