WO2004082721A1

WO2004082721A1 - Complexes of gd +3 gadolinium ions with derivatives of n-2- (2- (phenylamino) -2- oxoethyl) -n- (carboxymethyl) - glycine and method for obtaining these complexes

Info

Publication number: WO2004082721A1
Application number: PCT/PL2004/000017
Authority: WO
Inventors: Elzbieta Olasik; Boleslaw Karwowski; Malgorzata Witczak; Michal Studniarek
Original assignee: Uniwersystet Medyczny
Priority date: 2003-03-20
Filing date: 2004-03-12
Publication date: 2004-09-30
Also published as: PL359249A1

Abstract

Method for obtaining new complexes of Gd+3 gadolinium ions with derivatives of 2,2'-(2(R1, R2, R3, R4, R5-phenyl)amine)-2-oxoethyl))diacetic acid of the formula (I), in which R1, R2, R3, R4 and R5 are the same or different and stand for 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 including an atom of oxygen or an atom of nitrogen or an atom of sulphur, characterized in that hexahydrous gadolinium chloride is exposed to reaction with lithium salt of derivatives of 2,2'-(2-(R1, R2, R3, R4, R5-phenyl)amine)-2-oxoethyl)) diacetic acid in the medium of aliphatic alcohol, aliphatic amine, aromatic amine, dimethylsulfoxide (DMSO), dimethylformemide (DMF) at the temperature 60 °C, providing that the mole ratio of the reagents is 1:2, and next the obtained lithium salt of gadolinium complex is transformed into sodium salt which is purified by a known method. The new compounds can be applied as contrast media for non-invasive diagnostic technique, in medical imaging as for instance nuclear resonance for interior organs particularly liver.

Description

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 R_{l 5}R₂,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%.

R_f (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%)

Claims

1. New complexes of Gd⁺³ gadolinium ions with derivatives of 2,2'-(2-(R_{l 5}R₂,R₃,R₄,R₅-phenyl)amine)-2-oxoethyl))acetic acid of the formula I, in which Ri, R₂, R₃, R₄ and R₅ are the same or different and they stand for 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 including an atom of oxygen, an atom of nitrogen or an atom of sulphur.

2. Method for obtaining new complexes of Gd gadolinium ions with derivatives of 2,2'-(2-(R_{l 5}R₂,R₃,R₄,R₅-phenyl)amine)-2- oxoethyl))diacetic acid of the formula I, in which Ri, R₂, R₃, R₄ and R₅ are the same or different and they stand for an atom 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 including an atom of oxygen or an atom of nitrogen or an atom of sulphur, characterised in that hexahydrous gadolinium chloride is exposed to a reaction with lithium salt of derivatives of 2,2' -(2- (Rι ,R₂,R ,R₄,R₅-phenyl)amine)-2-oxoethyl))diacetic acid in the medium of aliphatic alcohol, aliphatic amine, aromatic amine, dimethylsulfoxide (DMSO), dimethylformamide (DMF) at the temperature of 60°C, providing that the mole ratio of the reagents is 1 :2, next lithium salt of gadolinium complex is transformed into sodium salt which is purified by a known method.