EP2111236A2 - Nouveaux complexes de polymères en cascade, procédés de fabrication et agents pharmaceutiques contenant ces complexes - Google Patents
Nouveaux complexes de polymères en cascade, procédés de fabrication et agents pharmaceutiques contenant ces complexesInfo
- Publication number
- EP2111236A2 EP2111236A2 EP08701131A EP08701131A EP2111236A2 EP 2111236 A2 EP2111236 A2 EP 2111236A2 EP 08701131 A EP08701131 A EP 08701131A EP 08701131 A EP08701131 A EP 08701131A EP 2111236 A2 EP2111236 A2 EP 2111236A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- mmol
- coch
- cascade
- ethoxy
- optionally
- 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.)
- Withdrawn
Links
- 229920000642 polymer Polymers 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title claims abstract description 26
- 239000008177 pharmaceutical agent Substances 0.000 title claims 3
- 238000004519 manufacturing process Methods 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 40
- 150000001413 amino acids Chemical class 0.000 claims abstract description 24
- 150000002500 ions Chemical class 0.000 claims abstract description 19
- 230000027455 binding Effects 0.000 claims abstract description 14
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 14
- 150000001768 cations Chemical class 0.000 claims abstract description 13
- 150000007530 organic bases Chemical class 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 72
- -1 aminopropyl Chemical group 0.000 claims description 62
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 40
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- 239000008139 complexing agent Substances 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 150000001408 amides Chemical class 0.000 claims description 19
- 150000001412 amines Chemical class 0.000 claims description 18
- 125000005647 linker group Chemical group 0.000 claims description 16
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 11
- 229910021645 metal ion Inorganic materials 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 10
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 9
- 125000004043 oxo group Chemical group O=* 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- FTQWRYSLUYAIRQ-UHFFFAOYSA-N n-[(octadecanoylamino)methyl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NCNC(=O)CCCCCCCCCCCCCCCCC FTQWRYSLUYAIRQ-UHFFFAOYSA-N 0.000 claims description 8
- 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 7
- 238000003745 diagnosis Methods 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 239000004202 carbamide Substances 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 150000003254 radicals Chemical class 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- 125000000464 thioxo group Chemical group S=* 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 4
- FKUUAMCSPLBGEE-UHFFFAOYSA-N 3,4,5-tris(2-aminoethoxy)aniline Chemical compound NCCOC1=CC(N)=CC(OCCN)=C1OCCN FKUUAMCSPLBGEE-UHFFFAOYSA-N 0.000 claims description 3
- XADBDUHWDPECBO-UHFFFAOYSA-N 3,4,5-tris(2-aminoethoxy)benzamide Chemical compound NCCOC1=CC(C(N)=O)=CC(OCCN)=C1OCCN XADBDUHWDPECBO-UHFFFAOYSA-N 0.000 claims description 3
- JJSMLVBHRDPIJL-UHFFFAOYSA-N 3,4,5-tris(3-aminopropoxy)aniline Chemical compound NCCCOC1=CC(N)=CC(OCCCN)=C1OCCCN JJSMLVBHRDPIJL-UHFFFAOYSA-N 0.000 claims description 3
- UCCKOBVJXCXHRD-UHFFFAOYSA-N 3,4,5-tris(3-aminopropoxy)benzamide Chemical compound NCCCOC1=CC(C(N)=O)=CC(OCCCN)=C1OCCCN UCCKOBVJXCXHRD-UHFFFAOYSA-N 0.000 claims description 3
- QTNUDOMJXXAGOW-UHFFFAOYSA-N 3,5-bis(2-aminoethoxy)aniline Chemical compound NCCOC1=CC(N)=CC(OCCN)=C1 QTNUDOMJXXAGOW-UHFFFAOYSA-N 0.000 claims description 3
- IOYSYBCPMGUQAS-UHFFFAOYSA-N 3,5-bis(2-aminoethoxy)benzamide Chemical compound NCCOC1=CC(OCCN)=CC(C(N)=O)=C1 IOYSYBCPMGUQAS-UHFFFAOYSA-N 0.000 claims description 3
