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
• • 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
• • 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 tetramides, derived from the pair of RRRR / SSSS enantiomers of the tetra- ( ⁇ -carboxyethyi) gadoterate represented by the formulas
• R is a bulky hydrophilic group with a molecular mass greater than 200 have a longitudinal relaxivity ⁇ markedly greater than that of chelates not carrying the bulky side group (CH 2 ) 2 CONHR and can be used as contrast agents in diagnostic imaging by magnetic resonance.
• WO97 / 01359 relates to the products of formula II in which R is a group of formula
• the relaxivity r- of a gadoiinium chelate is a complex function of different factors, more or less independent, including the electronic correlation, rotation correlation and water exchange times, factors which depend in particular of the spatial structure of the chelating agent around the paramagnetic cation, so that 2 stereoisomers can have significantly different relaxivities.
• R represents a phenyl or (C 1 -C 8 ) alkyl group, substituted or interrupted by one or more groups chosen from phenyl, alkyl, oxy, amino or amido groups, substituted or not by alkyl, the phenyl groups being able to be substituted by OH, Br, CI, i, (C 1 -C 8 ) alkyl,
• R 1 is H, (C r C 3 ) alkyl or (C 2 -C 8 ) mono- or polyhydroxyalkyl and R 2 is (C 2 -C 8 ) mono- or polyhydroxyalkyl, or else R 1 is H and R 2 is a formula group
• R'- ,, R ' 2 taking any of the meanings given for R- ,, R 2 , excluding A, it being understood that -CO-NR ⁇ or - CO-NR '-, R' 2 have at least two hydroxyl groups, and those in which R is a group
• Z ' is a bond, O, S, NQ, CH 2 , CO, CO-NQ, NQ-CO, NQ-CO-NQ or CO-NQ-CH 2 -CONQ
• Z "is CO-NQ, NQ-CO or CO-NQ-CH 2 -CO-NQ, NQ-CO-CH 2 -NQ-CO with Q is H or a group (CC 4 ) alkyl, optionally hydroxylated
• R * ,, R 2 , R 3 , R 4 , R 5 independently of one another, are chosen from H, Br, Cl, I, CO-NQ T Q S OR N (Q ⁇ ) -CO- Q 2 and Q, and Q 2 , identical or different, are chosen from (C 2 -C 6 ) alkyl groups, optionally hydroxylated, optionally interrupted by an oxygen atom, so that Q 2 and Q 2 comprise both of them from 4 to 10 OH groups, it being understood that at least 1, and at most 2 groups R 1 f R 2 , R 3 , R 4 , R 5 , are amide groups.
• racemic compounds of the invention can be prepared by a method known per se, by the action of the amine RNH 2 on the pair of enantiomeric octaacid complexes of formula I, in aqueous solution, with an agent activating the carboxylic functions, in the conventional conditions of peptide condensations, as described in the previously cited patents, for mixtures of isomers.
• the present invention relates to a method comprising the steps consisting in:
• the invention also relates to the compositions for nuclear magnetic resonance medical imaging which comprise the racemic compounds of the invention associated with the usual vehicles and additives.
• the doses at which these contrast agents will be administered depend on their magnetic efficacy, their biodistribution, their route of administration, as well as the size of the subject, the organ to be observed and the nature of the pathology.
• the unit concentration will be between 0.5 and 5 mM for adults, presented in aqueous solution.
• the isolated products are characterized by their retention times (t r ) in high performance liquid chromatography (HPLC). Their molecular weights were determined by mass spectrometry (electrospray).
• Gadolinium acid chelate [1, 4,7,10-tetraazacyclododecane] 1, 4,7,10-tetra (2-glutaric) (mixture of the 6 diastereoisomers).
• the sought product is purified by chromatography on silica, eluting with methylene chloride, optionally in admixture with acetone.
• 500 ml of cationic exchange resin in weak acid form are introduced into the cooled solution to neutralize, then after separation of the solid phase, 500 ml of anionic exchange resin in the form of a strong base.
• the resin is separated and introduced into 500 ml of aqueous solution and 6N acetic acid; the final product, passed into solution, is isolated in the form of a powder by evaporation under vacuum of the solvent.
• gadolinium oxide in 30 ml of a solution at a pH of 5.5 to 6 g of 2 g of the preceding octaacid, 0.47 g of gadolinium oxide is introduced and the mixture is kept at 80 ° C for 3 hours, during which the pH is adjusted if necessary.
• the medium is filtered and concentrated to one third and then poured into 100 ml of ethanol.
• the precipitate formed can be purified by treatment with a weak basic resin before further precipitation in ethanol.
• gadolinium chloride the mixture of 6.5 g of octaacid and 3.5 g of GdCI 3 , 6 H 2 O in 130 ml of pH 6.5 is added to the pH 6.5 by adding aqueous NaOH (1N). water, and it is brought to 60 ° C. for 2 hours during which the pH is maintained at 6.5 by adding a total of 21 ml of 1N aqueous NaOH. After a few hours at room temperature, the mixture is concentrated to 25 ml and the final product is precipitated in 250 ml of C 2 H 5 OH before purifying it.
• the solution After returning to room temperature, the solution is poured into 100 ml of ethanol and the precipitate formed is isolated and then dissolved in 100 ml of water to obtain a solution which is subjected to tangential ultrafiltration on a polyethersulfone membrane, the threshold of which cutoff is 1 Kdalton, in a Minisette® cell sold by Filtron® USA.
• the acid can also be suspended in toluene with tricaprylylmethylammonium chloride as catalyst.
• a solution of 1.4 equivalents of hydrazine hydrate in 6 ml of water is introduced into the above phthalimide solution at 70 ° C. After 2 hours of stirring at 90 ° C, the cooled mixture is poured into 125 ml of ethanol. 9 g of precipitate are isolated from which the phthalylhydrazide is separated by precipitation from an aqueous solution at pH 2, before ultrafiltration at pH 6 on a polyamide membrane to remove low-mass impurities. The final hydrochloride is then isolated by lyophilization. Yield 50% from acid chloride.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Radiology & Medical Imaging (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

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• 1999
  • 1999-05-21 FR FR9906517A patent/FR2793795B1/fr not_active Expired - Fee Related
• 2000
  • 2000-05-19 US US09/926,589 patent/US6827927B1/en not_active Expired - Lifetime
  • 2000-05-19 WO PCT/FR2000/001382 patent/WO2000071526A1/fr not_active Application Discontinuation
  • 2000-05-19 EP EP00929648A patent/EP1178975A1/de not_active Withdrawn
  • 2000-05-19 AU AU47658/00A patent/AU4765800A/en not_active Abandoned

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