WO1997001359A2 - Complexes metalliques de polyaminooxydes et leur utilisation en imagerie diagnostique - Google Patents
Complexes metalliques de polyaminooxydes et leur utilisation en imagerie diagnostique Download PDFInfo
- Publication number
- WO1997001359A2 WO1997001359A2 PCT/FR1996/000992 FR9600992W WO9701359A2 WO 1997001359 A2 WO1997001359 A2 WO 1997001359A2 FR 9600992 W FR9600992 W FR 9600992W WO 9701359 A2 WO9701359 A2 WO 9701359A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- solution
- complex according
- choh
- aqueous
- Prior art date
Links
- 0 C*=**c(c(Br)c1*)c(C)c(**)c1Br Chemical compound C*=**c(c(Br)c1*)c(C)c(**)c1Br 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0442—Polymeric X-ray contrast-enhancing agent comprising a halogenated group
-
- 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
-
- 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
- A61K49/103—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA
-
- 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
Definitions
- the present invention relates to metal complexes of polyamino acids, their preparation process and their use in diagnostic imaging.
- These compounds are branched derivatives of gadoteric acid, sold in the form of meglumine salt under the brand Dotarem® as a contrast agent for magnetic resonance imaging.
- the meglumine gadoterate is a stable complex whose spin-network relaxivity at 37 " C and 20 MHz is approximately 3.5 mM " V, of the same order of magnitude as that of other contrast agents on the market.
- the gadolinium complexes according to the invention have relaxivities R, greater than 20 rnM ' V 1 ; this allows the subject to be administered, in order to obtain the same signal intensity, a diagnostic composition whose molar concentration of complexed Gd 3+ , and therefore of compound according to the invention, is 6 times and even 10 times lower than the concentrations currently used in the clinic.
- these complexes have bromine or iodine atoms and are opaque to X-rays and they are sufficiently soluble, in particular by the presence of hydrophilic groups around the aromatic nuclei, to be used in radiology conventional or in dichromography.
- the compounds of the invention have the formula
- R represents a group
- R is H, (C ⁇ C ⁇ alkyl or (C 2 -C 8 ) mono- or polyhydroxyalkyl and
- R 2 is (C 2 -C 8 ) mono- or polyhydroxyalkyl, or else
- R is H and R 2 is a group
- R ' ⁇ and R' 2 independently taking any of the meanings given for R, and R 2 , excluding A, it being understood that -CO-NR-R., Or - CO-NR ' T R' J have at least 2 hydroxyl groups, and M represents H or an organic or inorganic cation.
- M represents H or an organic or inorganic cation.
- the alkyl groups can be linear or branched.
- the compounds of formula I can be prepared by the action of the amine of formula II
- A can be obtained by reaction of HNR-R-. with the diacid dichloride of formula IV:
- the amines of formula II for which R 2 represents A and R represents H are simply obtained by reacting an amine of formula H 2 NA with the diacid dichloride of formula IV previously N-protected. It will be noted that the amine H 2 NA, which corresponds to an amine of formula II in which R 2 is distinct from A, can be prepared according to the method proposed above.
- contrast agent compositions for magnetic resonance imaging which contain a compound of formula I in a pharmaceutically acceptable vehicle.
- Their pharmaceutical form will be adapted to the route of administration.
- compositions of contrast agents will be aqueous solutions of physiologically acceptable salts of the complex of formula I.
- the compositions of the invention may also contain stabilizers, various additives intended to make the solution isotonic or make it possible to fix its pH, as well as any other type of additive commonly used in the art.
- the concentration of the composition will be adapted to the route and the area of administration; it will generally be between 0.01 M and 0.5 M and preferably between 0.05 M and 0.1 M.
- the unit dose will obviously depend on the structure of the complex and the nature of the examination; in general, 0.005 mmol / kg to 0.1 mmol / kg will be administered.