- ZASLJBCFQFNYQP-UHFFFAOYSA-N 3,5-bis(3-aminopropoxy)aniline Chemical compound NCCCOC1=CC(N)=CC(OCCCN)=C1 ZASLJBCFQFNYQP-UHFFFAOYSA-N 0.000 claims description 3
- UAYTZLSRAXKKJC-UHFFFAOYSA-N 3,5-bis(3-aminopropoxy)benzamide Chemical compound NCCCOC1=CC(OCCCN)=CC(C(N)=O)=C1 UAYTZLSRAXKKJC-UHFFFAOYSA-N 0.000 claims description 3
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 claims description 3
- HKXLAGBDJVHRQG-YFKPBYRVSA-N L-lysinamide Chemical compound NCCCC[C@H](N)C(N)=O HKXLAGBDJVHRQG-YFKPBYRVSA-N 0.000 claims description 3
- 239000007983 Tris buffer Substances 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 3
- 238000007911 parenteral administration Methods 0.000 claims description 3
- MBYLVOKEDDQJDY-UHFFFAOYSA-N tris(2-aminoethyl)amine Chemical compound NCCN(CCN)CCN MBYLVOKEDDQJDY-UHFFFAOYSA-N 0.000 claims description 3
- UGDSCHVVUPHIFM-UHFFFAOYSA-N 1,1,1-tris(aminomethyl)ethane Chemical compound NCC(C)(CN)CN UGDSCHVVUPHIFM-UHFFFAOYSA-N 0.000 claims description 2
- UUEQNWFHJLYOPW-UHFFFAOYSA-N 1,4,7,10,13,16,19,22,25,28-decazacyclotriacontane Chemical compound C1CNCCNCCNCCNCCNCCNCCNCCNCCNCCN1 UUEQNWFHJLYOPW-UHFFFAOYSA-N 0.000 claims description 2
- RVJABZUDCPZPPM-UHFFFAOYSA-N 1,4,7,10,13,16-hexazacyclooctadecane Chemical compound C1CNCCNCCNCCNCCNCCN1 RVJABZUDCPZPPM-UHFFFAOYSA-N 0.000 claims description 2
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 claims description 2
- ITWBWJFEJCHKSN-UHFFFAOYSA-N 1,4,7-triazonane Chemical compound C1CNCCNCCN1 ITWBWJFEJCHKSN-UHFFFAOYSA-N 0.000 claims description 2
- VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 claims description 2
- VVJIVFKAROPUOS-UHFFFAOYSA-N 2,2-bis(aminomethyl)propane-1,3-diamine Chemical compound NCC(CN)(CN)CN VVJIVFKAROPUOS-UHFFFAOYSA-N 0.000 claims description 2
- FCIGUPDFRXUJSZ-UHFFFAOYSA-N 4-(3-aminopropyl)-4-nitroheptane-1,7-diamine Chemical compound NCCCC(CCCN)(CCCN)[N+]([O-])=O FCIGUPDFRXUJSZ-UHFFFAOYSA-N 0.000 claims description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical group C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 2
- IDWDEHYPSCTKFU-UHFFFAOYSA-N [3,5-bis(aminomethyl)phenyl]methanamine Chemical compound NCC1=CC(CN)=CC(CN)=C1 IDWDEHYPSCTKFU-UHFFFAOYSA-N 0.000 claims description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 2
- ZMUADARPXLFDHP-UHFFFAOYSA-N nitrocarbamic acid Chemical group OC(=O)N[N+]([O-])=O ZMUADARPXLFDHP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002504 physiological saline solution Substances 0.000 claims description 2
- FAGUFWYHJQFNRV-UHFFFAOYSA-N tetraethylenepentamine Chemical compound NCCNCCNCCNCCN FAGUFWYHJQFNRV-UHFFFAOYSA-N 0.000 claims description 2
- OERRZAJTKPMGBB-BYPYZUCNSA-N (2s)-2,5-diaminopentanamide Chemical compound NCCC[C@H](N)C(N)=O OERRZAJTKPMGBB-BYPYZUCNSA-N 0.000 claims 1
- FIDRAVVQGKNYQK-UHFFFAOYSA-N 1,2,3,4-tetrahydrotriazine Chemical compound C1NNNC=C1 FIDRAVVQGKNYQK-UHFFFAOYSA-N 0.000 claims 1
- KDCBVVQAMMXRFB-UHFFFAOYSA-N 1,4,7,10,13-pentazacyclopentadecane Chemical compound C1CNCCNCCNCCNCCN1 KDCBVVQAMMXRFB-UHFFFAOYSA-N 0.000 claims 1
- LDOMKUVUXZRECL-UHFFFAOYSA-N 2-aminobenzene-1,3-dicarboxylic acid Chemical compound NC1=C(C(O)=O)C=CC=C1C(O)=O LDOMKUVUXZRECL-UHFFFAOYSA-N 0.000 claims 1
- 125000005157 alkyl carboxy group Chemical group 0.000 claims 1
- WXWQVSOHWXJBDF-UHFFFAOYSA-N benzene-1,3,5-tricarboxamide Chemical compound NC(=O)C1=CC(C(N)=O)=CC(C(N)=O)=C1 WXWQVSOHWXJBDF-UHFFFAOYSA-N 0.000 claims 1
- 230000010076 replication Effects 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 14
- 150000007529 inorganic bases Chemical class 0.000 abstract description 9
- 229910052700 potassium Inorganic materials 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 114
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 93
