ES2253114B1 - HETEROCICLIC LINKS AND THEIR GADOLIN COMPLEX (III) WITH BIOMEDICAL APPLICATIONS. - Google Patents

Abstract

Compounds of General Formula A and B whose paramagnetic complexes of lanthanides can be used as contrast agents for Magnetic Resonance Imaging. Compounds of General Formula A and B wherein R {sub, 1} and R {sub, 2} are hydrogens; attractor substituents or electron donors. An experimental procedure for obtaining these compounds from the corresponding bromoethylpyrazoles, which involves the following steps: Compounds A, 1) alkylation of the starting amine; 2) deprotection of tert-butoxycarbonylamino groups; 3) alkylation of the amino groups with methyl bromoacetate and finally, 4) the basic hydrolysis leading to the tetrasodium salt. Compounds B, 1) cyclone monoalkylation; 2) alkylation of the rest of the amino groups with methyl bromoacetate and finally, 4) the basic hydrolysis leading to the trisodium salt. The experimental and clinical use of the corresponding complexes in the clinical diagnosis by image.

Description

Heterocyclic ligands and their complexes gadolinium (III) with biomedical applications.

Technical Field of the Invention

The synthesis and characterization of a series of ligands with pyrazolylethyl groups of General Formula A as indicated below:

one

A new series of complexes of Gd (III) and other lanthanides derived from structure A that They are used as contrast agents for Resonance Imaging Magnetic (MRI).

Prior art

The great differentiation and spatial resolution of Soft tissue has made Magnetic Resonance Imaging (MRI) is one of the most used techniques in diagnosis clinical.

The main determinants of contrast in an MR image is the relaxation times of the protons of the water, T1 and T2. So, when the contrast difference between healthy and pathological regions of a tissue is very small, due to small variations in relaxation times, the use of contrast agents is highly beneficial. The agents of contrast are substances capable of significantly altering the relaxation times of water protons in tissues in Where they are distributed. The use of these agents is a great improvement in clinical diagnosis in terms of high specificity, better tissue characterization, reduction of artifacts in the image and functional information thereof. The agents of most commonly used contrast are paramagnetic chelates of gadolinium Their effectiveness in acting as an agent of contrast is valued, first, by the determination of its relaxativity, that is, by increasing the relaxation of water protons

In the last 15 years, they have been published numerous articles aimed at the study of structure and dynamics of the complexes of Gd (III), which has meant a great advance in the understanding of structural parameters, dynamic and electronic determinants in the relaxation of these complex. The early diagnosis of cancer and diseases vascular, together with the follow-up of an effective therapy, can be made using new probes capable of informing us about specific events that occur both on a cellular level as molecular Therefore, contrast agents can be considered as substances capable of giving information about biological environment of tissues.

The most commonly used contrast agents in Diagnostic imaging are gadolinium complexes derived from diethylenetriaminepentaacetic acid (DTPA) and acid 1,4,7,10-tetraaza-1,4,7,10-cyclododecanotetraacetic acid (DOTA).