- the methanol is removed under reduced pressure and the aqueous phase extracted with methylene chloride, before introducing therein about 800 ml of cationic ion exchange resin Amberlite®, marketed by Rohm and Haas, under the designation IRC 50 (weak acid ).
- the resin is separated and introduced into a column; the sought product is isolated by elution using 4 I of an aqueous 3N acetic acid solution and then 4 I of 6N solution.
- 29.4 g of the octaacid previously obtained are suspended in 530 ml of water, with 15.8 g of GdCI 3 , 6 H 2 O; with stirring, an aqueous 1N NaOH solution is introduced slowly until the pH of the medium is stabilized at 6.5.
- the medium is then filtered through a Millipore® filter with a 0.45 ⁇ m mesh and the filtrate concentrated to dryness. After drying 49.3 g of the sodium salt of the gadolinium complex of formula III is obtained, in the form of a beige solid containing the NaCl formed during the complexation.
- This product can be purified by precipitation in aqueous ethanol and treatment, to remove an excess of uncomplexed Gd 3+ , with a chelating resin such as that sold by Biorad Laborato ⁇ ries under the brand CHELEX.
- Relaxivity R, (37 ° C; 20 MHz) 5.9 mM ' V;
- a solution, in 1000 ml of dimethylacetamide, of 104 g of the above acid dichloride, 208 g of disorbitylamine and 50 ml of triethylamine is kept at 80 ° C. for 5 hours.
- the precipitate formed is separated and the solvent is removed by distillation under reduced pressure; the residue is dissolved in water at pH 3 and brought into contact with 750 ml of resin cationic ion exchange Amberlite® sold by Rohm and Haas under the name IRN 77 (strong acid).
- the resin is separated and 17 ml of hydrazine hydrate are introduced into the aqueous solution (700 ml) of the purified diamide.
- the medium is acidified at room temperature by the addition of 26 ml of a 10N aqueous hydrochloric acid solution.
- the precipitate formed is isolated and the solution is passed through a column of 500 ml of a weak ion exchange resin (Amberlite® IRA 67) then 80 ml of a weak cationic resin (Amberlite® IRC 50); the solution obtained is treated with 4 I of strong acid Amberlite® resin, on which the final product is fixed; it is eluted with an aqueous NH 4 OH solution.
- Amine II is obtained with 70% yield in the form of a beige solid.
- the starting 5-amino-2,4,6-tribromoisophthalic acid is prepared with 85% yield per action of 100 ml of bromine on a solution in 1300 ml of water and 380 ml of concentrated hydrochloric acid, of 87 g 5-aminoisophthalic acid.
- the corresponding acid dichloride is prepared conventionally by the action of SOCI 2 on the corresponding diacid with 88% yield.
- aqueous solution which contains the expected phthalimide (80% of theory), is treated as in the previous preparation by hydrazine hydrate to give the expected amine II with a yield of 85%.
- a solution of 37.5 g of the compound previously isolated in 130 ml of water and 2 ml of aqueous 35% hydrazine solution is kept at 80 ° C. for 5 hours. After cooling, the medium is brought to pH 1 by addition of 10N aqueous HCl and then chromatography successively on 100 ml of cationic (IRN77) and anionic (IRA67) Amberlite® resins and on 500 ml of a polystyrenic acid resin, cation exchange type IMAC HP222 marketed by Rohm and Haas, from which the sought product is eluted by a aqueous NH 4 OH solution 3M and then isolated by precipitation in ethanol after concentration.
- IRN77 cationic
- IRA67 anionic
- 75 g of the product previously obtained are introduced at 80 ° C. into 50 ml of water containing 1.43 ml of 35% aqueous hydrazine solution and the mixture is maintained at this temperature for 5 hours before being brought to pH. 1 by addition of 10N aqueous HCl.
- the precipitate is separated and the aqueous phase is chromatographed on 100 ml of cationic resin H + Amberlite® IRC50 then on 200 ml of anionic resin OH " Amberlite® IRA67.