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 60
- 239000000243 solution Substances 0.000 description 59
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- 238000006243 chemical reaction Methods 0.000 description 41
- 238000000921 elemental analysis Methods 0.000 description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 239000000203 mixture Substances 0.000 description 39
- 239000000047 product Substances 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- 229960004132 diethyl ether Drugs 0.000 description 31
- 239000002872 contrast media Substances 0.000 description 28
- 239000000126 substance Substances 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 25
- 238000007792 addition Methods 0.000 description 25
- 238000012512 characterization method Methods 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- 239000000741 silica gel Substances 0.000 description 21
- 229910002027 silica gel Inorganic materials 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 20
- 239000000725 suspension Substances 0.000 description 20
- 235000001014 amino acid Nutrition 0.000 description 19
- 239000000706 filtrate Substances 0.000 description 19
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- JMQURLDQTNONQC-UHFFFAOYSA-N benzyl N-[1-[[1-(2-aminoethylamino)-6-[2,6-bis(phenylmethoxycarbonylamino)hexanoylamino]-1-oxohexan-2-yl]amino]-1-oxo-6-(phenylmethoxycarbonylamino)hexan-2-yl]carbamate Chemical compound C(C1=CC=CC=C1)OC(=O)NC(C(=O)NC(C(=O)NCCN)CCCCNC(C(CCCCNC(=O)OCC1=CC=CC=C1)NC(=O)OCC1=CC=CC=C1)=O)CCCCNC(=O)OCC1=CC=CC=C1 JMQURLDQTNONQC-UHFFFAOYSA-N 0.000 description 17
- 239000000843 powder Substances 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 235000011152 sodium sulphate Nutrition 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 16
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 150000003839 salts Chemical class 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 229960000583 acetic acid Drugs 0.000 description 14
- 229910052688 Gadolinium Inorganic materials 0.000 description 13
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 13
- 238000001816 cooling Methods 0.000 description 13
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 13
- 239000012043 crude product Substances 0.000 description 12
- 239000012362 glacial acetic acid Substances 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- 125000006239 protecting group Chemical group 0.000 description 11
- 239000012465 retentate Substances 0.000 description 11
- PUXJRFSROJSYDG-UHFFFAOYSA-N 2-[2,5-dimethyl-4-(2,4,6-trimethylphenyl)phenoxy]acetic acid Chemical compound CC1=CC(C)=CC(C)=C1C1=CC(C)=C(OCC(O)=O)C=C1C PUXJRFSROJSYDG-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 229920001429 chelating resin Polymers 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 238000003384 imaging method Methods 0.000 description 9
- 238000011065 in-situ storage Methods 0.000 description 9
- 238000002595 magnetic resonance imaging Methods 0.000 description 9
- 230000007935 neutral effect Effects 0.000 description 9
- 102000008100 Human Serum Albumin Human genes 0.000 description 8
- 108091006905 Human Serum Albumin Proteins 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 8
- 239000000412 dendrimer Substances 0.000 description 8
- 229920000736 dendritic polymer Polymers 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 7
- 230000002378 acidificating effect Effects 0.000 description 7
- 238000005917 acylation reaction Methods 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 238000005804 alkylation reaction Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 229920002521 macromolecule Polymers 0.000 description 5
- 230000005291 magnetic effect Effects 0.000 description 5
