KR20240034693A - 이량체 조영제의 제조 - Google Patents
이량체 조영제의 제조 Download PDFInfo
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- KR20240034693A KR20240034693A KR1020237042178A KR20237042178A KR20240034693A KR 20240034693 A KR20240034693 A KR 20240034693A KR 1020237042178 A KR1020237042178 A KR 1020237042178A KR 20237042178 A KR20237042178 A KR 20237042178A KR 20240034693 A KR20240034693 A KR 20240034693A
- Authority
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- South Korea
- Prior art keywords
- solution
- formula
- compound
- gadolinium
- water
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 239000000539 dimer Substances 0.000 title claims description 41
- 239000002872 contrast media Substances 0.000 title abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 131
- 229910052688 Gadolinium Inorganic materials 0.000 claims abstract description 99
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims abstract description 95
- 230000008569 process Effects 0.000 claims abstract description 75
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 69
- 239000000243 solution Substances 0.000 claims description 204
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 101
- 239000000203 mixture Substances 0.000 claims description 86
- 239000003446 ligand Substances 0.000 claims description 79
- 239000003960 organic solvent Substances 0.000 claims description 53
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 53
- 150000001875 compounds Chemical class 0.000 claims description 50
- HHLZCENAOIROSL-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound OC(=O)CN1CCNCCN(CC(O)=O)CCN(CC(O)=O)CC1 HHLZCENAOIROSL-UHFFFAOYSA-N 0.000 claims description 47
- 239000007864 aqueous solution Substances 0.000 claims description 46
- 238000000746 purification Methods 0.000 claims description 33
- 239000003125 aqueous solvent Substances 0.000 claims description 27
- 150000000921 Gadolinium Chemical class 0.000 claims description 26
- 229940125898 compound 5 Drugs 0.000 claims description 23
- 238000001914 filtration Methods 0.000 claims description 20
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 17
- SDOFMBGMRVAJNF-SLPGGIOYSA-N (2r,3r,4r,5s)-6-aminohexane-1,2,3,4,5-pentol Chemical compound NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO SDOFMBGMRVAJNF-SLPGGIOYSA-N 0.000 claims description 16
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 16
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 15
- 239000003791 organic solvent mixture Substances 0.000 claims description 14
- 238000004587 chromatography analysis Methods 0.000 claims description 13
- 239000000725 suspension Substances 0.000 claims description 10
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- 229910019142 PO4 Inorganic materials 0.000 claims description 8
- 239000003929 acidic solution Substances 0.000 claims description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims description 7
- 239000013058 crude material Substances 0.000 claims description 7
- 239000010452 phosphate Substances 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 238000007865 diluting Methods 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 5
- 150000001447 alkali salts Chemical class 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 238000001694 spray drying Methods 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical group CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-M oxalate(1-) Chemical compound OC(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-M 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- 235000011007 phosphoric acid Nutrition 0.000 claims description 3
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 abstract description 19
- 238000002955 isolation Methods 0.000 abstract description 11
- 238000002595 magnetic resonance imaging Methods 0.000 abstract description 7
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 239000007983 Tris buffer Substances 0.000 abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 238000010668 complexation reaction Methods 0.000 description 26
- 150000003839 salts Chemical class 0.000 description 25
- 239000000543 intermediate Substances 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000002585 base Substances 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 20
- 238000010511 deprotection reaction Methods 0.000 description 20
- 150000002148 esters Chemical class 0.000 description 20
- 229920001429 chelating resin Polymers 0.000 description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 18
- 238000000926 separation method Methods 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 239000000047 product Substances 0.000 description 15
- 229920005989 resin Polymers 0.000 description 15
- 239000011347 resin Substances 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 238000004821 distillation Methods 0.000 description 13
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
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- 239000008213 purified water Substances 0.000 description 12
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- 239000000523 sample Substances 0.000 description 10
- 238000005804 alkylation reaction Methods 0.000 description 9
