IE920409A1 - Complexing agents - Google Patents

Abstract

Complexing agents of the general formula I in which R1, R2, R3 and R4 are identical or different and represent H, COOH, C(O)NHR5, where R5 denotes H and C1-C4-alkyl, PO3H2, SO3H and the radical 3-hydroxy-1-(R6)-4-[1H]pyridon-2-yl, where R6 denotes H and C1-C4-alkyl, with the proviso that at least one of the radicals R1, R2, R3 and R4 has the meaning 3-hydroxy-1-(R6)-4-[1h]pyridon-2-yl where R6 = H and C1-C4-alkyl, X represents a single bond, (CH2)m and NR7 where R7 denotes H, C1-C4-alkyl and (CH2)nR1 and m denotes 1 and 2, n, q represent integers from 0 to 2, where n and q are identical or different and their sum is at least 1, and p represents an integer from 1 to 3, but not 1 if X has the meaning NR7, and their salts with organic and inorganic bases and acids, are suitable for the preparation of paramagnetic complexes which can advantageously be employed as contrast agents for MR diagnosis.

Description

Complexing agents Technical field The invention relates to novel complexing agents .

Prior art It is known in MR diagnosis to employ paramagnetic metal complex compounds to increase contrast. Solutions of a gadolinium(III) complex with the complexing agent diethylenetriaminepentaacetic acid [Gd(DTPA)] have already proved suitable in practice as MR contrast agents. In order to avoid the use of gadolinium, which is highly toxic in free form, and in order to achieve a specificity for the demonstration of certain organs, various complexes of other paramagnetic metal ions have been proposed. EP-A-0235361 proposes, inter alia, to employ an iron(III) complex of the known trihydroxamic acid desferrioxamine (Desferal®) as an MR contrast agent, in particular for the demonstration of the urogenital tract.

In clinical investigations, this complex has proved very effective with respect to the contrastincreasing effect. A disadvantage of this complex, however, is found to be its undesired blood pressure- and heart rate- reducing effect (W.L. Niedrach et al., Investigative Radiology, 23 [1988] 687 - 691).

From G. J. Kontoghiorghes, Inorg. Chim. Acta 135 [1987] 145 - 150, and C. Hershko, Brit. Med. J. 296 [1988] 1081, it is known that certain hydroxypyridones are suitable for forming stable complexes with iron(III) ions and can therefore be employed in orally administered form for the elimination of excess iron from the human body.

M. Streater et al., J. Med. Chem. 33 [1990] 1749-1755 describe the hexadentate complexing agents N, N, N-tr is [ 2 - (3 -hydroxy-2-oxo-1,2 -dihydropyr idin- 1-y 1) 35 acetamido]alkylamines and their complexes with iron(III).

The complexing agents are intended to be suitable for the removal of iron from patients having too high a content - 2 of iron.

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

It is the object of the present invention to make available novel complexing agents whose complexes with paramagnetic metal ions are distinguished by high complex stability, good water solubility at physiological pH values, high relaxivity and by pronounced organ specificity combined with reduced side effects and more rapid excretion.

Description of the invention The invention relates to complexing agents of the general formula I (HC) (CH) 2, P I 2 P RI. <CH2>n-N N — (CH,) — R2 z n (I) , (H C)q (CH,)q I I R3 R4 in which RI, R2, R3 and R4 are identical or different and stand for H, COOH, C(O)NHR5, where R5 denotes H and ClC4-alkyl, PO3H2, SO3H and the radical 3-hydroxy-l-(R6)-4-[1H]pyridon-2-yl, where R6 denotes H and Cl-C4-alkyl, with the proviso that at least one of the radicals RI, R2, R3 and R4 has the meaning 3-hydroxy-l-(R6)4-(lH]pyridon-2-yl where R6 = H and Cl-C4-alkyl, X stands for a single bond, (CH2)m and NR7, where R7 denotes H, Cl-C4-alkyl and (CH2)nRl and m denotes 1 and 2, n and q stand for integers from 0 to 2, where n and q are identical or different and their sum is at least 1, and - 3 p stands for an integer from I to 3, but not for 1 when X has the meaning NR7, and their salts with organic and inorganic bases and acids .

