WO1994001406A1

WO1994001406A1 - Contrast agents for mr diagnosis

Info

Publication number: WO1994001406A1
Application number: PCT/EP1993/001698
Authority: WO
Inventors: Bernhard Kohl; Rolf-Peter Hummel; Klaus-Peter Lodemann; Klaus-Dieter Beller; Hildegard Boss
Original assignee: Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority date: 1992-07-01
Filing date: 1993-07-01
Publication date: 1994-01-20
Also published as: JPH07508527A; EP0648209A1; AU4562693A

Abstract

Complexing agents of general formula (I) in which R1, R2, R3 and R4 are the same or different and stand for H, COOH, C(O)NHR5, where R5 is H and C1-C4 alkyl, PO3H2, SO3H and a radical of general formula (IIa) or (IIb) in which R6 and R7 in general formula (IIa) are the same or different and signify H, methyl and benzyl, R7 in general formula (IIb) is methyl and benzyl, and R8 is H or C1-C4 alkyl, with the proviso that at least one of the radicals R1, R2, R3 and R4 is a radical of general formula (IIa) or (IIb), X is a single bond and NR9, where R9 is H, C1-C4 alkyl and (CH2)nR1; n, q are 1 or 2 and n and q are the same or different, p is 1 or 2 but not 1 if X is NR9, and their salts with organic and inorganic bases and acids are suitable for producing paramagnetic complexes which can advantageously be used as a contrast agent for MR diagnosis.

Description

CONTRAST AGENTS FOR MR DIAGNOSTICS

Technical field

The invention relates to new complexing agents.

State of the art

It is known to use paramagnetic metal complex compounds for contrast enhancement in MR diagnostics. Solutions of a gadolinium (III) complex with the complexing agent diethylenetriaminepentaacetic acid [Gd (DTPA)] have already proven themselves in practice as MR contrast agents.

From G. J. Kontoghiorghes, Inorg. Chim. Acta 135 [1987] 145-150, and C. Hershko, Brit. Med. J. 295 [1988] 1081, it is known that certain hydroxypyridones are suitable for forming stable complexes with iron (III) ions and can therefore be administered orally when used to eliminate excess iron from the human body.

M. Streater et al., J. Med. Chem. 33 [1990] 1749-1755, described the hexidentate complexing agents N, N, N-tris- [2- (3-hydroxy-2-oxo-l, 2- dihydropyridin-1-yl) acetamido] alkylamines and their complexes with iron (III). The complexing agents are said to be suitable for removing iron from iron overloaded patients.

From EP-A-0290047 manganese (II) complexes with N, N'-bis (pyridoxal-5-phosphate) -α, ω- (alkylene) diamine-N, N'-acetic acids are known, which are known as MR contrast agents are said to be suitable.

The object of the present invention is to provide new complexing agents whose complexes with paramagnetic metal ions are characterized by high complex stability, good solubility in water at physiological pH values, strong relaxivity and by a pronounced organ specificity combined with reduced side effects and faster out Mark divorce.

Description of the invention

The invention relates to complexing agents of the general formula I,

wherein

R1, R2, R3 and R4 are the same or different and are H, COOH, C (O) NHR5, where R5 is H and C1-C4-alkyl,

PO ₃ H ₂ , SO ₃ H and a radical of the general formulas Ila or IIb

,,,

in which

R6 and R7 in the general formula Ila are identical or different and are H, methyl and benzyl,

R7 in the general formula Ilb denotes methyl and benzyl, and

R8 denotes H or C1-C4-alkyl,

with the proviso that at least one of the radicals R1, R2, R3 and R4 represents a radical of the general formulas Ila or Ilb,

X for a single bond and NR9,

in which

R9 denotes H, C1-C4-alkyl and (CH ₂ ) _n R1,

n, q for 1 or 2, where n and q are the same or different, and

p for 1 or 2, but not for 1 if X is NR9 9at,

stand, and their salts with organic and inorganic bases and acids. A preferred subject of the invention are complexing agents of the general formula I above,

in which

R1, R2, R3 and R4 are the same or different and for COOH, C (O) NHR5,

in which

R5 denotes H, methyl and ethyl, and a radical of the general

Formula Ila,

in which

R6 and R7 are the same or different and are H and methyl,

with the proviso that at least one of the radicals R1, R2, R3 and R4 is a radical of the general formula Ila,

X for a single bond and NR9,

in which

R9 (CH ₂ ) _n R1 means

n, q for 1 and

p for 1 and 2, but not for 1 if X is NR9,

stand, and their salts with organic and inorganic bases and acids.