2

Currently, research in this field is focused on the design and synthesis of new chelating agents that have a high affinity for the corresponding paramagnetic metal, as well as high relajativity. In this sense, a family of ligands that include pyrazolic rings and an iminodiacetic acid unit, with affinity for the Gd (III) ion (Ballesteros García, Paloma et al ., Complexons with the structure of N- [2- [ azol-1 (2) -yl] ethyl] iminodiacetic acids, synthesis, analytical study, and biological applications. PCT Int. Appl. (1996), 43, WO9641797; P. López et al , N-2- (Azol-1 (2) -yl) ethyliminodiacetic acids: a novel series of Gd (III) chelators as T2 relaxation agents for magnetic resonance imaging. Bioorg. Med. Chem ., 1999 , 7 , 517). These chelating agents have low affinity for the gadolinium ion but nevertheless, they have relaxation properties superior to that of the commercial complexes used in the clinic. Recently a new series of mixed ligands with bi- or bispyrazole structure (P. Ballesteros and S. Cerdán, New Gd (III) Ligands with bi- and bis-azolic structures has been described. PCT Int. Appl., WO 0259097 , 2002; E. Pérez Mayoral et al . A novel series of complexones with bis- or biazole structure as mixed ligands of paramagnetic contrast agents for MRI. Bioorg. Med. Chem ., 2003 , 11 , 5555). In this case, the stability constant with the metal has been slightly improved although equally low, because these compounds form double complexes tetradentated with the metal. However, as in the previous cases, they have relaxation properties (r1 and r2) that are far superior to those described for low molecular weight complexes. The magnetic properties of these complexes represent a great advance, with respect to commercial complexes, in terms of effectiveness as contrast agents. However, they have a low affinity with Gd (III), which means that they cannot be used for diagnostic purposes due to their toxicity. In principle, this improvement in relaxation properties could be due, in addition to a high hydration number, to the incorporation of azoles in the structure of these ligands. For this reason, this series presents a series of new organic ligands and their Gd (III) complexes that have a greater stability constant with the metal ion and therefore less
toxicity.

Detailed description of the invention

This invention presents a new family of pyrazolylethyldiethylenetriaminetetraacetic acids (A) and their synthesis, with the General Formula indicated below:

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3

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A magnetic resonance study is presented (RM) detailed that allows to calculate some of the parameters that govern the behavior of their Gd (III) complexes in dissolution. The analysis of the results allows establishing the participation of the azol in the complexation with the center metal.

This Report describes, as an example, the synthesis of ligands 1-4 (figure 1).

4

Compounds 1-3 have been synthesized from bis ( tert -butoxycarbonylamino) diethylenetriamine (5) as indicated in scheme 1. Alkylation of 5 with the corresponding bromoethylpyrazole 6 leads to amines 7, which by treatment in acidic medium and subsequent alkylation with methyl bromoacetate gives rise to the amino esters 8. Finally, the basic hydrolysis of 8 leads to the ligands object of the invention. The alkylating agents 6 are obtained from the corresponding pyrazole by reaction with 1,2-dibromoethane under phase transfer conditions.

Scheme one

5

Ligand 4 is synthesized by reduction of corresponding nitro-derivative 8c, using Pd over C as catalyst and ammonium formate as a hydrogen donor (scheme 2).

Scheme 2

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6

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Gadolinium complexes are obtained by reaction between equimolecular amounts of GdCl3 \ cdot6H2O and the corresponding organic ligand in aqueous solution at 80 ° C.

Synthesis of compounds 7

Process TO

A mixture of 1 equivalent of the corresponding Bromoethylpyrazole 6 and 2 equivalents of amine 5 is heated to 80 ° C for 15 h. The reaction mixture is allowed to cool and it is add 10 mL of CH2Cl2. Then the solid formed and the solvent is removed under reduced pressure.

Process B

A mixture of 1 equivalent of the corresponding Bromoethylpyrazole 6, 1 equivalent of amine 5 and 1 equivalent of NaHCO 3 or Na 2 CO 3 in acetonitrile (20-30 mL), heated to reflux until total reaction evolution. The reaction mixture is allowed to cool, the solid formed is filtered and the solvent is removed under pressure reduced The reaction crude is purified by chromatography on column on silica gel.

{2 - [(2- tert- Butoxycarbonylaminoethyl) - (2-pyrazol-1-yl-ethyl) amino] ethyl} carbamic acid tert -butyl ester (7a)