The invention preferably relates to complexing agents of the above general formula I in which Rl, R2, R3 and R4 are identical or different and stand for H, COOH, C(0)NHR5, where R5 denotes H, methyl and ethyl, and the radical 3-hydroxy-4-[IH]-pyridon10 2-yl, with the proviso that at least one of the radicals Rl, R2, R3 and R4 stands for the meaning 3-hydroxy-4-[IH]pyridon-2-yl, X stands for a single bond, CH2 and NR7, where R7 denotes H and (CH2)aRl, n and q stand for 1 and p stands for 1 and 2, but not for 1 when X has the meaning NR7, and not for 2 when X denotes a single bond, and their salts with organic and inorganic bases and acids.

The invention particularly preferably relates to complexing agents of the above general formula I in which Rl, R2, R3 and R4 are identical or different and stand for H, COOH and the radical 3-hydroxy-4-[lH]pyridon25 2-yl, with the proviso that at least one of the radicals Rl, R2, R3 and R4 stands for the radical 3-hydroxy-4-[lH]pyridon-2-yl, X stands for a single bond, n stands for 1, 30 q stands for 0 and 1 and P stands for 1, and their salts with organic and inorganic bases and acids.

The invention equally preferably relates to 35 complexing agents of the above general formula I in which Rl, R2, R3 and R4 are identical or different and stand for H, COOH and the radical 3-hydroxy-4-[lH]pyridon2-yl, with the proviso that at least one of the radicals Rl, R2, R3 and R4 stands for the radical - 4 3-hydroxy-4-[1H]pyridon-2-yl, X stands for NR7, where R7 denotes (CH2)nRl, n stands for 1, q stands for 0 and 1 and p stands for 2, and their salts with organic and inorganic bases and acids.

Particularly preferred complexing agents are N,N' -bis ( 3-hydroxy-4-[ 1H]pyridon-2-ylmethyl) ethylene10 diamine-Ν,Ν'-diacetic acid, N,N'-bis(3-hydroxy-4-[1H]pyridon-2-ylmethyl)ethylenediaminemonoacetic acid, N,N' -bis ( 3-hydroxy-4- [ 1H]pyridon-2 -ylmethyl) ethylenediamine, N,N-bis(3-hydroxy-4-[1H]pyridon-2-ylmethyl) diethylenetriamine-Ν,Ν',N-triacetic acid, N-(3-hydroxy15 4-[1H]pyridon-2-ylmethyl)ethylenediamine-N,N',N'-triacetic acid, N'-(3-hydroxy-4-[lH]pyridon-2-ylmethyl)diethylenetriamine-Ν,Ν,Ν,N-tetraacetic acid and N-(3-hydroxy4 - [ 1H ] pyridon-2 -ylmethyl) ethylenediamine-N, N' -diaceticacid and their salts with organic and inorganic bases and acids. The 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 characterised in that a compound of the general formula I, in which the 3-hydroxy-4-[1H]pyridon-2-yl radicals are replaced by 3,4-dihydroxypyridin-2-yl radicals whose hydroxyl groups are protected by protective groups customary for hydroxyl groups, preferably benzyl and methyl, is reacted under conditions which remove the protective groups and, if desired, the 3-hydroxy-4-[ 1H]pyridon-2-yl radicals are Cl-C4-alkylated in the 1-position.