- PATVTXAXTZIAMN-UHFFFAOYSA-N n-(2-aminoethyl)-4-phenylbenzamide Chemical compound C1=CC(C(=O)NCCN)=CC=C1C1=CC=CC=C1 PATVTXAXTZIAMN-UHFFFAOYSA-N 0.000 description 5
- 230000035699 permeability Effects 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 4
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 230000010933 acylation Effects 0.000 description 4
- 150000008064 anhydrides Chemical class 0.000 description 4
- 239000000010 aprotic solvent Substances 0.000 description 4
- 230000008499 blood brain barrier function Effects 0.000 description 4
- 210000001218 blood-brain barrier Anatomy 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
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- GZCRRIHWUXGPOV-UHFFFAOYSA-N terbium atom Chemical compound [Tb] GZCRRIHWUXGPOV-UHFFFAOYSA-N 0.000 description 1
- ZNMQQKJEWXWDAY-UHFFFAOYSA-N tert-butyl 2-[2,5-dimethyl-4-(2,4,6-trimethylphenyl)phenoxy]acetate Chemical compound CC1=CC(C)=CC(C)=C1C1=CC(C)=C(OCC(=O)OC(C)(C)C)C=C1C ZNMQQKJEWXWDAY-UHFFFAOYSA-N 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- ORZHVTYKPFFVMG-UHFFFAOYSA-N xylenol orange Chemical compound OC(=O)CN(CC(O)=O)CC1=C(O)C(C)=CC(C2(C3=CC=CC=C3S(=O)(=O)O2)C=2C=C(CN(CC(O)=O)CC(O)=O)C(O)=C(C)C=2)=C1 ORZHVTYKPFFVMG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/12—Macromolecular compounds
- A61K49/124—Macromolecular compounds dendrimers, dendrons, hyperbranched compounds
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
- C08G73/02—Polyamines
Definitions
- the complexing agent residues K are described by the general formulas IA, IB and IC:
- Suitable HSA-binding groups R are given by way of example:
- the cascade polymer complexes according to the invention contain at least 4 ions of an element of the abovementioned atomic number.
- the cascade polymer complexes according to the invention have surprising properties compared to known cascade polymer complexes, as described in the European patent EP 0 836 485. These surprising properties allow an even more flexible choice of imaging times and a more favorable signal-to-background ratio, especially at certain imaging times.
- Particularly surprising in comparison to the known cascade polymer complexes from EP 0 836 485 is, above all, that although the cascade polymer complexes according to the invention presented here have one polymer arm less than the known cascade complexes and are therefore rather smaller in comparison Thus, these should tend to extravasation, the novel cascade polymer complexes according to the invention even have a significantly improved residence time in the blood.
- the complexes and complexing agents of the general formula I 1 A and I 1 B are prepared by or analogously to the instructions described in the experimental section or by methods known from the literature, see, for example, European Patent Applications Nos. 0 512 661, 0430 863, 0 255 471 and 0 565 930.
- the preparation of the pharmaceutical compositions according to the invention is likewise carried out in a manner known per se by suspending or dissolving the complex compounds according to the invention in aqueous medium, if appropriate with addition of the additives customary in galenicals, and then optionally sterilizing the suspension or solution.
- suitable additives are, for example, physiologically acceptable buffers (such as tromethamine), additions of complexing agents or weak complexes (such as diethylenetriaminepentaacetic acid or the corresponding Ca-cascade polymer complexes) or, if necessary, electrolytes such as sodium chloride or, if necessary - Antioxidants such as ascorbic acid.
- the compounds according to the invention are particularly suitable for use as coronary angiographic contrast agents and their use in NMR diagnosis by means of higher Magnetic fields such as 1.5 or 3 Tesla, as offered by modern NMR devices.