Procedure B: 1- (2-Bromoethyl) 1- H -pyrazol (6a) (613 mg; 3.5 mmol) and the amine 5 (1.06 g; 3.5 mmol) and NaHCO 3 (294 mg; 3.5 mmol) are used . 7a (940 mg; 68%) is obtained in the form of a yellow oil; IR (ATR): 33 3337, 1697, 1514, 1170 cm -1; 1 H-NMR (400 MHz, CDCl 3): δ 7.55 (1 H, d, J = 1.2 Hz, H 3), 7.46 (1 H, wide s, H 5) , 6.26 (1 H, wide s, H 4), 5.03 (2 H, wide s NH-BOC), 4.14 (2 H, t, J = 5.6 Hz, CH 2 -N (azol)), 2.99 (4 H, m, C H 2 -NH-BOC), 2.84 (2 H, apparent t, J = 5.6, 5.3 Hz, NC H 2), 2.51 (4 H, t J = 5.6 Hz, C H 2 -N), 1.45 (18 H, s, CH 3) ppm; 13 C-NMR (100 MHz, CDCl 3): δ 156.0, 139.5, 129.8, 105.3, 78.8, 54.0, 53.1, 50.2, 38.1, 28.3 ppm;

(2 - {(2- tert -Butoxycarbonylaminoethyl) - [2- (3,5-dimethylpyrazol-1-yl) -ethyl] amino} ethyl) carbamic acid tert -butyl ester (7b)

Procedure A: 2-Bromoethyl-3,5-dimethylpyrazole (6b) (345 mg; 1.7 mmol) and the amine 5 (1 g; 3.3 mmol) are used. 7b (700 mg; 97%) is obtained as a white solid (mp 106-108 ° C H / EtOH); IR (ATR): 33 3396, 3264, 1698, 1505, 1458, 1249, 1164 cm -1; 1 H-NMR (400 MHz, CDCl 3): δ 5.81 (1 H, s, H 4), 5.29 (2 H, wide s, NH-BOC), 3.99 (2 H, apparent t, J = 5.6, 5.5 Hz, CH 2 -N (azol)), 3.01 (4 H, m, C H 2 -NH-BOC), 2.73 (2 H, t, J = 5.5 Hz, CH 2 -N), 2.52 (4 H, apparent t, J = 5.6, 5.3 Hz, CH 2 -N), 2.26 (3 H, s, CH 3), 2.23 (3 H , s, CH 3), 1.49 (18 H, s, CH 3) ppm; 13 C-NMR (100 MHz, CDCl 3): δ 156.2, 138.5, 105.1, 78.7, 53.6, 46.6, 38.5, 28.4, 13.3, 10.9 ppm; Anal. Calcdo for C_ {21} H_ {39} N_ {5} {4}: C 59.27, H 9.24, N 16.46. Found C 59.30, H 9.00, N 16.46.

Acid tert-butyl ester (2 - {(2- tert - butoxycarbonylaminoethyl) - [2- (3-nitropyrazol-1-yl) ethyl] amino} ethyl) ester (7c)

Procedure B: 1- (2-Bromoethyl) -3-nitro-1 H -pyrazol (6c) (700 mg; 3.18 mmol) and amine 5 (964 mg; 3.18 mmol) and NaHCO3 (267 mg) are used ; 3.18 mmol). 7c (700 mg; 50%) is obtained in the form of a yellow oil; IR (ATR): 33 3343, 1687, 1504, 1164 cm -1; 1 H-NMR (400 MHz, CDCl 3): δ 7.58 (1 H, d, J = 2.4 Hz, H 5), 6.87 (1 H, d, J = 2.4 Hz, H_ {4}), 4.77 (2 H, wide s, NH), 4.22 (2 H, t, J = 5.6 Hz, CH2 -N (azol)), 3.07 (4 H, m, CH2} NH-BOC), 2.95 (2 H, t, J = 5.6 Hz, CH 2 -N), 2.56 (4 H, t, J = 5.9 Hz, N-CH 2), 1.44 (18 H, s, CH 3) ppm; 13 C-NMR (100 MHz, CDCl 3): δ 155.9, 132.9, 102.5, 79.3, 53.7, 52.1, 38.3, 28.3 ppm;

Synthesis of compounds 8

General procedure : A solution of the corresponding carbamate 7 in HCl / MeOH (6N) is kept under stirring at room temperature for 1 h. The solvent is then removed under reduced pressure to obtain a residue in the form of a white solid. Then, the solid residue obtained together with 4.4 equivalents of methyl bromoacetate, 8-9 equivalents of K 2 CO 3 in acetonitrile, is heated at reflux until the total disappearance of the starting product. Then, it is allowed to cool, the formed salts are filtered and the solvent is removed under reduced pressure. The reaction crude is purified by column chromatography on silica gel.

