COMPLEXES OF GD +3 GADOLINIUM IONS WITH DERIVATIVES OF N-2- (2- (PHENYLAMINO) -2-OXOETHYL) -N- ( CARBOXYMETHYL) -GLYCINE AND METHOD FOR
OBTAINING THESE COMPLEXES
New Complexes of Gd+3 Gadolinium Ions with Derivatives of 2,2'- (2-(Rι ,R2,R3,R4,R5-phenyl) amine)-2-oxoethyl))diacetic Acid and
Method for Obtaining New Complexes of Gd Gadolinium Ions with Derivatives of 2,2'-(2-(Rι ,R2,R3,R4,R5-phenyl)amine)-2- oxyethyl))diacetic Acid.
The subject of the invention are new complexes of Gd+3 gadolinium ions with derivatives of 2,2'-(2- (Rι ,R2,R3,R4,R5-phenyl)amine)-2- oxyethyl))diacetic acid of the formula I, in which Rl 5R2,R3,R4 and R5 are the same or different and they stand for either an atom of hydrogen or an atom of halogen or an aliphatic group or an aromatic group or a nitro group or a phosphonic group or a phosphate group or a heterocyclic system containing an atom of oxygen of an atom of nitrogen or an atom of sulphur of any configuration and a method for these compounds obtaining.
The compounds being the subject of the invention are new and they have not been described in any chemical literature. Initial research indicates a possibility to apply these new compounds as contrasting for non-invasive diagnostic technique in medical imaging, for instance magnetic nuclear resonance for internal organs particularly liver.
There are known radioactive complexes of technetium99"1 Tc and iodine I for liver diagnostics by scanning techniques and CT
(computer tomography), being derivatives of the nitrilotriacetic acid system including various substituents. Their main application is in liver diagnostics, for instance in biliary canalicula occlusion.
Tests performed with their application have low resolving power in comparison to the results achieved by the MRJ technique.
Technetium complexes do not allow diagnostics of small lesions.
The known contrast media used in CT for liver diagnostics require application of high doses, which is connected with their toxicity increase.
According to the invention new complexes of gadolinium GD+ are obtained in reaction of hexahydrous gadolinium chloride
[GdCl3(H2O)6] with lithium salt of derivatives of 2,2' -(2-
(Rι .R2,R3,R4,R5-phenyl)amine)-2-oxyethyl))diacetic acid in the medium of aliphatic alcohol, aliphatic amine, aromatic amine, dimethylsulfoxide (DMSO), dimethylformamide (DMF) at the temperature of 60°C.
The mole ratio of the reagents is 1 : 2.
Gadolinium complex lithium salt obtained in the above mentioned way is transformed into a derivative of sodium salt in reaction with sodium hydroxide.
The medium of the reaction is aliphatic alcohol or aliphatic amine or aromatic amine or dimethylsulfoxide (DMSO) or dimethylformamide.
The reaction is carried out at the room temperature and the ratio of the reagents is 1 : 1.
The obtained new gadolinium complex is purified by a known method.
Ligands for new complexes of derivatives of 2,2'-(2-(R1R2,R3,R ,R5- phenyl)amine)-2-oxoethyl))diacetic acid, being an initial product for synthesis with hexahydrous gadolinium oxide according to the invention is obtained in reaction between appropriately substituted derivatives of aniline and mixed anhydride of nitrilotriacetic acid and acetic acid (Nunn A.D., Loberg M.D., US Patent N° 4,418,208).
Identity of the new gadolinium complexes obtained according to the invention and structure of obtained combinations have been confirmed by elementary analysis and spectrally (IR, FAB MS,
MALDI TOF).
Biological tests performed with animals showed that new compounds were preparations of selective affinity for liver structures and they are of low toxicity.
The idea of the invention is explained more closely on the below example.
Example:
Obtaining sodium salt of gadolinium complex with 2,2'-(2-
(phenyl amine -2-oxoethyl )diacetic acid
1 weight part of lithium salt of 2,2'-(2-(phenyl)amine)-2- oxoethyl))diacetic acid was dissolved in 10.6 weight parts of methanol and mixed with 0.67 weight part of GdCl36H O dissolved in 4.26 weight parts of methanol; the obtained solutions being mixed for 24 hours at the temperature of 60°C. Next there was added 0.7 weight part of NaOH solved in 6.4 weight parts of methanol. After
30 minutes the solvent was evaporated and the residue was crystallised from the methanol/acetonitrile system.
The process yield was 85%.
Rf (MeOH) - 0.56 t.t.->300°C
IR (cm"1): 3403.9 (H2O), 3078.7 (Ph), 1630.6; 1598.5 (C=0)
MS (-FAB): (m/z) 683, 684.2, 685, 686.2, 688.1 (M1); 706, 708.1
(M_1+Na)
MALDI TOF: (m/z) 685, 686, 687, 689 (M"1)
Elemental analysis:C24H24Gd N4O10Na 6(H2O) 6(CO2)
Calculated: C(33.34%) ,H(3.36%) Gd(14.55%) N(5.18%) Na(2.13%)
0(41.45%)
Obtained: C(33.0%) H(3.32%) N(5.43%)