HRP20221291T1 - Kompleks gadolinija i kelirajući ligand dobiven iz dijastereoizomerno obogaćenog pcta i postupak sinteze - Google Patents
Kompleks gadolinija i kelirajući ligand dobiven iz dijastereoizomerno obogaćenog pcta i postupak sinteze Download PDFInfo
- Publication number
- HRP20221291T1 HRP20221291T1 HRP20221291TT HRP20221291T HRP20221291T1 HR P20221291 T1 HRP20221291 T1 HR P20221291T1 HR P20221291T T HRP20221291T T HR P20221291TT HR P20221291 T HRP20221291 T HR P20221291T HR P20221291 T1 HRP20221291 T1 HR P20221291T1
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- Croatia
- Prior art keywords
- formula
- complex
- image
- gadolinium
- hexaacid
- Prior art date
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- 229910052688 Gadolinium Inorganic materials 0.000 title claims 8
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 title claims 8
- 239000003446 ligand Substances 0.000 title 1
- 238000001308 synthesis method Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 8
- 239000000203 mixture Substances 0.000 claims 5
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims 5
- 239000002253 acid Substances 0.000 claims 4
- KQIGMPWTAHJUMN-UHFFFAOYSA-N 3-aminopropane-1,2-diol Chemical compound NCC(O)CO KQIGMPWTAHJUMN-UHFFFAOYSA-N 0.000 claims 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- 239000007864 aqueous solution Substances 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 claims 3
- 238000002425 crystallisation Methods 0.000 claims 3
- 230000008025 crystallization Effects 0.000 claims 3
- 238000006317 isomerization reaction Methods 0.000 claims 3
- 150000005691 triesters Chemical class 0.000 claims 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- 238000007098 aminolysis reaction Methods 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 claims 2
- 238000010438 heat treatment Methods 0.000 claims 2
- 238000002955 isolation Methods 0.000 claims 2
- -1 methyl triester Chemical class 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 230000002152 alkylating effect Effects 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 238000010668 complexation reaction Methods 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- WZAIBHOPSSMDTE-UHFFFAOYSA-N dibutyl 2-bromopentanedioate Chemical compound CCCCOC(=O)CCC(Br)C(=O)OCCCC WZAIBHOPSSMDTE-UHFFFAOYSA-N 0.000 claims 1
- 238000007865 diluting Methods 0.000 claims 1
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 238000010899 nucleation Methods 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 239000012429 reaction media Substances 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 claims 1
- 238000005292 vacuum distillation Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 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
-
- 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
- C07D471/08—Bridged systems
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- 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)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Claims (14)
1. Postupak priprave kompleksa formule (II), niže:
[image]
,
koji se sastoji od najmanje 80 % dijastereoizomernog suviška koji sadrži smjesu izomera II-RRR i II-SSS formula:
[image]
i
[image]
,
gdje se postupak sastoji od sljedećih uzastopnih koraka:
a) kompleksiranja heksakiseline formule (III), niže:
[image]
s gadolinijem kako bi se dobilo kompleks gadolinija s heksakiselinom formule (I), niže:
[image]
,
b) izomeriziranja grijanjem kompleksa gadolinija s heksakiselinom formule (I) u vodenoj otopini s pH između 2 i 4, kako bi se dobilo dijastereoizomerno obogaćeni kompleks koji se sastoji od najmanje 80 % dijastereoizomernog suviška koji sadrži smjesu izomera I-RRR i I-SSS navedenog kompleksa gadolinija s heksakiselinom formule (I), formula:
[image]
i
[image]
,
te
c) stvaranja, iz dijastereoizomerno obogaćenog kompleksa dobivenog u koraku b), kompleksa formule (II), reakcijom s 3-amino-1,2-propandiolom.
2. Postupak u skladu s patentnim zahtjevom 1, naznačen time što se kompleks gadolinija s heksakiselinom formule (I), nastao tijekom koraka a), izravno podvrgava koraku izomeriziranja b) bez izoliranja ili pročišćavanja.
3. Postupak u skladu s patentnim zahtjevom 1 ili 2, naznačen time što vodena otopina koraka b) sadrži octenu kiselinu.
4. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 3, naznačen time što se korak b) provodi na temperaturi između 100 °C i 120 °C, u pravilu u trajanju između 12 sati i 48 sati.
5. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 4, naznačen time što se korak b) sastoji od sljedećih uzastopnih koraka:
b1) izomeriziranja grijanjem kompleksa gadolinija s heksakiselinom formule (I) u vodenoj otopini s pH između 2 i 4, kako bi se dobilo dijastereoizomerno obogaćeni kompleks koji se sastoji od najmanje 80 % dijastereoizomernog suviška koji sadrži smjesu izomera I-RRR i I-SSS navedenog kompleksa gadolinija s heksakiselinom formule (I), te
b2) izoliranja kristaliziranjem navedenog dijastereoizomerno obogaćenog kompleksa, po mogućnosti kristaliziranjem uz zasijavanje.
6. Postupak u skladu s patentnim zahtjevom 5, naznačen time što se dijastereoizomerno obogaćeni kompleks iz koraka b) izoliran kristaliziranjem pročišćava prekristaliziranjem, kako bi se dobilo dijastereoizomerno obogaćeni i pročišćeni kompleks.
7. Postupak u skladu s patentnim zahtjevom 5 ili 6, naznačen time što se dijastereoizomerno obogaćeni kompleks iz koraka b) dodatno obogaćuje selektivnim dekompleksiranjem dijastereoizomera kompleksa formule (I) koji nisu dijastereoizomeri I-RRR i I-SSS, tj. selektivnim dekompleksiranjem dijastereoizomera I-RSS, I-SRR, I-RSR, I-SRS, I-RRS i I-SSR.
8. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 7, naznačen time što dijastereoizomerno obogaćeni kompleks dobiven na završetku koraka b) u skladu s bilo kojim od gore opisanih varijanti ima najmanje 85 % dijastereoizomernog suviška koji sadrži smjesu izomera I-RRR i I-SSS.
9. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 8, naznačen time što dijastereoizomerno obogaćeni kompleks dobiven na završetku koraka b) u skladu s bilo kojim od gore opisanih varijanti ima najmanje 90 % dijastereoizomernog suviška koji sadrži smjesu izomera I-RRR i I-SSS.
10. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 9, naznačen time što se korak c) sastoji od sljedećih uzastopnih koraka:
c1) stvaranja triestera formule (VIII)
[image]
,
u kojoj R1 predstavlja (C1-C6) alkilnu skupinu, osobito reakcijom u alkoholu formule R1OH u prisutnosti kiseline, poput klorovodične kiseline, te
c2) aminolize triestera formule (VIII) s 3-amino-1,2-propandiolom, osobito u alkoholu formule R1OH u prisutnosti kiseline, poput klorovodične kiseline.
11. Postupak u skladu s patentnim zahtjevom 10, naznačen time što se triester formule (VIII) ne izolira između koraka c1) i c2).
12. Postupak u skladu s patentnim zahtjevom 10 ili 11, naznačen time što R1 predstavlja metilna skupina.
13. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 12, naznačen time što se korak c) sastoji od sljedećih uzastopnih koraka:
c1) stvaranja metilnog triestera formule (IV)
[image]
,
osobito reakcijom u metanolu u prisutnosti kiseline, poput klorovodične kiseline, te
c2) aminolize metilnog triestera formule (IV) s 3-amino-1,2-propandiolom u metanolu u prisutnosti kiseline, poput klorovodične kiseline, tijekom koje se metanol ukloni vakuumskom destilacijom, dok se ne dosegne temperaturu višu od 55 °C, gdje se reakcijski medij održava na toj temperaturi pod vakuumom u trajanju u pravilu duljem od 5 sati prije hlađenja do sobne temperature, te razrijedi vodom.
14. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 13, naznačen time što se heksakiselinu formule (III) u skladu s patentnim zahtjevom 1 dobiva alkiliranjem piklena formule (V):
[image]
s dibutil-2-bromglutaratom, kako bi se dobilo butilni heksaester formule (VI)
[image]
,
za čim slijedi korak hidrolize, kojom se dobiva navedenu heksakiselinu formule (III).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1900433A FR3091872B1 (fr) | 2019-01-17 | 2019-01-17 | Complexe de gadolinium et d’un ligand chelateur derive de pcta diastereoisomeriquement enrichi et procede de synthese |
| PCT/EP2020/051142 WO2020148431A1 (fr) | 2019-01-17 | 2020-01-17 | Complexe de gadolinium et d'un ligand chelateur derive de pcta diastereoisomeriquement enrichi et procede de synthese |
| EP20700830.1A EP3902799B1 (fr) | 2019-01-17 | 2020-01-17 | Complexe de gadolinium et d'un ligand chelateur derive de pcta diastereoisomeriquement enrichi et procede de synthese |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20221291T1 true HRP20221291T1 (hr) | 2022-12-23 |
Family
ID=67001954
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20221291TT HRP20221291T1 (hr) | 2019-01-17 | 2020-01-17 | Kompleks gadolinija i kelirajući ligand dobiven iz dijastereoizomerno obogaćenog pcta i postupak sinteze |
| HRP20231161TT HRP20231161T1 (hr) | 2019-01-17 | 2020-01-17 | Kompleks gadolinija i kelirajućeg liganda izvedenog iz dijastereoizomerno obogaćenog pcta i postupak za njegovu sintezu |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20231161TT HRP20231161T1 (hr) | 2019-01-17 | 2020-01-17 | Kompleks gadolinija i kelirajućeg liganda izvedenog iz dijastereoizomerno obogaćenog pcta i postupak za njegovu sintezu |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US20220098218A1 (hr) |
| EP (2) | EP3902799B1 (hr) |
| JP (2) | JP7101897B2 (hr) |
| KR (2) | KR102593187B1 (hr) |
| CN (2) | CN113646309A (hr) |
| AR (1) | AR117834A1 (hr) |
| AU (2) | AU2020208793B2 (hr) |
| BR (2) | BR122022025041B1 (hr) |
| CA (2) | CA3126337C (hr) |
| CL (1) | CL2021001869A1 (hr) |
| CO (1) | CO2021009253A2 (hr) |
| DK (1) | DK3902799T3 (hr) |
| ES (1) | ES2929699T3 (hr) |
| FI (1) | FI3936505T3 (hr) |
| FR (1) | FR3091872B1 (hr) |
| HR (2) | HRP20221291T1 (hr) |
| HU (2) | HUE063338T2 (hr) |
| IL (1) | IL284883A (hr) |
| MA (2) | MA54624A (hr) |
| MX (1) | MX2021008654A (hr) |
| PL (1) | PL3902799T3 (hr) |
| PT (2) | PT3902799T (hr) |
| RS (1) | RS65146B1 (hr) |
| SG (1) | SG11202107781WA (hr) |
| TW (1) | TWI812832B (hr) |
| WO (1) | WO2020148431A1 (hr) |
| ZA (1) | ZA202104993B (hr) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR3091873B1 (fr) * | 2019-01-17 | 2020-12-25 | Guerbet Sa | Complexe de gadolinium et d’un ligand chelateur derive de pcta diastereoisomeriquement enrichi et procede de preparation et de purification |
| CN114031513B (zh) * | 2021-11-01 | 2022-07-26 | 中国人民解放军总医院第八医学中心 | 钆塞酸二钠异构体的分离及其在作为mr成像对比剂中的应用 |
| WO2024049087A1 (ko) * | 2022-09-01 | 2024-03-07 | 주식회사 테라노큐어 | 신규한 화합물 및 이를 포함하는 mri 조영제 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4647447A (en) | 1981-07-24 | 1987-03-03 | Schering Aktiengesellschaft | Diagnostic media |
| DE4001655A1 (de) | 1990-01-18 | 1991-07-25 | Schering Ag | 6-ring enthaltende makrocyclische tetraaza-verbindungen, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel |
| FR2793795B1 (fr) * | 1999-05-21 | 2001-08-03 | Guerbet Sa | Isomeres de tetramides du complexe de gadolinium de l'acide (1,4,7,10-tetrazacyclododecane)1,4,7,10-tetra(2-glutarique) leur procede de preparation et leur application en imagerie medicale |