- -1 carboxy- Chemical class 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 230000029936 alkylation Effects 0.000 description 8
- 239000012045 crude solution Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 230000001376 precipitating effect Effects 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 239000012085 test solution Substances 0.000 description 8
- 235000021317 phosphate Nutrition 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 159000000000 sodium salts Chemical class 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000012546 transfer Methods 0.000 description 7
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 6
- 239000005695 Ammonium acetate Substances 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 229940043376 ammonium acetate Drugs 0.000 description 6
- 235000019257 ammonium acetate Nutrition 0.000 description 6
- 238000006386 neutralization reaction Methods 0.000 description 6
- 239000011877 solvent mixture Substances 0.000 description 6
- 238000001179 sorption measurement Methods 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 5
- 150000001450 anions Chemical class 0.000 description 5
- 150000001768 cations Chemical class 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 231100001261 hazardous Toxicity 0.000 description 5
- 238000001728 nano-filtration Methods 0.000 description 5
- 230000005298 paramagnetic effect Effects 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 239000011550 stock solution Substances 0.000 description 5
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical group [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 230000005526 G1 to G0 transition Effects 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 238000011033 desalting Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 239000011368 organic material Substances 0.000 description 4
- 230000020477 pH reduction Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000012490 blank solution Substances 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
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- 150000002500 ions Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000011002 quantification Methods 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
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- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000002616 MRI contrast agent Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003957 anion exchange resin Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 150000003841 chloride salts Chemical class 0.000 description 2
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- GXCUBNRUECGTSC-UHFFFAOYSA-K gadolinium(3+);triacetate;hydrate Chemical compound O.[Gd+3].CC([O-])=O.CC([O-])=O.CC([O-])=O GXCUBNRUECGTSC-UHFFFAOYSA-K 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
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- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 description 1
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
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- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 101000897493 Homo sapiens C-C motif chemokine 26 Proteins 0.000 description 1
- 101100446506 Mus musculus Fgf3 gene Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
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- XQGPKZUNMMFTAL-UHFFFAOYSA-L dipotassium;hydrogen phosphate;trihydrate Chemical compound O.O.O.[K+].[K+].OP([O-])([O-])=O XQGPKZUNMMFTAL-UHFFFAOYSA-L 0.000 description 1
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- SQORATIMOBOFKR-UHFFFAOYSA-H gadolinium(3+);oxalate Chemical compound [Gd+3].[Gd+3].[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O SQORATIMOBOFKR-UHFFFAOYSA-H 0.000 description 1
- JAOZQVJVXQKQAD-UHFFFAOYSA-K gadolinium(3+);phosphate Chemical compound [Gd+3].[O-]P([O-])([O-])=O JAOZQVJVXQKQAD-UHFFFAOYSA-K 0.000 description 1
- LYQGMALGKYWNIU-UHFFFAOYSA-K gadolinium(3+);triacetate Chemical compound [Gd+3].CC([O-])=O.CC([O-])=O.CC([O-])=O LYQGMALGKYWNIU-UHFFFAOYSA-K 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- RVRCFVVLDHTFFA-UHFFFAOYSA-N heptasodium;tungsten;nonatriacontahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W] RVRCFVVLDHTFFA-UHFFFAOYSA-N 0.000 description 1
- VOAPTKOANCCNFV-UHFFFAOYSA-N hexahydrate;hydrochloride Chemical compound O.O.O.O.O.O.Cl VOAPTKOANCCNFV-UHFFFAOYSA-N 0.000 description 1
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- 238000012544 monitoring process Methods 0.000 description 1
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- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
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- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- KYKNRZGSIGMXFH-ZVGUSBNCSA-M potassium bitartrate Chemical compound [K+].OC(=O)[C@H](O)[C@@H](O)C([O-])=O KYKNRZGSIGMXFH-ZVGUSBNCSA-M 0.000 description 1
- 229940081543 potassium bitartrate Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004094 preconcentration Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- ZNCPFRVNHGOPAG-UHFFFAOYSA-L sodium oxalate Chemical compound [Na+].[Na+].[O-]C(=O)C([O-])=O ZNCPFRVNHGOPAG-UHFFFAOYSA-L 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- NMHVTLJFPDOJOD-UHFFFAOYSA-N tert-butyl 2-[4,7-bis[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,4,7,10-tetrazacyclododec-1-yl]acetate Chemical compound CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1 NMHVTLJFPDOJOD-UHFFFAOYSA-N 0.000 description 1