A particularly preferred object of the invention are complexing agents of the above general formula I,

wherein

R1, R2, R3 and R4 are the same or different and are for COOH and a radical of the general formula Ila,

in which

R6 and R7 are the same or different and are H and methyl,

X for a single bond,

n, q and stand for 1,

and their salts with organic and inorganic bases and acids.

An equally preferred subject of the invention are complexing agents of the general formula 1 above, wherein

in which

R6 and R7 are the same or different and are H and methyl, with the proviso that at least one of the radicals R1, R2, R3 and R4 is a radical of the general formula Ila,

X for NR9, where R9 is (CH ₂ ) _n R1,

n and q for 1 and

p for 2

stand,

and their salts with organic and inorganic bases and acids.

Particularly preferred complexing agents are N, N'-bis - [(3-hydroxy-4-methoxypyridin-2-yl) methyl] ethylenediamine-N, N'-diacetic acid, N, N "- bis - [(3-hydroxy- 4-methoxypyridin-2-yl) methyl] diethylenetriamine-N, N ', N' '- tri-acetic acid, N' - [(3¬-hydroxy-4-methoxypyridin-2-yl) methyl] diethylenetriamine-N, N, N ' ', N' '- tetraacetic acid N, N "-bis - [(3,4-dimethoxy-2-pyridinyl) methyl] diethylenetriamine¬N, N', N" -triacetic acid, N '- [3,4-dimethoxy- 2-pyridinyl) methyl] diethylenetriamine-N, N, N ", N" -tetraacetic acid and their salts with organic and inorganic bases and acids. The sodium salts or hydrochlorides and hydrobromides are preferred.

The invention also relates to a process for the preparation of the complexing agents of the general formula I, which is characterized in that a compound of the general formula I in which the 3-hydroxy-4-methoxypyridin-2-yl radicals are substituted by 3-hydroxy -4-methoxypyridin-2-yl radicals, the hydroxyl groups of which are protected by protective groups which are customary for hydroxyl groups, preferably benzyl and methyl, are reacted under conditions which selectively remove protective groups.

The complexing agents according to the invention can be prepared starting from the corresponding 3,4-bis-hydroxypyridine-2-aldehydes, in which the hydroxy groups which are to be retained in the end product of the formula I are protected by suitable protective groups, for example methyl or, in particular, benzyl . By implementation for the condensation of aldehyde Groups with usual amine conditions with the corresponding alkylenediamines or dialkylenetriamines and subsequent reduction give OH-protected 3,4-bishydroxy-2-pyridylamines. These are reacted with corresponding ω-halogen, preferably ω-bromo, - (CH ₂ ) _n -R1 compounds. For the production of complexing agents, in which R1 is COOH, ω-halogen (CH ₂ ) _n -R1 compounds can also be used, in which R1 represents a derivative of the carboxyl group, such as a nitrile or ester group which can be converted into the free carboxyl group by hydrolysis. After the protective groups have been split off, if necessary, for example by hydrogenation, the complexing agents according to the invention are obtained which, if desired, can be reacted with organic and inorganic acids and bases.

Another subject is complexes of paramagnetic metal ions with the complexing agents according to the invention and their salts, with complexes and their salts with gadolinium (III) and manganese (II) being preferred.

Possible paramagnetic metal ions are the cations of the transition metals of atomic numbers 21 to 29, 42 and 44 and the cations of the lanthanide elements of atomic numbers 57 to 70, gadolinium being preferred by the lanthanide elements.

The sodium and N-methylglucamine salts are preferred as salts of the complexes according to the invention.

Further objects of the invention are contrast media for MR diagnostics containing complexes according to the invention and their salts as well as the use of the complexes according to the invention and their salts for the production of contrast media for MR diagnostics.

Preferred complexes are the gadolinium (III) and manganese (II) complexes of N, N '' - bis - [(3,4-dimethoxy-2-pyridinyl) methyl] diethyltriamine-N, N ', N "- triacetic acid, N, N '' bis - [(3-hydroxy-4-methoxypyridin-2-yl) methyl] diethylenetriamine-N, N ', N''- triacetic acid and N, N'-bis - [(3- hydroxy-4-methoxypyridin-2-yl) methyl] ethylenediamine-N, N'-diacetic acid. Particularly preferred objects are the gadolinium (III) complex and the manganese (II) complex of N, N "-bis - [(3,4-dimethoxy-2-pyridinyl) methyl] di-ethylenetriamine-N, N ', N "triacetic acid.