- reaction medium to which 50 ml of water has been added is subjected to ultrafiltration with a mini-cassette cassette of the nova type sold by the company Filtron (U.S.A.) comprising a polyethersulfone membrane of 5 KDa cut-off threshold.
- Filtron U.S.A.
- the reaction can also be carried out at around 40 ° C., optionally in the presence of a catalytic amount of sodium salt of (N-hydroxysuccinimidyl) -3-sulfonic acid.
- the product can be purified by precipitation in isopropanol.
- the solution is ultrafiltered as previously on a membrane of 1 kdalton cut-off threshold. After evaporation of the water, 15 g of the sought product are obtained in the form of a white powder.
- HPLC operating conditions of Example 2. Retention time: 3 minutes.
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Radiology & Medical Imaging (AREA)
- Medicinal Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Polyamides (AREA)
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ312720A NZ312720A (en) | 1995-06-29 | 1996-06-25 | Metal complexes of polyaminoacids, and their utilization in diagnostic imaging |
US08/981,022 US5886158A (en) | 1995-06-29 | 1996-06-25 | Metal complexes of polyamino oxides, and their utilization in diagnostic imaging |
PL96325531A PL325531A1 (en) | 1995-06-29 | 1996-06-25 | Metal complexes of amino polyacids and their application in diagnostic visualisation |
EA199800101A EA000378B1 (ru) | 1995-06-29 | 1996-06-25 | Комплекс гадолиния с полиаминокислотами и его применение для формирования изображений при диагностике |
AT96924020T ATE207762T1 (de) | 1995-06-29 | 1996-06-25 | Polyaminosäuren-metallkomplexe und ihre anwendung in diagnostischer bilderzeugung |
IL12262196A IL122621A0 (en) | 1995-06-29 | 1996-06-25 | Metal complexes of polyamino oxides and their use in diagnostic imaging |
JP9504203A JPH11508550A (ja) | 1995-06-29 | 1996-06-25 | ポリアミノ酸の金属錯体類および診断用イメージングにおけるそれらの使用 |
SK1737-97A SK282197B6 (sk) | 1995-06-29 | 1996-06-25 | Komplex gadolínia a zmesi na použitie v diagnostickom zobrazení |
BR9609519A BR9609519A (pt) | 1995-06-29 | 1996-06-25 | Complexos metálicos de poliaminoóxidos e sua utilização em produção de imagens de diagnóstico |
AU64616/96A AU708180B2 (en) | 1995-06-29 | 1996-06-25 | Metal complexes of polyamino oxides and their use in diagnostic imaging |
DE69616548T DE69616548T2 (de) | 1995-06-29 | 1996-06-25 | Polyaminosäuren-metallkomplexe und ihre anwendung in diagnostischer bilderzeugung |
EP96924020A EP0835140B1 (fr) | 1995-06-29 | 1996-06-25 | Complexes metalliques de polyaminoacides et leur utilisation en imagerie diagnostique |
NO976098A NO976098L (no) | 1995-06-29 | 1997-12-29 | Metallkomplekser av polyaminosyrer og deres anvendelse innen avbildning for diagnoseformål |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9507860A FR2736051B3 (fr) | 1995-06-29 | 1995-06-29 | Complexes metalliques de polyaminoacides, leur procede de preparation et leur utilisation en imagerie diagnostique |
FR95/07860 | 1995-06-29 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1997001359A2 true WO1997001359A2 (fr) | 1997-01-16 |