- GMECCVFSBLSIKE-UHFFFAOYSA-N tert-butyl 2-[4,7-bis[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,4,7,10-tetrazacyclododec-1-yl]acetate;hydrobromide Chemical compound Br.CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1 GMECCVFSBLSIKE-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 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
-
- 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
- C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
-
- 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
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
-
- 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
- A61K49/122—Macromolecular compounds dimers of complexes or complex-forming compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP21187883.0 | 2021-07-27 | ||
| EP21187883 | 2021-07-27 | ||
| PCT/EP2022/070901 WO2023006721A1 (en) | 2021-07-27 | 2022-07-26 | Manufacturing of dimeric contrast agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20240034693A true KR20240034693A (ko) | 2024-03-14 |
Family
ID=77367218
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020237042178A Pending KR20240034693A (ko) | 2021-07-27 | 2022-07-26 | 이량체 조영제의 제조 |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US12290576B2 (https=) |
| EP (1) | EP4377323B1 (https=) |
| JP (1) | JP7774081B2 (https=) |
| KR (1) | KR20240034693A (https=) |
| CN (1) | CN117412980A (https=) |
| AU (1) | AU2022317221A1 (https=) |
| BR (1) | BR112023022921A2 (https=) |
| CA (1) | CA3216972A1 (https=) |
| ES (1) | ES3041651T3 (https=) |
| IL (1) | IL308888A (https=) |
| MX (1) | MX2023014582A (https=) |
| PL (1) | PL4377323T3 (https=) |
| WO (1) | WO2023006721A1 (https=) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL4188912T3 (pl) * | 2020-07-27 | 2024-11-18 | Bracco Imaging Spa | Wytwarzanie dimerycznych środków kontrastujących |
| CN117440959A (zh) * | 2021-07-27 | 2024-01-23 | 伯拉考成像股份公司 | 用于制造钆络合物溶液的方法 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4009119A1 (de) * | 1990-03-19 | 1991-09-26 | Schering Ag | 1,4,7,10-tetraazacyclododecan-butyltriole, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel |
| DE4035760A1 (de) * | 1990-11-08 | 1992-05-14 | Schering Ag | Mono-n-substituierte 1,4,7,10-tetraazacyclododecan-derivate, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel |
| IT1291624B1 (it) * | 1997-04-18 | 1999-01-11 | Bracco Spa | Chelati complessi di metalli paramagnetici a bassa tossicita' |
| DE19849465A1 (de) | 1998-10-21 | 2000-04-27 | Schering Ag | Dimere Ionenpaare, Verfahren zu ihrer Herstellung und ihre Verwendung als Kontrastmittel |
| IT1304501B1 (it) * | 1998-12-23 | 2001-03-19 | Bracco Spa | Uso di derivati di acidi biliari coniugati con complessi metallicicome "blood pool agents" per l'indagine diagnostica tramite risonanza |
| HRP20210061T1 (hr) | 2015-12-10 | 2021-03-05 | Bracco Imaging S.P.A | Dimerna kontrastna sredstva |
| US12297180B2 (en) * | 2019-12-13 | 2025-05-13 | Bracco Imaging S.P.A. | Manufacturing of protected DO3A |
-
2022
- 2022-07-26 US US18/565,770 patent/US12290576B2/en active Active
- 2022-07-26 WO PCT/EP2022/070901 patent/WO2023006721A1/en not_active Ceased
- 2022-07-26 CA CA3216972A patent/CA3216972A1/en active Pending
- 2022-07-26 AU AU2022317221A patent/AU2022317221A1/en active Pending
- 2022-07-26 IL IL308888A patent/IL308888A/en unknown
- 2022-07-26 KR KR1020237042178A patent/KR20240034693A/ko active Pending
- 2022-07-26 CN CN202280039128.1A patent/CN117412980A/zh active Pending
- 2022-07-26 BR BR112023022921A patent/BR112023022921A2/pt unknown
- 2022-07-26 PL PL22754878.1T patent/PL4377323T3/pl unknown
- 2022-07-26 EP EP22754878.1A patent/EP4377323B1/en active Active
- 2022-07-26 JP JP2023577348A patent/JP7774081B2/ja active Active
- 2022-07-26 MX MX2023014582A patent/MX2023014582A/es unknown
- 2022-07-26 ES ES22754878T patent/ES3041651T3/es active Active
Also Published As
| Publication number | Publication date |
|---|---|
| IL308888A (en) | 2024-01-01 |
| JP7774081B2 (ja) | 2025-11-20 |
| US20240269330A1 (en) | 2024-08-15 |
| CN117412980A (zh) | 2024-01-16 |
| EP4377323A1 (en) | 2024-06-05 |
| EP4377323B1 (en) | 2025-07-02 |
| WO2023006721A1 (en) | 2023-02-02 |
| JP2024527691A (ja) | 2024-07-26 |
| BR112023022921A2 (pt) | 2024-02-27 |
| US12290576B2 (en) | 2025-05-06 |
| EP4377323C0 (en) | 2025-07-02 |
| AU2022317221A1 (en) | 2023-11-16 |
| ES3041651T3 (en) | 2025-11-13 |
| CA3216972A1 (en) | 2023-02-02 |
| PL4377323T3 (pl) | 2025-12-01 |
| MX2023014582A (es) | 2023-12-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PA0105 | International application |
Patent event date: 20231206 Patent event code: PA01051R01D Comment text: International Patent Application |
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| PG1501 | Laying open of application | ||
| A201 | Request for examination | ||
| PA0201 | Request for examination |
Patent event code: PA02012R01D Patent event date: 20250422 Comment text: Request for Examination of Application |