Acid methyl ester [(2 - {[2- (bis-methoxycarbonylmethylamino) ethyl] - [2-pyrazol-1-yl) ethyl] -amino} ethyl) methoxycarbonylmethylamino] acetic acid (8a)

Following the general procedure 7a (0.9 g; 2.27 mmol), HCl / MeOH (25 mL) is used. Then, the solid obtained together with methyl bromoacetate (1.53 g; 10 mmol) K 2 CO 3 (18.2 g; 2.5 mmol) in acetonitrile (30 mL) is refluxed for 7 h. The ester 8a (814 mg; 74%; CH2Cl2 / EtOH 98: 2) is obtained as a yellow oil; IR (ATR): 17 1748, 1737, 1204 cm -1; 1 H-NMR (400 MHz, CDCl 3): δ 7.46 (2 H, wide s, H 3 and H 5), 6.17 (1 H, wide s, H 4 ), 4.18 (2 H, m, CH 2 -N (azol)), 3.68 (12 H, s, OCH 3), 3.5 (8 H, s, CH 2 CO 2 Me) , 2.90 (2 H, m, CH 2 -N), 2.71 (4 H, m, NC H 2 CH 2 -N), 2.59 (4 H, m, N-CH 2 C H2 -N) ppm; 13 C-NMR (100 MHz, CDCl 3): δ 171.5, 139.1, 129.9, 104.9, 55.1, 54.6, 53.3, 52.1, 51.4 ppm.

Acid methyl ester [(2 - {[2- (bis-methoxycarbonylmethylamino) ethyl] - [2- (3,5-dimethylpyrazol-1-yl) ethyl] amino} ethyl) methoxycarbonylmethylamino] acetic (8b)

Following the general procedure, 7b (800 mg; 1.88 mmol) and HCl / MeOH (10 mL) are used. Then, the solid obtained together with methyl bromoacetate (1.44 g; 9.4 mmol) K 2 CO 3 (2.6 g; 18.8 mmol) in acetonitrile (30 mL) is refluxed for 17 h. The ester 8b (817 mg; 85%; CH2Cl2 / EtOH 95: 5) is obtained as a yellow oil; IR (ATR): 17 1733, 1434, 1198, 1174, 881 cm -1; 1 H-NMR (400 MHz, CDCl 3): δ 5.71 (1 H, s, H 4), 3.96 (2 H, apparent t, J = 6.8, 6.7 Hz, CH 2 } -N (azol)), 3.68 (12 H, s, OCH 3), 3.51 (8 H, s, CH 2 CO 2 Me), 2.33 (2 H, apparent t, J = 6.6 , 6.5 Hz, CH 2 -N), 2.72 (4 H, m, NC H 2 CH 2 -N), 2.58 (4 H, m, N-CH 2 C H 2 -N), 2.20 (3 H, s, CH 3), 2.17 (3 H, s, CH 3) ppm;
13 C-NMR (100 MHz, CDCl 3): δ 171.5, 147.2, 139.0, 104.6, 55.0, 54.5, 53.3, 52.2, 51.3, 47.1, 13.3, 10.9 ppm.