| FR2794744B1 (fr) * | 1999-06-09 | 2001-09-21 | Guerbet Sa | Complexes metalliques de polyaminoacides bicycliques, leur procede de preparation et leur application en imagerie medicale |
| FR2891830B1 (fr) * | 2005-10-07 | 2011-06-24 | Guerbet Sa | Composes a chaines aminoalcools courtes et complexes metalliques pour l'imagerie medicale |
| EP2786768A1 (en) * | 2013-04-04 | 2014-10-08 | Agfa Healthcare | Process for preparing a material comprising a macrocyclic ligand and for producing a pharmaceutical formulation comprising said ligand with a lanthanide |
| WO2014174120A1 (fr) | 2013-04-26 | 2014-10-30 | Guerbet | Formulation de produit de contraste et son procede de preparation associe |
| BR112021001102B1 (pt) * | 2018-08-06 | 2022-12-20 | Bracco Imaging Spa | Misturas isoméricas de um derivado de amida de gd(pcta - ácido tris-glutárico) e composições farmacêuticas |
| FR3091873B1 (fr) * | 2019-01-17 | 2020-12-25 | Guerbet Sa | Complexe de gadolinium et d’un ligand chelateur derive de pcta diastereoisomeriquement enrichi et procede de preparation et de purification |
-
2019
- 2019-01-17 FR FR1900433A patent/FR3091872B1/fr active Active
-
2020
- 2020-01-17 TW TW109101778A patent/TWI812832B/zh active
- 2020-01-17 DK DK20700830.1T patent/DK3902799T3/da active
- 2020-01-17 HR HRP20221291TT patent/HRP20221291T1/hr unknown
- 2020-01-17 CA CA3126337A patent/CA3126337C/fr active Active
- 2020-01-17 KR KR1020217036450A patent/KR102593187B1/ko active IP Right Grant
- 2020-01-17 US US17/423,589 patent/US20220098218A1/en active Pending
- 2020-01-17 PT PT207008301T patent/PT3902799T/pt unknown
- 2020-01-17 CA CA3186302A patent/CA3186302C/fr active Active
- 2020-01-17 PL PL20700830.1T patent/PL3902799T3/pl unknown
- 2020-01-17 CN CN202080009659.7A patent/CN113646309A/zh active Pending
- 2020-01-17 FI FIEP21190150.9T patent/FI3936505T3/fi active
- 2020-01-17 AR ARP200100124A patent/AR117834A1/es unknown
- 2020-01-17 KR KR1020217025765A patent/KR102442900B1/ko active IP Right Grant
- 2020-01-17 BR BR122022025041-6A patent/BR122022025041B1/pt active IP Right Grant
- 2020-01-17 EP EP20700830.1A patent/EP3902799B1/fr active Active
- 2020-01-17 PT PT211901509T patent/PT3936505T/pt unknown
- 2020-01-17 ES ES20700830T patent/ES2929699T3/es active Active
- 2020-01-17 WO PCT/EP2020/051142 patent/WO2020148431A1/fr active Application Filing
- 2020-01-17 HR HRP20231161TT patent/HRP20231161T1/hr unknown
- 2020-01-17 BR BR112021014087-5A patent/BR112021014087B1/pt active IP Right Grant
- 2020-01-17 MA MA054624A patent/MA54624A/fr unknown
- 2020-01-17 EP EP21190150.9A patent/EP3936505B1/fr active Active
- 2020-01-17 MA MA055227A patent/MA55227A/fr unknown
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- 2020-01-17 AU AU2020208793A patent/AU2020208793B2/en active Active
- 2020-01-17 JP JP2021541200A patent/JP7101897B2/ja active Active
- 2020-01-17 RS RS20231021A patent/RS65146B1/sr unknown
- 2020-01-17 MX MX2021008654A patent/MX2021008654A/es unknown
- 2020-01-17 HU HUE21190150A patent/HUE063338T2/hu unknown
- 2020-01-17 CN CN202111050874.4A patent/CN113698400A/zh active Pending
- 2020-01-17 HU HUE20700830A patent/HUE060073T2/hu unknown
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2021
- 2021-07-14 CL CL2021001869A patent/CL2021001869A1/es unknown
- 2021-07-15 ZA ZA2021/04993A patent/ZA202104993B/en unknown
- 2021-07-15 CO CONC2021/0009253A patent/CO2021009253A2/es unknown
- 2021-07-15 IL IL284883A patent/IL284883A/en unknown
- 2021-10-25 JP JP2021173862A patent/JP7503532B2/ja active Active
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2023
- 2023-01-25 AU AU2023200400A patent/AU2023200400B2/en active Active
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