WO1997001359A3 WO1997001359A3 (fr) | 1997-05-22 |
Family
ID=9480531
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR1996/000992 WO1997001359A2 (fr) | 1995-06-29 | 1996-06-25 | Complexes metalliques de polyaminooxydes et leur utilisation en imagerie diagnostique |
Country Status (21)
Country | Link |
---|---|
US (1) | US5886158A (fr) |
EP (1) | EP0835140B1 (fr) |
JP (1) | JPH11508550A (fr) |
KR (1) | KR19990028556A (fr) |
CN (1) | CN1074934C (fr) |
AT (1) | ATE207762T1 (fr) |
AU (1) | AU708180B2 (fr) |
BR (1) | BR9609519A (fr) |
CA (1) | CA2222697A1 (fr) |
CZ (1) | CZ414197A3 (fr) |
DE (1) | DE69616548T2 (fr) |
EA (1) | EA000378B1 (fr) |
FR (1) | FR2736051B3 (fr) |
HU (1) | HUP9900449A3 (fr) |
IL (1) | IL122621A0 (fr) |
NO (1) | NO976098L (fr) |
NZ (1) | NZ312720A (fr) |
PL (1) | PL325531A1 (fr) |
SK (1) | SK282197B6 (fr) |
TR (1) | TR199701716T1 (fr) |
WO (1) | WO1997001359A2 (fr) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2772025A1 (fr) * | 1997-12-10 | 1999-06-11 | Guerbet Sa | Chelates metalliques de macrocycles polyaminocarboxyliques et leur application a l'imagerie par resonance magnetique |
FR2793795A1 (fr) * | 1999-05-21 | 2000-11-24 | 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 |
JP2003501430A (ja) * | 1999-06-09 | 2003-01-14 | ゲルベ | 2環式ポリアミノ酸金属複合体、その製法および医療用画像化での使用 |
FR2836916A1 (fr) * | 2002-03-05 | 2003-09-12 | Guerbet Sa | Oligomeres de chelates de gadolinium, leur application comme produits de contraste en imagerie par resonance magnetique et leurs intermediaires de synthese |
DE10307759B3 (de) * | 2003-02-19 | 2004-11-18 | Schering Ag | Trimere makrocyclisch substituierte Benzolderivate, deren Herstellung und Verwendung als Kontrastmittel sowie diese enthaltende pharmazeutische Mittel |
WO2004112839A2 (fr) * | 2003-06-25 | 2004-12-29 | Guerbet | Composes specifiques a relaxivite elevee |
DE102007058220A1 (de) | 2007-12-03 | 2009-06-04 | Bayer Schering Pharma Aktiengesellschaft | Dimere macrocyclisch substituierte Benzolderivate |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1297035B1 (it) | 1997-12-30 | 1999-08-03 | Bracco Spa | Derivati dell'acido 1,4,7,10-tetraazaciclododecan-1,4-diacetico |
KR100309386B1 (ko) * | 1999-08-04 | 2001-09-26 | 이계안 | 파트타임 4륜구동차량의 자동절환식 차동장치 |
US20060275217A1 (en) * | 2005-05-06 | 2006-12-07 | Caravan Peter D | Chemical exchange saturation transfer contrast agents |
KR101193686B1 (ko) * | 2005-08-29 | 2012-10-22 | 니혼앗짜쿠단시세이소 가부시키가이샤 | 전기 커넥터 및 액정 표시 장치 |
US20090208421A1 (en) * | 2008-02-19 | 2009-08-20 | Dominique Meyer | Process for preparing a pharmaceutical formulation of contrast agents |
MX2014001623A (es) | 2011-08-10 | 2015-03-09 | Digna Biotech Sl | Uso de la cardiotofina-1 para el tratamiento de enfermedades renales. |
WO2017165841A1 (fr) | 2016-03-25 | 2017-09-28 | Nanoprobes, Inc. | Particules à base d'iode |
Citations (3)
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EP0414287A1 (fr) * | 1989-07-21 | 1991-02-27 | Nycomed Imaging As | Agent de contraste particulaire |