Acid methyl ester [(2 - {[2- (bis-methoxycarbonylmethylamino) ethyl] - [2- (3-nitro-pyrazol-1-yl) -ethyl] amino} ethyl) methoxycarbonylmethylamino] acetic acid (8c)

Following the general procedure, 7c (1.1 g; 2.5 mmol), HCl / MeOH (30 mL) is used. Then, the solid obtained together with methyl bromoacetate (1.68 g; 11 mmol) K2CO3 (3.1 g; 22.5 mmol) in acetonitrile (30 mL) is refluxed for 18 h. The ester 8c (1.25 g; 94%; CH2Cl2 / EtOH 98: 2) is obtained as a yellow oil; IR (ATR): 17 1734, 1199, 1177, 1129 cm -1; 1 H-NMR (400 MHz, CDCl 3): δ 7.3 (1 H, d, J = 2.4 Hz, H 5), 6.82 (1 H, d, J = 2.4 Hz, H_ {4}), 4.29 (2 H, t, J = 5.9 Hz, CH 2 -N (azol)), 3.68 (12 H, s, OCH 3), 3.48 (8 H, s, C H 2 CO 2 Me), 2.96 (2 H, t, J = 5.9 Hz, CH 2 -N), 2.68 (4 H, m, NC H 2 CH 2 -N ), 2.58 (4 H, m, N-CH 2 C H 2 -N) ppm; 13 C-NMR (100 MHz, CDCl 3): δ 171.5, 155.7, 133.9, 102.1, 54.9, 54.1, 53.4, 52.2, 52.0, 51.4 ppm.

Acid methyl ester [(2 - {[2- (3-aminopyrazol-1-yl) -ethyl] - [2- (bis-methoxycarbonylmethylamino) ethyl] amino} ethyl) methoxycarbonylmethylamino] acetic acid  (8d)

To a solution of the ester 8c (0.4 g; 0.75 mmol) in MeOH (15 mL) is added ammonium formate (200 mg; 3.23 mmol) and Pd / C (5%, 400 mg) and the reaction mixture is maintained at room temperature for 48 h. The catalyst is then removed by filtering on celite and the solvent is removed under reduced pressure. The reaction product is purified by column chromatography on silica gel (EtOH / NEt3 98: 2) to obtain the 8d ester (205 mg; 55%;) as a yellow oil; IR (ATR): 33 3354, 3208, 1735, 1203, 1177, 1136 cm -1; 1 H-NMR (400 MHz, DMSO- d 6): δ 7.26, (1 H, d, J = 2.4 Hz, H 4), 5.33 (1 H, d, J = 2.4 Hz, H 5), 3.87 (2 H, t, J = 6.2 Hz, CH 2 -N (azol)), 3.59 (12 H, s, OCH 3), 3.49 (8 H, s, C H 2 CO 2 Me), 2.81 (4 H, m, NC H 2 CH 2 -N), 2.68 (2 H, t, J = 6.2 Hz, CH_ 2 -N), 2.58 (4 H, m, N-CH 2 C H 2 -N) ppm; 13 C-NMR (100 MHz, CDCl 3): δ 171.3, 155.1, 130.5, 91.3, 54.6, 54.0, 52.5, 51.5, 51.0, 49.0
ppm.

Synthesis of compounds 1-4

General procedure : A suspension of one equivalent of the corresponding ester 8 together with 4 equivalents of NaOH in distilled H2O (0.6%) is maintained with stirring at room temperature until the total disappearance of the starting compound. The reaction mixture is then washed with CH 2 Cl 2 and the solvent is removed under reduced pressure.

Tetrasodium acid salt [(2 - {[2- (bis-methoxycarbonylmethylamino) ethyl] - [2-pyrazol-1-yl) ethyl] -amino} ethyl) methoxycarbonylmethylamino] acetic acid (one)

Following the general procedure, 8a (440 mg; 0.91 mmol) and NaOH (146 mg; 3.64 mmol) are used. 1 (462 mg, 98%) is obtained as a yellow solid; IR (ATR): 15 1574, 1401, 1330 cm -1; 1 H-NMR (400 MHz, D 2 O): δ 7.63 (1 H, d, J = 2.04 Hz, H 3), 7.53 (1 H, d, J = 1.76 Hz, H 5), 6.28 (1 H, apparent t, J = 2.08, 2.04 Hz, H 4), 4.21 (2 H, t,
J = 6.4 Hz, CH 2 -N (azol)), 3.10 (8 H, s, CH 2 CO 2 Na), 2.91 (2 H, t, J = 6.4 Hz, CH 2 -N), 2.56 (8 H, m, N-CH 2 CH 2 -N) ppm; 13 C-NMR (100 MHz, D 2 O): δ 178.4, 138.8, 130.6, 104.9, 57.8, 51.9, 50.4, 50.2, 47.8 ppm