The complexing agents according to the invention can be prepared starting from the corresponding 3,4-bis35 hydroxypyridine-2-aldehydes whose hydroxyl groups are protected by suitable protective groups, for example methyl or benzyl. By reaction, according to the conditions customary for the condensation of aldehyde groups with amines, with the appropriate alkylenediamines or - 5 dialkylenetriamines and subsequent reduction, OH-protected 3,4-bis-hydroxy-2-pyridylamines are obtained. These are reacted with appropriate ω-halo, preferably ω-bromo, -(CH2)n-Rl compounds. To prepare complexing agents in which R1 has the meaning COOH, in this case also ω-halo-(CH2)n-Rl compounds can be used in which R1 is a derivative of the carboxyl group, such as, for example, a nitrile or ester group which can be converted into the free carboxyl group by hydrolysis. After removal, for example by hydrogenation of the protective groups, the complexing agents according to the invention are obtained and, if desired, can be reacted with organic and inorganic acids and bases.

The invention further relates to complexes of paramagnetic metal ions with the complexing agents according to the invention and their salts, complexes and their salts with iron(III), manganese (II) and gadolinium(III) being preferred.

Suitable paramagnetic metal ions are the cations of the transition metals of atomic numbers 21 to 29, 42 and 44 and also the cations of the lanthanide elements of atomic numbers 57 to 70, where, of the lanthanide elements, gadolinium is preferred.

Preferred salts of the complexes according to the invention are the sodium and N-methylglucamine salts.

The invention further relates to contrast agents for MR diagnosis containing complexes according to the invention and their salts and to the use of the complexes according to the invention and their salts for the preparation of contrast agents for MR diagnosis.

Preferred complexes are the iron(III) complexes of N,N' -bis ( 3-hydroxy-4-[ lH]pyridon-2-ylmethyl)ethylenediaminediacetic acid, N-(3-hydroxy-4-[lH]pyridon-2-ylmethyl)ethylenediamineΝ,Ν'-diacetic acid and N,N' -bis ( 3-hydroxy-4-[ IH]pyridon-2-yImethy 1) ethylenediamine , the gadolinium(III) complexes of - 6 N,N'-bis ( 3-hydroxy-4-[ lH]pyridon-2-ylmethyl) ethylenediaminediacetic acid, N,N-bis ( 3-hydroxy-4 - [ IH]pyridon-2-ylmethyl)diethylenetriamine-Ν,Ν',N-triacetic acid and N' - ( 3-hydroxy-4 - [ lH]pyridon-2-ylmethyl) diethylenetriamine-Ν,Ν,Ν,N-tetracetic acid and also the manganese(II) complex of N,N'-bis (3-hydroxy-4-[IH]pyridon-2-ylmethy1)ethylenediamine-N,N'-diacetic ac id.

The invention further relates to a process for 10 the preparation of complexes, characterised in that compounds of the general formula I, in which RI, R2, R3, R4, R5, R6, R7, X, m, n, p and q have the abovementioned meanings, 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 give a very good increase in contrast in MR diagnosis and compared with the prior art are distinguished by numerous advantages. In the dosages relevant to MR diagnosis, they cause no reduction in the blood pressure and the heart rate. They are excreted unchanged and rapidly by the kidneys. 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 have carboxyl groups instead of the 3-hydroxy-l-(R6)-4-[lH]-pyridon-2-yl radicals. Their preparation is simple and less expensive in terms of cost and solutions of physiological pH can be prepared.

Contrast agents according to the invention for MR diagnosis 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 stirring with the appropriate amount of the complexing agent, optionally with heating at 50°C to 120°C, until the reaction is complete. Instead of the salts of the paramagnetic metals, complexes of the paramagnetic - 7 metal ions can also be employed, for example the corresponding acetylacetonato complexes, whose ligands are exchangeable with the complexing agents according to the invention. If the complex formed is insoluble in the solvent used, it crystallises and can be filtered off. If the complex is soluble in the solvent used, it can be isolated by evaporation of the solution to dryness or precipated by addition of another organic solvent. The complex compound obtained is then dissolved or suspended in water and treated with the desired inorganic or organic base or acid until the point of neutrality is reached. After filtration of undissolved components, the solution is evaporated and the desired complex salt is obtained as a residue or the complex salt is precipitated from aqueous solution using 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 dropwise to a solution of the appropriate amount of the complexing agent plus the appropriate amount of base, for example sodium hydroxide, and sterile-filtering the aqueous solution of the sodium salt of the complex.