For complexes capable of salt formation, the sodium and methyl glucamine salts are preferred.

Another object of the invention is a process for the preparation of complexes, characterized in that compounds of the general formula I, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X, m, n, p and q have the meanings given above, are reacted with paramagnetic metal ions and, if desired, the complexes obtained are converted into the salts with the aid of strong bases.

The complexes according to the invention result in a very good increase in contrast in MR diagnostics and are distinguished by numerous advantages over the prior art. In the dosages relevant for MR diagnostics, they do not cause a drop in blood pressure and heart rate. They are excreted unchanged and quickly renally. They are not sensitive to hydrolysis. In addition, the complexing agents according to the invention give more stable complexes than those according to the prior art which, instead of a radical of the general formula II, have carboxyl groups or -CONHR5. In addition, neutral complexes of particularly high complex stability can be prepared by choosing the number and type of the radical of the general formula II, depending on the charge of the central atom. Their preparation is simple and inexpensive and solutions with a physiological pH and low osmolality can be produced.

Contrast agents according to the invention for MR diagnostics contain one or more of the complexes of paramagnetic metal ions with complexing agents of the general formula I and, if desired, customary additives.

The complexes are prepared in a manner known per se by dissolving salts of the paramagnetic metals in water and / or an alcohol, such as methanol, ethanol, etc., and with the appropriate amount of the complexing agent, if necessary with heating to 50 ° C. to 120 ° C as long as stir until the implementation is complete. Instead of the salts of the paramagnetic metals, complexes of the paramagnetic metal ions can also be used, for example the corresponding acetylacetonato complexes, the ligands of which are exchangeable by the complexing agents according to the invention. If the complex formed is insoluble in the solvent used, it crystallizes and can be filtered off. If the complex is soluble in the solvent used, it can be isolated by evaporating the solution to dryness or precipitated by adding another organic solvent. The complex compound obtained is then dissolved or suspended in water and mixed with the desired inorganic or organic base or acid until the neutral point is reached. After filtration of undissolved portions, the solution is evaporated and the desired complex salt is obtained as a residue or the complex salt is precipitated from an aqueous solution with an organic solvent. The salts of the complexes are obtained, for example, by reaction with strong bases.

The complexes can also be prepared in a manner known per se by adding an aqueous solution of the salt of the paramagnetic metal to a solution of the appropriate amount of the complexing agent plus the appropriate amount of base, e.g. Sodium hydroxide, or added dropwise to a salt (e.g. sodium salt) of the complexing agent and sterile filtering the aqueous solution of the salt of the complex or its sodium salt.

After sterile filtration, the complexes can be lyophilized in the form of their salts or precipitated by adding a non-polar, water-miscible solvent (e.g. acetone, isopropanol). In this way, the desired complex salts are obtained in solid form free from inorganic salts.

The separation of inorganic salts can also be carried out by precipitation of the complexes by means of mineral acid (e.g. aqueous hydrochloric acid) at pH 2.5-4 and filtration or in a manner known per se using ion exchangers or by chromatography, e.g. on silica gel.

The aqueous solution or a suspension of the precipitated complex compound eluted from the ion exchanger is converted into the desired form (eg sodium salt or meglumine salt) which is soluble at physiological pH values dung in water with the appropriate amount of strong base (eg sodium hydroxide solution or N-methylglucamine). In this way, solutions of the desired complex salts free of inorganic acids are obtained.

The new contrast media are prepared in a manner known per se by dissolving the complexes and / or their salts in water or physiological salt solution and, if desired, adding additives customary in galenics, such as, for example, physiologically compatible buffer solutions (e.g. sodium dihydrogen phosphate solution), albumin and the like and sterilized the solution.

As such, the solutions can be filled into ampoules or freeze-dried to a soluble powder. The aqueous solutions are adjusted to a pH with sufficient local tissue tolerance, for example to a pH of 7 to 9. The aqueous solutions are administered orally or parenterally, in particular intravascularly. For MR diagnostics in humans, aqueous solutions are used which contain the paramagnetic complex in a concentration of 30 to 500 mmol / liter. Approximately 1 to 300 μmol of the complex per kg body weight are administered per application. For an adult, a dose of 1 to 100 mmol proves to be appropriate for an iv application.