Tetrasodium acid salt [(2 - {[2- (bis-carboxymethylamino) ethyl] - [2- (3,5-dimethylpyrazol-1-yl) ethyl] amino} ethyl) carboxymethylamino] acetic acid (2)

Following the general procedure, 8b (696 mg; 1.36 mmol) and NaOH (218 mg; 5.44 mmol) are used. 2 (662 mg, 89%) is obtained as a yellow solid; IR (ATR): 15 1579, 1404, 1103 cm -1; 1 H-NMR (400 MHz, D 2 O): δ 5.86 (1 H, s, H 4), 4.02 (2 H, apparent t, J = 7.1, 7.0 Hz, CH_ { 2} -N (azol)), 3.12 (8 H, s, CH 2 CO 2 Me), 2.80 (2 H, apparent t, J = 7.1, 7.0 Hz, CH 2 -N), 2.61 (8 H, m, N-CH 2 CH 2 -N), 2.20 (3 H, s, CH 3), 2.09 (3 H, s, CH 3) ppm; 13 C-NMR (100 MHz, D 2 O): δ 176.7, 148.0, 140.8, 57.4, 51.5, 50.3, 49.9, 44.4, 11.2, 9.4 ppm.

Tetrasodium acid acid salt [(2 - {[2- (bis-methoxycarbonylmethylamino) ethyl] - [2- (3-nitro-pyrazol-1-yl) -ethyl] amino} ethyl) methoxycarbonylmethylamino] acetic acid (3)

Following the general procedure, 8c (180 mg; 0.34 mmol) and NaOH (54 mg; 1.36 mmol) are used. 3 (158 mg, 93%) is obtained as a yellow solid; IR (ATR): 15 1578, 1404, 1329 cm -1; 1 H-NMR (400 MHz, D 2 O): δ 7.79 (1 H, d, J = 2.32 Hz, H 5), 6.95 (1 H, d, J = 2.6 Hz, H 4) ), 4.31 (2 H, apparent t, J = 6.5, 6.4 Hz, CH 2 -N (azol)), 3.11 (8 H, s, CH 2 CO 2 Na), 3.00 (2 H , apparent t, J = 6.5, 6.4 Hz, CH 2 -N), 2.62 (8 H, m, N-CH 2 CH 2 -N) ppm; 13 C-NMR (100 MHz, D 2 O): δ 180.3, 156.1, 135.5, 104.1, 59.7, 53.5, 52.3, 52.1, 51.5 ppm.

Tetrasodium acid salt [(2 - {[2- (3-aminopyrazol-1-yl) -ethyl] - [2- (bis-methoxycarbonylmethylamino) ethyl] amino} ethyl) methoxycarbonylmethylamino] acetic acid  (4)

Following the general procedure, 8d (180 mg; 0.36 mmol) and NaOH (58 mg; 1.44 mmol) are used. 4 (187 mg, 97%) is obtained as a yellow solid; IR (ATR): 15 1578, 1404, 1329, 1113 cm -1; 1 H-NMR (400 MHz, D 2 O): δ 7.35 (1 H, d, J = 2.4 Hz, H 4), 5.63 (1 H, d, J = 2.4 Hz, H 5), 3.98 (2 H, apparent t, J = 6.5, 6.4 Hz, CH 2 -N (azol)), 3.11 (8 H, s, CH 2 CO 2 Na), 2.84 (2 H, apparent t, J = 6.5, 6.4 Hz, CH 2 -N), 2.57 (8 H, m, N-CH 2 CH 2 -N) ppm; 13 C-NMR (100 MHz, D 2 O): δ 180.3, 155.4, 134.12, 94.4, 59.6, 53.6, 52.4, 52.1, 49.6 ppm.