After sterile filtration, the complexes can be precipitated in the form of their salts by addition of a non-polar water-miscible solvent (for example acetone, isopropanol). In this manner, the desired complex salts are obtained in solid form free from inorganic salts.

The removal of inorganic salts can also be carried out by precipitation of the complexes by mineral acid (for example aqueous hydrochloric acid) at pH 2.5 4 and filtration or, in a procedure known per se, by means of ion exchangers.

For conversion into the desired form which is soluble at physiological pH values (for example sodium salt or meglumine salt), the aqueous solution eluted from the ion exchanger or a suspension of the precipitated complex compound in water is treated with the appropriate - 8 amount of strong base (for example sodium hydroxide solution or N-methylglucamine). In this manner, solutions of the desired complex salts are obtained free of inorganic acids.

The novel contrast agents are prepared in a manner known per se by dissolving the complexes and/or their salts in water or physiological saline solution and, if desired, adding additives customary in pharmacy, such as, for example, physiologically tolerable buffer solutions (for example sodium dihydrogen phosphate solution), albumin and the like, and sterilizing the solution.

Ampoules can be filled with the solutions as such or the latter can be freeze-dried to give a soluble powder. The aqueous solutions are adjusted to a pH of adequate local tissue compatibility, for example to a pH from 7 to 9. The aqueous solutions are administered orally or parenterally, in particular intravasally. For MR diagnosis in humans, aqueous solutions which contain the paramagnetic complex in a concentration of from 30 to 500 mmol/litre are used. Per administration, approximately 1 to 300 μπιοί of the complex are administered per kg of body weight. For an adult, a dose of 1 to 100 mmol turns out to be appropriate for i.v. administration.

Examples 1. N,Ν'-Bis I 3-hvdroxv-4-ΓlHlpvridon-2-vlmethvl)ethylenediaminediacetic acid dihvdrochloride a) N,N'-Bis (3-hydroxy-4-[lH]pyridon-2-ylmethyl)ethylenediaminediacetic acid dihydrochloride 2.0 g of N,N'-bis[(3,4-bis-benzyloxy-2-pyridyl)methyljethylenediaminediacetic acid are dissolved in 50 ml of methanol with the addition of 2.5 ml of 2N hydrochloric acid and, after addition of 0.1 g of 10% strength palladium on active carbon catalyst, hydro35 genated in a revolving hydrogenation apparatus at a hydrogen overpressure of about 0.1 bar. After 2 hours, the solution is filtered from the catalyst, concentrated and crystallised by addition of diethyl ether. 1.28 g (95% of theory) of the title compound are - 9 obtained as a colourless crystallisate {dihydrate; decomposition from 75°C).