- the compounds according to the invention are also suitable for the differentiation of malignant and benign tumors in areas without a blood-brain barrier.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
L'invention concerne de nouveaux complexes de polymères en cascade, des agents contenant ces complexes, l'utilisation des complexes dans le diagnostic par IRM, et des procédés de fabrication de ces compositions et agents. Les complexes de polymères en cascade complexants sont représentés par la formule (I) : R - L - A -{ X - [ Y - ( Z - { W - K<SUB>w </SUB>}<SUB>z</SUB> )<SUB>y</SUB> ]<SUB>x</SUB>}<SUB>a-1</SUB>, dans laquelle R est une unité liant HSA; L est un lieur ou une liaison; A est un noyau de cascade azoté de multiplicité de base a; X et Y sont indépendamment l'un de l'autre une liaison directe ou une unité de production de cascade de multiplicité de reproduction x ou y; Z et W sont indépendamment l'un de l'autre une liaison directe ou une unité de production de cascade de multiplicité de reproduction z ou w; K est le reste d'un complexant; a est 2 à 12; et x, y, z et w sont indépendamment l'un de l'autre 1 à 4, à la condition qu'exactement une multiplicité de la multiplicité de base a du noyau de cascade A représente exactement une zone de liaison à L, et que les complexes de polymères en cascade dans les restes de complexants K contiennent au total 4 ions d'un élément de numéro atomique 20 à 29, 39, 42 à 44 ou 57 à 83, ainsi qu'éventuellement des cations de bases anorganiques et/ou organiques, des acides aminés ou des amides d'acides aminés.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102007002726A DE102007002726A1 (de) | 2007-01-18 | 2007-01-18 | Neue Kaskaden-Polymer-Komplexe, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Mittel |
| PCT/EP2008/000285 WO2008087017A2 (fr) | 2007-01-18 | 2008-01-16 | Nouveaux complexes de polymères en cascade, procédés de fabrication et agents pharmaceutiques contenant ces complexes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2111236A2 true EP2111236A2 (fr) | 2009-10-28 |
Family
ID=39560934
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP08701131A Withdrawn EP2111236A2 (fr) | 2007-01-18 | 2008-01-16 | Nouveaux complexes de polymères en cascade, procédés de fabrication et agents pharmaceutiques contenant ces complexes |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US20080213187A1 (fr) |
| EP (1) | EP2111236A2 (fr) |
| JP (1) | JP2010516643A (fr) |
| KR (1) | KR20090110838A (fr) |
| CN (1) | CN101657219A (fr) |
| CA (1) | CA2676313A1 (fr) |
| DE (1) | DE102007002726A1 (fr) |
| WO (1) | WO2008087017A2 (fr) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2279190A1 (fr) * | 2008-04-18 | 2011-02-02 | Ge Healthcare As | Composés comprenant des chélates paramagnétiques disposés autour d'un c ur central et leur utilisation en imagerie et spectroscopie par résonance magnétique |
| EP3101012A1 (fr) | 2015-06-04 | 2016-12-07 | Bayer Pharma Aktiengesellschaft | Nouveaux composés de chélate de gadolinium pour une utilisation dans l'imagerie par résonance magnétique |
| CA3044877A1 (fr) | 2016-11-28 | 2018-05-31 | Bayer Pharma Aktiengesellschaft | Composes de chelate de gadolinium a relaxivite elevee pour utilisation dans l'imagerie par resonance magnetique |
| JP7520007B2 (ja) | 2018-11-23 | 2024-07-22 | バイエル アクチェンゲゼルシャフト | 造影剤の製剤およびその調製方法 |
| CN115894181A (zh) * | 2022-09-30 | 2023-04-04 | 渭南高新区海泰新型电子材料有限责任公司 | 一种环己烯基环己基二氟苯类液晶化合物的合成方法 |
| CN116751260B (zh) * | 2023-04-11 | 2024-05-28 | 苏州有诺真生物科技有限公司 | 一种通过级联聚合反应生成尺寸可控的通用多聚显色物的方法 |
Family Cites Families (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1203164A (fr) | 1982-03-09 | 1986-04-15 | Thomas J. Mckearn | Conjugats d'anticorps |
| NL194579C (nl) | 1983-01-21 | 2002-08-05 | Schering Ag | Diagnostisch middel. |
| US4707352A (en) | 1984-01-30 | 1987-11-17 | Enzo Biochem, Inc. | Method of radioactively labeling diagnostic and therapeutic agents containing a chelating group |