General procedure for the synthesis of the Gd (III) complexes of ligands 1-4 : A solution of an equivalent of the corresponding tetrasodium salt 1-4 and an equivalent of GdCl 3 • 6 H 2 O in 5 mL of water (MQ) at pH ~ 5-7, heated at 80 ° C for 4 h. It is then allowed to cool and the solvent is removed under reduced pressure.

MRI study: relaxivity

Magnetic Resonance studies that are presented in this invention have been performed on a spectrometer of 60 MHz (1.5 T). The longitudinal relaxation times and transverse have been measured at a concentration of 1 mM ligand organic 1-4 or the corresponding complex of Gd (III), 150 mM NaCl (phonic force) and 100 mM TRIS / HCl using water (MQ) as a solvent, at different temperatures and pH

The relaxivity has been calculated according to the equation represented below:

r_ {1 (2)} = \ Delta [1 / T_ {1 (2)}] / [LGd]

where, r_ {1 (2)} is the longitudinal (transversal) relaxivity, Δ [1 / T_ {1 (2)}] is the difference between the inverse of the Longitudinal (transverse) relaxation times of corresponding complex of Gd (III) and ligand and, [LGd] is the concentration of the complex of Gd (III) used (equal at the concentration of ligand).

Table 1 shows the values of T_ {1 (2)} and r_ {1 (2)} of the synthesized complexes at T 25 ° C and pH 7 7.

Complex T_ {1} (s) T_ {2} (s) R 1 (mM-1 s-1) R2 (mM <-1> s <-1>) 1-Gd (III) 0.20 0.17 4.60 ± 0.01 5.20 ± pm 0.01 2-Gd (III) 0.15 0.14 6.36 ± 0.01 6.70 ± 0.02 3-Gd (III) 0.27 0.22 3.41 ± 0.01 4.00 ± pm 0.01 4-Gd (III) 0.16 0.14 5.72 ± 0.01 6.65 ± 0.02 DTPA-Gd 0.20 0.18 4.62 ± 0.01 5.15 ± 0.01  \ begin {minipage} [t] {160mm} T_ {1}: inversion-recovery sequence. T_ {2}: sequence of Carr-Purcell-Maiboom-Gill, both in a 60 MHz spectrometer (1.5 Tesla). \ end {minipage}

The present invention includes the graphs in which the dependence of r_ {1 (2)} with temperature and pH.

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Figure 2

Variation of the relaxivity r_ {1 (2)} with the temperature. 1 mM solutions of the ligand (complex), 150 mM NaCl and 100 mM TRIS / HCl

Figure 2 shows the variation of both r1 and r2 with the temperature at a pH of approximately 7. It is observed that the relaxivity increases as the temperature drops, this behavior being typical of complexes derived from polyamopolopolycarboxylic acids with a molecule of water in its first sphere of coordination. According to the Theory of relaxivity and according to the equations of Solomon-Bloembergen and Morgan it can happen that: a) the relaxation time of the water protons of the first coordination sphere (T_ {1 (2) M}) is less than the residence time of the water molecule (\ tau_ {M}) so that the relaxivity decreases when the temperature drops, or on the contrary, b) that T_ {1 (2) M} is greater than \ tau_ {M } increasing relaxivity by decreasing temperature. This last case is the one that justifies the increase of r1 (2) at low temperatures in the complexes presented in this invention.
tion.

Equations of Solomon-Bloembergen and Morgan:

r1 (2) = q /55\text{.}5 (T_ {1 (2) (M)} + \ tau_ {M})

1 / T_ {1 (2) M} = k / r 6 f (\ tau_ {c})

where, q is the number of hydration of the complex, T_ {1 (2) M} is the time of  longitudinal (transverse) relaxation of the water molecule directly attached to the metal, \ tau_ {M} is the time of water residence in the first sphere of coordination with the metal, K is a constant, r is the distance between the protons of the water and metal and finally, \ tau_ {c} is the time of correlation cash.