Analysis : Calculated: C 40.83 H 5.33 N 10.58 Cl 13.40 Found: C 41.08 H 5.16 N 10.30 Cl 13.21 b) N,N'-Bis[(3,4-bis-benzyloxy-2-pyridyl)methyl]ethylenediaminediacetic acid g of N,N'-bis[(3,4-bis-benzyloxy-2-pyridyl)methyl]ethylenediamine are dissolved in 50 ml of ethanol and 10 ml of water and a mixture of 1.83 g of bromoacetic acid and 13.2 ml of IN sodium hydroxide solution is added dropwise at 60°C. During the course of this, the pH of the reaction mixture is kept between 10 and 11 with sodium hydroxide solution, After 4 hours, excess ethanol is distilled off in vacuo, the pH is adjusted to 3 with hydrochloric acid and the residue is extracted several times with dichloromethane. The combined organic phases are washed with water, dried (magnesium sulphate) and completely concentrated in a rotary evaporator. The amorphous residue is crystallised from hot acetone. 3.2 g (68% of theory) of the title compound are obtained as a colourless solid of m.p. 159-161°C. c) N,N'-Bis[ ( 3,4-bis-benzyloxy-2-pyridyl)methyl ]ethylenediamine 7.5 g of N,N'-bis[(3,4-bis-benzyloxy-2-pyridyl)methylene]ethylenediamine, dissolved in 100 ml of methanol, are treated, in portions, with 1.1 g of sodium borohydride and the mixture is stirred for 18 hours. The solvent is completely concentrated in vacuo, the residue is taken up in dichloromethane, the insoluble inorganic salt is filtered, and the organic phase is washed with water until neutral, dried (potassium carbonate) and completely concentrated. The residue is crystallised from ethyl acetate/cyclohexane. 6.1 g (81% of theory) of the title compound of m.p. 61-62*C are obtained. d) N,N'-Bis[(3,4-bis-benzyloxy-2-pyridyl)methylene]ethylenediamine g of 3,4-bis-benzyloxypyridine-2-aldehyde are condensed in 250 ml of dioxane with 1.05 ml - 10 (0.5 equivalent) of ethylenediamine, water of reaction formed being removed azeotropically. After 4 hours, the solvent is distilled off in vacuo, the residue is dissolved in diisopropyl ether at 60°C and the solution is cooled to room temperature. The crystalline product is filtered and dried. 3.4 g (91% of theory) of the title compound of m.p. 124-126°C are obtained. e) N,Ν' -Bis[(3,4-bis-benzyloxy-2-pyridyl)methyl]ethylenediaminediacetic acid The compound lb) is also obtained by reaction of Ν,Ν'-bis [(3,4-bis-benzyloxy-2-pyridyl)methyl]-N,N'-biscyanomethylethylenediamine with excess KOH in ethylene glycol under reflux, after working up, as described in Example lb). f) N,N'-Bis[(3,4-bis-benzyloxy-2-pyridyl)methyl]N,N'-bis-cyanomethylethylenediamine To 0.5 g of N,N'-bis[(3,4-bis-benzyloxy-2-pyridyl)methyl]ethylenediamine and 2 equivalents of 0. IN HCl are added 0.15 g (4 equivalents) of sodium cyanide in ml of water and 0.09 g of formaldehyde solution (35% strength; 4 equivalents). The resulting suspension is vigorously stirred for 36 hours. After filtration, the solid is again stirred in 10 ml of water, filtered, washed thoroughly with water and dried in vacuo at 58°C. 0.45 g (81% of theory) of the title compound of m.p. 103-105°C is obtained. 2. Ν,Ν'-Bisf 3-hvdroxv-4-rlHlPvridon-2-vlmethvl)ethvlenediamine-Ν,Ν'-diacetic acid dihydrobromide a) N,N'-Bis ( 3-hydroxy-4 - [ lH]pyridon-2-ylmethyl) ethyl30 enediamine-Ν,Ν'-diacetic acid dihydrobromide The title compound is also obtained as dihydrobromide by reaction of Ν,Ν'-bis[(3,4-dimethoxy2-pyridyl)methyl]ethylenediamine-N,N'-diethyl acetate with 48% strength hydrobromic acid. After reaction at 100°C for 3 hours, the mixture is completely evaporated, the residue is dissolved in water and the solution is clarified with active carbon. After evaporating completely again and recrystallising from ethanol/ diisopropyl