WO1993016375A1 (fr) * | 1992-02-06 | 1993-08-19 | Mallinckrodt Medical, Inc. | Agents de contraste utilises pour les radiographies et l'irm |
WO1994027644A1 (fr) * | 1993-06-02 | 1994-12-08 | Bracco S.P.A. | Chelates paramagnetiques iodes et leur utilisation comme agents de contraste |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5116599A (en) * | 1989-07-31 | 1992-05-26 | Johns Hopkins Univ. | Perfluoro-t-butyl-containing compounds for use in fluorine-19 nmr and/or mri |
-
1995
- 1995-06-29 FR FR9507860A patent/FR2736051B3/fr not_active Expired - Lifetime
-
1996
- 1996-06-25 HU HU9900449A patent/HUP9900449A3/hu unknown
- 1996-06-25 CN CN96195154A patent/CN1074934C/zh not_active Expired - Fee Related
- 1996-06-25 JP JP9504203A patent/JPH11508550A/ja active Pending
- 1996-06-25 WO PCT/FR1996/000992 patent/WO1997001359A2/fr not_active Application Discontinuation
- 1996-06-25 EA EA199800101A patent/EA000378B1/ru not_active IP Right Cessation
- 1996-06-25 BR BR9609519A patent/BR9609519A/pt active Search and Examination
- 1996-06-25 DE DE69616548T patent/DE69616548T2/de not_active Expired - Lifetime
- 1996-06-25 EP EP96924020A patent/EP0835140B1/fr not_active Expired - Lifetime
- 1996-06-25 AT AT96924020T patent/ATE207762T1/de not_active IP Right Cessation
- 1996-06-25 TR TR97/01716T patent/TR199701716T1/xx unknown
- 1996-06-25 SK SK1737-97A patent/SK282197B6/sk unknown
- 1996-06-25 AU AU64616/96A patent/AU708180B2/en not_active Ceased
- 1996-06-25 CA CA002222697A patent/CA2222697A1/fr not_active Abandoned
- 1996-06-25 PL PL96325531A patent/PL325531A1/xx unknown
- 1996-06-25 KR KR1019970709876A patent/KR19990028556A/ko not_active Application Discontinuation
- 1996-06-25 IL IL12262196A patent/IL122621A0/xx not_active IP Right Cessation
- 1996-06-25 NZ NZ312720A patent/NZ312720A/en unknown
- 1996-06-25 US US08/981,022 patent/US5886158A/en not_active Expired - Fee Related
- 1996-06-25 CZ CZ974141A patent/CZ414197A3/cs unknown
-
1997
- 1997-12-29 NO NO976098A patent/NO976098L/no not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0414287A1 (fr) * | 1989-07-21 | 1991-02-27 | Nycomed Imaging As | Agent de contraste particulaire |
WO1993016375A1 (fr) * | 1992-02-06 | 1993-08-19 | Mallinckrodt Medical, Inc. | Agents de contraste utilises pour les radiographies et l'irm |
WO1994027644A1 (fr) * | 1993-06-02 | 1994-12-08 | Bracco S.P.A. | Chelates paramagnetiques iodes et leur utilisation comme agents de contraste |
Non-Patent Citations (1)
Title |
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M.E. WOLFF (ED.): BURGER'S MEDICINAL CHEMISTRY, EDITION 4, PARTIE III, 1979, J. WILEY & SONS, NEW YORK, US, pages 1139-1203, XP002005069 PENG C T: "CHAPITRE 61: RADIOPAQUES" * |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0922700A1 (fr) * | 1997-12-10 | 1999-06-16 | Guerbet | Chelates métalliques de dérivés macrocycliques polyaminocarboxyliques et leur application à l'imagerie diagnostique |