At game e

1. N, N '' - bis - [(3,4-dimethoxy-2-pyridinyl) methvndiethylenetriamine-N, N ', N' '- triacetic acid monosodium manganese (II) salt (water-containing)

30 g (38.6 mmol) of N, N "-bis - [(3,4-dimethoxy-2-pyridinyl) methyl] diethylenetriamine-N, N ', N" -triacetic acid trisodium salt (with 16.8% H ₂ O) are dissolved in 150 ml of water, manganese dichloride tetrahydrate (40.6 mmol) is added and the mixture is stirred at 70 ° C. for 4 hours. After centrifugation of insoluble salts, the mixture is concentrated and the residue is chromatographed on 1.2 kg of silica gel

(Mobile solvent ethanol / water 1: 1). The clean fractions are pooled, sterile filtered and lyophilized. The yield of almost colorless solid is 23.3 g; Decomposition with brown coloring from 150 ° C. (Water content 4.4%).

Analysis:

Calculated: C 45.82 H 5, 47 N 10, 28

Found: C 45.60 H 5, 43 N 10, 30

C 45.80 H 5.41 N 10.15

2. NN ^,, -Bis - [(3,4-dimethoxy-2-pyridinyl) methyl] diethylenetriamine-N, N ', N''- triacetic acid-gadolinium (III) salt (water-containing)

According to the procedure described in Example 1, reaction of 14.4 g (18.5 mmol) of N, N "-bis - [(3,4-dimethoxy-2-pyridinyl) methyl] -diethylenetriamine-N, N ' "N" -triacetic acid trisodium salt (with 16.8% H., 0) with 20 mmol of gadolinium trichloride hexahydrate after chromatography on silica gel and sterile filtration, the title compound as a colorless, solid residue of mp> 280 ° C. Yield 11.0 g (water content 9.1%).

Analysis:

Calculated: C 38.67 H 5.26 N 8.67

Found: C 38.30 H 5.00 N 8.36 3. N.N '' - bis - [(3,4-dimethoxy-2-pyridinyl) methyl] diethylenetriamine-N, N ', N''- triacetic acid trisodium salt (containing water)

A. N, N "-Bis - [(3,4-dimethoxy-2-pyridinyl) methyl] diethylenetriamine-N, N ', N" -trisacetic acid trisodium salt (containing water)

72 g (109 mmol) of N, N "-bis - [(3,4-dimethoxy-2-pyridinyl) methyl] diethylenetriamine-N, N ', N" -triethyl acetate are dissolved in 1.1 l of acetone , 3 equivalents of NaOH were added and the mixture was stirred at 20 ° C. for 48 hours. It is filtered, washed with acetone and dried in vacuo (40-50 ° C). The water-containing title compound is obtained as a colorless solid with a melting point of 110-112 ° C. (dec.). Yield: 61 g (87% of theory). (Water content 14%).

Analysis:

Calculated: C 41.60 H 6.12 N 9.33

Found: C 41.33 H 5.88 N 9.04

B. N, N "-Bis - [(3,4-dimethoxy-2-pyridinyl) methyl] diethylenetriamine-N, N ', N" - triethyl triethyl ester

77 g (190 mmol) of N, N "-bis - [(3,4-dimethoxy-2-pyridinyl) methyl] diethylenetriamine are dissolved in 300 ml of toluene, 280 ml of triethylamine are added and 190 g (1.14 Mol) ethyl bromoacetate, dissolved in 300 ml of toluene, added dropwise, the mixture is stirred for 3 days at 25 ° C., extracted several times with 200 ml of water each time, the organic phase is dried over potassium carbonate and concentrated completely, giving 72 g of the title compound (57% of theory) as a yellow oil, which is used directly in A).

C. N, N "-Bis - [(3,4-dimethoxy-2-pyridinyl) methyl] diethylenetriamine

67 g (0.4 mol) of 3,4-dimethoxy-pyridine-2-aldehyde are refluxed in 1 liter of dioxane together with 0.2 mol of diethyl entriamine, the water of reaction formed being removed by means of a drying tube filled with calcium chloride . After the reaction is complete, dioxane is largely distilled off in vacuo, the oily imine intermediate in 2 1 of etha nol dissolved and mixed with 20 g of sodium borohydride. The mixture is stirred for 24 hours, concentrated, the residue is partitioned between dichloromethane and water, the organic phase is washed several times with water, dried over potassium carbonate and concentrated to dryness. 73.7 g (91% of theory) of the title compound are obtained as a pale yellow oil, which is directly reacted further in B.