ether, the title compound is obtained as - 11 hygroscopic dihydrobromide. b) N,N'-Bis[ ( 3,4-dimethoxy-2-pyridyl)methyl Jethylenediamine-Ν,Ν'-bis-ethyl acetate .0 g of N,N'-bis[(3,4-dimethoxy-2-pyridyl)5 methyl]ethylenediamine are heated to reflux for 1 hour with 5.07 g of ethyl bromoacetate in 100 ml of toluene and 20 ml of water with the addition of 6.9 g of potassium hydrogencarbonate and 0.2 g of potassium iodide. After cooling, the phases are separated. The organic phase is washed with water, dried (potassium carbonate) and then concentrated. The residue is chromatographed on silica gel. 3.7 g (50% of theory) of the title compound are obtained as a colourless oil. c) Ν,N' -Bis[(3,4-dimethoxy-2-pyridyl)methyl]ethylene15 diamine According to the procedure described in Example lc), reaction of 27 g of N,N'-bis[(3,4-dimethoxy-2-pyridyl)methylene]ethylenediamine with 10.8 g of sodium borohydride in 300 ml of methanol gives, after crystal20 lisation from diisopropyl ether, 20.8 g (76% of theory) of the title compound of m.p. 69-70°C. d) Ν,N'-Bis[(3,4-dimethoxy-2-pyridyl)methylene]ethylenediamine According to the procedure given in Example Id), 25 reaction of 32 g of 3,4-dimethoxypyridine-2-aldehyde with 6.40 ml of ethylenediamine in 300 ml of dioxane gives, after crystallisation from diisopropyl ether, 27.8 g (81% of theory) of N,N'-bis[(3,4-dimethoxy-2-pyridyl)methylene]ethylenediamine of m.p. 132-134’C. 3. N,N-Bis(3-hvdroxv-4-ΓlHlpyridon-2-vlmethvl)diethylenetriamine-N.N',N-triacetic acid a) N,N-Bis ( 3-hydroxy-4- [ lH]pyridone-2-ylmethyl) diethylenetriamine-Ν,Ν',N-triacetic acid N,N-Bis [(3,4-bis-benzyloxy-2-pyridyl)methyl]di35 ethylenetriamine-Ν,Ν',N-triacetic acid trisodium salt are hydrogenated, as described in Example la), with the addition of 6 equivalents of 4N hydrochloric acid. After hydrogenation is complete, the solution is filtered from the catalyst, concentrated and triturated with - 12 diisopropyl ether. The title compound is obtained as a colourless amorphous solid mixed with sodium chloride, b) Trisodium N,N-bis[(3,4-bis-benzyloxy-2-pyridyl) methyl]diethylenetriamine-N, N', N-triacetate 5 9.5 g of N,N-bis[(3,4-bis-benzyloxy-2-pyridyl) methyl]diethylenetriamine are reacted with 6.55 g of bromoacetic acid (3 equivalents) using the procedure described in Example lb) . After distilling off the ethanol, the residue is taken up in water, a pH of 13 to 14 is established and the mixture is extracted 3 times with 50 ml of dichloromethane. The combined organic phases are concentrated and the residue is crystallised by triturating with diisopropyl ether. The title compound is obtained as a colourless solid of m.p. >250°C (dec.). c) N,N-Bis[(3,4-bis-benzyloxy-2-pyridyl)methyl]diethylenetriamine g of 3,4-bis-benzyloxypyridine-2-aldehyde are reacted according to the procedure described in Example Id) with 0.81 g (0.5 equivalent) of diethylenetriamine in 50 ml of dioxane and the oily reaction product N,N-bis [(3,4-bis-benzyloxy-2-pyridyl)methylene]diethylenetriamine is reacted in 50 ml of methanol with 0.88 g of sodium borohydride as described in Example lc). From ethyl acetate/cyclohexane, 3.1 g (55% of theory) of the title compound of m.p. 55-57 °c are obtained as the monohydrate. 4. 3,4-Bis-benzvloxv-pvridine-2-aldehyde a) 3,4-Bis-benzyloxy-pyridine-2-aldehyde g of 3,4-bis-benzyloxy-2-hydroxymethylpyridine are dissolved in 500 ml of dioxane and the solution is treated with 50 g of active manganese dioxide. The water of reaction is removed by azeotropic distillation at normal pressure for 20 hours. After filtration, the filtrate is concentrated in vacuo to about 100 ml and treated at 70 to 80eC with diisopropyl ether until it becomes turbid. After cooling, it is filtered. 