8

Figure 3

Variation of relaxivity with pH. 1 mM solutions of ligand (complex), 150 mM NaCl and 100 mM TRIS / HCl

Figure 3 represents the variation of r1 (2) with the pH measured at 60 MHz and 37 ° C and it is observed that, while the relaxivity of DTPA-Gd (III) stays constant in a pH range of 9 to about 4.5, the relaxivity of the complexes presented in the invention It is pH dependent. In the case of 2-Gd (III), r1 (2) increases at acidic pHs while in 1-Gd (III) and 3-4-Gd (III) r1 (2) It decreases to basic pHs. In the complexes 1-4-Gd (III) the value of both r1 as r2 is greater than or equal to that observed for DTPA-Gd, except for 3-Gd (III), in a pH range close to physiological pH That is why these complexes meet one of the requirements essential for use as image contrast agents diagnostic.

Considering the resonance study magnetic detailed above, the complexes 2-Gd (III) and 4-Gd (III) of the invention have greater efficacy than DTPA-Gd (III) (commercial complex currently used in clinical diagnosis) while, 1-Gd (III) shows the same efficacy. Without However, the 3-Gd (III) complex has a lower efficiency It should be noted that 4-Gd (III), more effectively than DTPA-Gd (III) as already mentioned, is obtained from organic ligand 8c, precursor of 3, so that the synthesis and study of 3-Gd (III) They are justified.

Claims (14)

1. A compound of General Formula A, 9 Where the radicals R_ {1} and R2_ are hydrogens, methyl groups, nitro groups and amino groups, and X is hydrogen, alkaline ions I N-methylglucosamine and, whose complexes of Gd (III) and other lanthanides are used as contrast agents for Magnetic Resonance Imaging (MRI) 2. The compound of claim 1 wherein the radicals R 1 and R 2 are hydrogens. 3. The compound of claim 1 wherein the radicals R 1 and R 2 are methyl groups. 4. The compound of claim 1 wherein the radical R 1 is a nitro group and R 2 is a hydrogen. 5. The compound of claim 1 wherein the radical R 1 is an amino group and R 2 is a hydrogen. 6. A process for obtaining the compounds of General Formula A of claim 1 wherein part of the corresponding bromoethylpyrazoles, previously synthesized, and involving the steps indicated below: 1) alkylation in the central nitrogen of protected diethylenetriamine; 2) deprotection of tert -butoxycarbonylamino (BOC) groups in acidic medium; 3) alkylation of the terminal amino groups with methyl bromoacetate in basic medium and finally, 4) the basic hydrolysis of the methyl esters to obtain the tetrasodium salt. 7. The complexes of Gd (III) of the compounds of claim 1 wherein the radicals R1 and R2 are hydrogens, methyl groups, nitro groups and groups Not me. 8. The Gd (III) complex of the compound of claim 2 wherein the radicals R1 and R2 are hydrogens 9. The Gd (III) complex of the compound of claim 3 wherein the radicals R1 and R2 are methyl groups 10. The Gd (III) complex of the compound of claim 4 wherein the radical R1 is a group nitro and R2 is a hydrogen. 11. The Gd (III) complex of the compound of claim 5 wherein the radical R1 is a group amino and R2 is a hydrogen. 12. The synthesis of paramagnetic complexes of Gd (III), and other lanthanides, of the ligands of the claim 1 to 5 by a single synthetic step, which consists of reacting equimolecular amounts of the ligand organic and the corresponding lanthanide chloride in water deionized (MQ) at 80 ° C. 13. The use of the compounds of the claim 1 to 5 in the manufacture of contrast agents for Magnetic Resonance in clinical diagnosis. 14. The use of the complexes of the claim 7 to 11 in the manufacture of contrast agents for Resonance Magnetic in clinical diagnosis.