D. 3,4-Dimethoxypyridine-2-aldehyde

50 g of 3,4-dimethoxy-2-hydroxymethyl-pyridine are dissolved in 500 ml of dioxane and mixed with 50 g of active manganese dioxide. The water of reaction is removed by azeotropic distillation at normal pressure for 20 hours over a drying tube filled with calcium chloride. After filtration, the mixture is concentrated in vacuo to about 100 ml and diisopropyl ether is added at 70 to 80 ° C. until it becomes cloudy. After cooling, it is filtered. 46.5 g (94% of theory) of the title compound of mp 64-66 ° C. are obtained.

4. N, N '' - bis - [(3,4-dimethoxy-2-pyridinyl) methyldiethylenetriamine-N, N ', N' '- triacetic acid monohydrate

5.0 g of the trisodium salt from Example 3.A are dissolved in 40 ml of methanol and 4N hydrochloric acid (3 equivalents) are added. After 2 hours, the mixture is completely concentrated, the residue is triturated with methanol, filtered from the sodium chloride, concentrated again and crystallized from acetone. 3.3 g (74% of theory) of the title compound of mp 84-85 ° C. (dec.) Are obtained as a colorless powder.

5. N, N '' - bis-r (3-benzylo 4y-4-methoxy-2-pyridinyl) methylldiethylenetriamine- N.N ', N' '- triacetic acid trisodium salt

A. N, N '' - bis - [(3-benzyloxy-4-methoxy-2-pyridinyl) methyl] diethylenetriamine-N, N ', N' '- triacetic acid trisodium salt

According to the procedure given in Example 3.A, 4.0 g of N, N "-bis - [(3-benzyloxy-4-methoxy-2-pyridinyl) methyl] diethylenetriamine-N, N ', N" -triacetic acid are obtained triethyl ester by reaction with 4N sodium hydroxide solution (3 equivalents) in 50 ml of acetone 2.15 g of the title compound as a colorless solid of melting point 73 ° C. (dec.). B. N, N "-Bis - [(3-benzyloxy-4-methoxy-2-pyridinyl) methyl] diethylenetriamine-N, N ', N" -triethyl acetate triethyl ester

According to the procedure given in Example 3.C, reaction of 5.0 g of 3-benzyloxy-4-methoxy-pyridine-2-aldehyde with 0.5 equivalents of diethyl entriamine 6.9 g of imine intermediate as a reddish oil, which with 1.0 g of sodium borohydride in 100 ml of ethanol is reduced. After chromatography on silica gel (mobile phase: methanol / ethyl acetate / triethylamine 1: 1: 0.1), 2.9 g of N, N "bis - [(3-benzyloxy-4-methoxy-2-pyridinyl) methyl] di -ethylenetriamine, which with 6 equivalents of ethyl bromoacetate and

10 equivalents of triethylamine is converted to the title compound by the procedure given in Example 3.B. Removed: 4.0 g of yellow oil.

C. 3-Benzyloxy-4-methoxy-pyridine-2-aldehyde

According to the procedure described in Example 3.D, 8.0 g of the title compound of melting point 72-74 ° C. is obtained from 20 g of 3-benzyloxy-2-hydroxymethyl-4-methoxypyridine in 200 ml of dioxane with 30 g of manganese dioxide.

Animal imaging

The complex compounds according to Preparation Examples 1 and 2 were tested in comparison to the located under the trade name Magnevist ^® commercially Ga dolinium (III) complex Gadopentetic Acid (INN) [Gd (DTPA)] in rats and rabbits on MR imaging. In all cases, a contrast medium concentration of 100 μmol / ml was administered intravenously in a dose of 100 μmol / kg. 3 animals were examined for each substance. The measurements in rats after 24 hours were carried out only on two or on one animal. The investigations were carried out on a 1.0 Tesla MR device [SE sequence T1 (TR = 400 and 600 ms, TE = 15 ms, layer thickness = 3 mm, matrix = 256)].

Table 1 summarizes the results of the presentation of the liver of rats. The specified intensity values are standardized to the value 100 before contrast medium administration (KM).