FR2772025A1 (fr) * | 1997-12-10 | 1999-06-11 | Guerbet Sa | Chelates metalliques de macrocycles polyaminocarboxyliques et leur application a l'imagerie par resonance magnetique |
US6827927B1 (en) * | 1999-05-21 | 2004-12-07 | Guerbet | Gadolinium complex tetramides and use in medical imaging |
FR2793795A1 (fr) * | 1999-05-21 | 2000-11-24 | 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 |
WO2000071526A1 (fr) * | 1999-05-21 | 2000-11-30 | Guerbet | Tetramides d'un complexe de gadolinium et application en imagerie medicale |
JP2003501430A (ja) * | 1999-06-09 | 2003-01-14 | ゲルベ | 2環式ポリアミノ酸金属複合体、その製法および医療用画像化での使用 |
EP1183255B1 (fr) * | 1999-06-09 | 2003-03-05 | Guerbet | Complexes metalliques de polyaminoacides bicycliques, leur procede de preparation et leur application en imagerie medicale |
FR2836916A1 (fr) * | 2002-03-05 | 2003-09-12 | Guerbet Sa | Oligomeres de chelates de gadolinium, leur application comme produits de contraste en imagerie par resonance magnetique et leurs intermediaires de synthese |
WO2003074523A3 (fr) * | 2002-03-05 | 2004-03-25 | Guerbet Sa | Oligomeres de chelates de gadolinium, leur application comme produits de contraste en imagerie par resonance magnetique et leur intermediaires de synthese |
WO2003074523A2 (fr) * | 2002-03-05 | 2003-09-12 | Guerbet | Oligomeres de chelates de gadolinium, leur application comme produits de contraste en imagerie par resonance magnetique et leur intermediaires de synthese |
DE10307759B3 (de) * | 2003-02-19 | 2004-11-18 | Schering Ag | Trimere makrocyclisch substituierte Benzolderivate, deren Herstellung und Verwendung als Kontrastmittel sowie diese enthaltende pharmazeutische Mittel |
WO2004112839A2 (fr) * | 2003-06-25 | 2004-12-29 | Guerbet | Composes specifiques a relaxivite elevee |
WO2004112839A3 (fr) * | 2003-06-25 | 2005-05-06 | Guerbet Sa | Composes specifiques a relaxivite elevee |
DE102007058220A1 (de) | 2007-12-03 | 2009-06-04 | Bayer Schering Pharma Aktiengesellschaft | Dimere macrocyclisch substituierte Benzolderivate |
Also Published As
Publication number | Publication date |
---|---|
NZ312720A (en) | 1999-04-29 |
EP0835140B1 (fr) | 2001-10-31 |
AU708180B2 (en) | 1999-07-29 |
CN1074934C (zh) | 2001-11-21 |
FR2736051B3 (fr) | 1997-09-26 |
JPH11508550A (ja) | 1999-07-27 |
DE69616548D1 (de) | 2001-12-06 |
US5886158A (en) | 1999-03-23 |
PL325531A1 (en) | 1998-08-03 |
ATE207762T1 (de) | 2001-11-15 |
HUP9900449A2 (hu) | 1999-06-28 |
EP0835140A2 (fr) | 1998-04-15 |
TR199701716T1 (xx) | 1998-04-21 |
EA199800101A1 (ru) | 1998-08-27 |
WO1997001359A3 (fr) | 1997-05-22 |
BR9609519A (pt) | 1999-02-23 |
CA2222697A1 (fr) | 1997-01-16 |
CN1189778A (zh) | 1998-08-05 |
HUP9900449A3 (en) | 2001-05-28 |
NO976098L (no) | 1998-02-27 |
FR2736051A1 (fr) | 1997-01-03 |
SK173797A3 (en) | 1998-06-03 |
MX9710380A (es) | 1998-07-31 |
DE69616548T2 (de) | 2002-07-18 |
IL122621A0 (en) | 1998-08-16 |
CZ414197A3 (cs) | 1998-03-18 |
NO976098D0 (no) | 1997-12-29 |
EA000378B1 (ru) | 1999-06-24 |
KR19990028556A (ko) | 1999-04-15 |
AU6461696A (en) | 1997-01-30 |
SK282197B6 (sk) | 2001-12-03 |
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