| DK172629B1 (da) | 1986-02-14 | 1999-03-22 | Nihon Mediphysics Co Ltd | Reaktive højmolekylære forbindelser med mindst én fri aminogruppe, højmolekylære forbindelser kombineret med et fysiologisk |
| DE3625417C2 (de) | 1986-07-28 | 1998-10-08 | Schering Ag | Tetraazacyclododecan-Derivate |
| GB8801646D0 (en) | 1988-01-26 | 1988-02-24 | Nycomed As | Chemical compounds |
| DE3806795A1 (de) | 1988-02-29 | 1989-09-07 | Schering Ag | Polymer-gebundene komplexbildner, deren komplexe und konjugate, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel |
| US5914095A (en) * | 1989-04-07 | 1999-06-22 | Salutar, Inc. | Polychelants containg amide bonds |
| US5364613A (en) * | 1989-04-07 | 1994-11-15 | Sieving Paul F | Polychelants containing macrocyclic chelant moieties |
| DE3938992A1 (de) | 1989-11-21 | 1991-05-23 | Schering Ag | Kaskadenpolymer-gebundene komplexbildner, deren komplexe und konjugate, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel |
| DE4115789A1 (de) | 1991-05-10 | 1992-11-12 | Schering Ag | Makrocyclische polymer-komplexbildner, deren komplexe, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel |
| AU663572B2 (en) | 1992-03-27 | 1995-10-12 | Nihon Medi-Physics Co., Ltd. | Tetraazacyclododecane derivative and its use |
| ES2104518T1 (es) * | 1994-03-07 | 1997-10-16 | Dow Chemical Co | Conjugados dendrimeros bioactivos y/o directores hacia diana. |
| DE4425857A1 (de) * | 1994-07-07 | 1996-01-11 | Schering Ag | Kaskaden-Polymer-Komplexe, Verfahren zur ihrer Herstellung und diese enthaltende pharmazeutische Mittel |
| DE4445065A1 (de) * | 1994-12-07 | 1996-06-13 | Diagnostikforschung Inst | Verfahren zur In-vivo-Diagnostik mittels NIR-Strahlung |
| TW319763B (fr) * | 1995-02-01 | 1997-11-11 | Epix Medical Inc | |
| DE19525924A1 (de) * | 1995-07-04 | 1997-01-09 | Schering Ag | Kaskaden-Polymer-Komplexe, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Mittel |
| DE19549286A1 (de) * | 1995-12-22 | 1997-06-26 | Schering Ag | Kaskaden-Polymer-Komplexe, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Mittel |
| DE19652386A1 (de) | 1996-12-04 | 1998-06-10 | Schering Ag | Verfahren zur Herstellung von Metallkomplexcarbonsäureamiden |
| DE19926154A1 (de) * | 1999-06-09 | 2000-12-14 | Ktb Tumorforschungs Gmbh | Verfahren zur Herstellung einer injizierbaren Arzneimittelzubereitung |
| EP1757311B1 (fr) * | 1999-12-24 | 2009-02-11 | Genentech, Inc. | Méthodes et compositions pour la prolongation de la demi-période d'élimination de composés bioactifs |
| CU23011A1 (es) * | 2000-11-03 | 2004-12-17 | Ct Ingenieria Genetica Biotech | Método de obtención de estructuras antigénicas quemétodo de obtención de estructuras antigénicas que potencian la reactividad cruzada específica y su potencian la reactividad cruzada específica y su uso en formulaciones uso en formulaciones |
| US7985401B2 (en) * | 2003-10-31 | 2011-07-26 | The Regents Of The University Of California | Peptides whose uptake by cells is controllable |
| WO2006029150A2 (fr) * | 2004-09-03 | 2006-03-16 | Alza Corporation | Conjugue d'albumine forme de maniere endogene |
-
2007
- 2007-01-18 DE DE102007002726A patent/DE102007002726A1/de not_active Withdrawn
-
2008
- 2008-01-16 WO PCT/EP2008/000285 patent/WO2008087017A2/fr active Application Filing
- 2008-01-16 JP JP2009545868A patent/JP2010516643A/ja active Pending
- 2008-01-16 KR KR1020097015081A patent/KR20090110838A/ko not_active Application Discontinuation
- 2008-01-16 CN CN200880002489A patent/CN101657219A/zh active Pending
- 2008-01-16 CA CA002676313A patent/CA2676313A1/fr not_active Abandoned
- 2008-01-16 EP EP08701131A patent/EP2111236A2/fr not_active Withdrawn
- 2008-01-17 US US12/015,769 patent/US20080213187A1/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2008087017A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2676313A1 (fr) | 2008-07-24 |
| KR20090110838A (ko) | 2009-10-22 |
| JP2010516643A (ja) | 2010-05-20 |
| CN101657219A (zh) | 2010-02-24 |
| US20080213187A1 (en) | 2008-09-04 |
| WO2008087017A2 (fr) | 2008-07-24 |
| DE102007002726A1 (de) | 2008-07-31 |
| WO2008087017A3 (fr) | 2009-01-22 |
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