Table 2 below shows the results of the illustration of brain abscesses produced by bacterial injection in rabbits.

Both experiments result in a surprising superiority of the two complexes according to the invention over the prior art. The importance of the complexes according to the invention is that they behave like typical extracellular markers with respect to MR imaging, but additionally provide diagnostically important information of certain organs.

Claims

1. Complete ex lender of general formula I,

.

wori n

PO ₃ H ₂ , SO ₃ H and a radical of the general formulas IIa or IIb,,

in which

R7 in the general formula IIb denotes methyl and benzyl, and

R8 denotes H or Cl-C4-alkyl,

X for a single bond and NR9,

in which

R9 denotes H, C1-C4-alkyl and (CH ₂ ) _n R1,

n, q for 1 or 2, where n and q are the same or different, and

p for 1 or 2 but not for 1 if X is NR9,

stand, and their salts with organic and inorganic bases and acids.

2. complexing agent according to claim 1, characterized in that in the general formula I

R1, R2, R3 and R4 are the same or different and for COOH, C (O) NHR5, in which

R5 denotes H, methyl and ethyl, and a radical of the general

Formula Ila,

in which

R6 and R7 are the same or different and are H and methyl,

with the proviso that at least one of the radicals R1, R2, R3 and R4 represents a radical of the general formula II,

X for a single bond and NR9,

in which

R9 (CH,) Rl means

v 2'n

n, q for 1 and

p for 1 and 2, but not for 1 if X is NR9,

stand, and their salts with organic and inorganic bases and acids.

3. complexing agent according to claim 1, characterized in that in the general formula I

in which

X for a single bond,

n, q and stand for 1,

and their salts with organic and inorganic bases and acids.

4. complexing agent according to claim 1, characterized in that in the general formula I

in which

R6 and R7 are identical or different and are H and methyl, with the proviso that at least one of the radicals R1, R2, R3 and 4 is a radical of the general formula Ila,

X for NR9, where R9 is (CH ₂ ) _p R1, n and q for 1 and

p for 2

stand,

and their salts with organic and inorganic bases and acids.

5. N, N'-bis - [(3-hydroxy-4-methoxypyridin-2-yl) methyl] ethylenediamine-N, N'-diacetic acid, N, N "bis - [(3-hydroxy-4-methoxypyridine -2-yl) methyl] diethylenetriamine-N, N ', N' '- triacetic acid, N' - [(3-hydroxy-4-methoxypyridin-2-yl) methyl] diethylenetriamine-N, N, N ", N ' '-tetraacetic acid, N, N "-bis - [(3,4-di-methoxy-2-pyridinyl) methyl] diethylenetriamine-N, N', N" - triacetic acid,

N '- [3,4-Dimethoxy-2-pyridinyl) methyl] diethylenetriamine-N, N, N ", N" -tetraacetic acid and its salts with organic and inorganic bases and acids.

6. Complex paramagnetic metal ions with complexing agents according to claims 1 to 5 and their salts.

7. Complexes according to claim 6, characterized in that the paramagnetic metal ions are gadolinium (III) and manganese (II).

8. Complexes according to claim 6, characterized in that they are present as sodium or N-methylglucamine salts.

9. Gadolinium (III) complex of N, N "bis - [(3,4-dimethoxy-2-pyridinyl) methyl] diethylenetriamine-N, N ', N" - triacetic acid.

10. Manganese (II) complex of N, N "-bis - [(3,4-dimethoxy-2-pyridinyl) methyl] -diethylenetriamine-N, N ', N" - triacetic acid.

11. Contrast agent for MR diagnostics containing complexes according to claims 6, 7, 8, 9 and 10.

12. A process for the preparation of complexes, characterized in that compounds of the general formula I in which R1, R2, R3, R4, R5, R6, R7, R8, R9, X, m, n, p and q are used 1 have the meanings given, reacted with paramagnetic metal ions and, if desired, the The complexes obtained are converted into the salts with the aid of strong bases.

13. A process for the preparation of the complexing agent of the general formula I, characterized in that a compound of the general formula I in which the 3-hydroxy-4-methoxypyridin-2-yl radicals are replaced by 3-hydroxy-4-methoxypyridin-2 -yl radicals, the hydroxyl groups of which are protected by protective groups which are customary for hydroxyl groups, preferably benzyl and methyl, are reacted under conditions which selectively split off the protective groups.