46.5 g (94% of theory) of the title compound of m.p. 98-100’C are obtained. b) 3,4-Bis-benzyloxy-2-hydroxymethylpyridine - 13 187 g of 3,4-bis-benzyloxy-2-methylpyridine1- oxide are introduced in portions in the course of 2 hours into 500 ml of acetic anhydride at 65°C. The mixture is stirred for a further 2 hours at 65-80°C and excess acetic anhydride is then removed at 10 mbar in a rotary evaporator. The residue is taken up in methanol, and the solution is adjusted to pH 11 to 12 with 300 ml of 2N sodium hydroxide solution and stirred at 80°C for 2 hours. During the course of this, the intermediate 2-acetoxymethyl-3,4-bis-benzyloxypyridine is hydrolysed to 2-hydroxymethyl-3,4-bis-benzyloxypyridine. After cooling, the mixture is extracted twice with 300 ml of dichloromethane each time, the combined organic phases are washed with water, dried over sodium sulphate and concentrated, and the residue is crystallised using diisopropyl ether. 3,4-Bis-benzyloxy-2-hydroxymethylpyridine of melting point 86-88°C are obtained. c) 3,4-Bis-benzyloxy-2-methylpyridine-1-oxide To a solution of sodium benzylalkoxide, prepared from 46 g of sodium hydride (80% strength) and 160 ml of benzyl alcohol in 800 ml of dimethyl sulphoxide is added dropwise with cooling a solution of 192 g of 3-benzyloxy4-chloro-2-methylpyridine-1-oxide in 500 ml of dimethyl sulphoxide and 250 ml of tetrahydro furan in a manner such that the temperature does not exceed 25°C. After stirring at 20°C for 3 hours, water is cautiously added dropwise until the evolution of gas is complete. 10 1 of water are then additionally added and the mixture is stirred for 20 hours. The crystalline precipitate is filtered through a suction filter, washed with water and dissolved in 500 ml of dichloromethane, and the solution is dried over sodium sulphate. The solvent is removed in vacuo in a rotary evaporator and the residue is crystallised from 50/70 petroleum ether. 135 g (55% of theory) of 3,4-bis35 benzyloxy-2-methylpyridine-l-oxide are obtained as a beige-coloured crystallisate of m.p. 118-120eC. d) 3-Benzyloxy-4-chloro-2-methylpyridine-1-oxide 289 g (1.24 mol) of 3-benzyloxy-4-chloro2- methylpyridine are dissolved in 1400 ml of glacial - 14 acetic acid, the solution is heated to 80°C, 3 ml of cone, sulphuric acid are added and 500 ml of 30% strength hydrogen peroxide solution are added dropwise in the course of 1 hour. The mixture is stirred for 20 hours at 80°C and cooled and the mixture at about 50°C is largely concentrated in vacuo. The residue is dissolved in dichloromethane, the peroxides still present are destroyed by cautious addition of manganese dioxide, and the mixture is filtered through celite and concentrated to dryness several times with the addition of toluene. The residue, 292 g (95% of theory) of oily pale yellow 3-benzyloxy-4-chloro-2-methylpyridine-l-oxide is of sufficient purity for a further reaction. On standing for a relatively long time the product crystallises.

For the purposes of characterisation, a sample was crystallised from diethyl ether. 3-Benzyloxy-4chloro-2-methylpyridine-l-oxide is obtained in the form of yellow prisms of m.p. 82-84°C. e) 3-Benzyloxy-4-chloro-2-methylpyridine 150 g (0.7 mol) of 3-benzyloxy-2-methyl-4 [ 1H]pyridone are metered into 1500 ml of phosphorus oxychloride in the course of 1 hour with stirring, the internal temperature rising to 32“C. The mixture is then stirred for 30 hours at 50°C, excess phosphorus oxy25 chloride is distilled off in vacuo and the residue is slowly allowed to run into an ice-cold solution of 280 g of sodium hydroxide in 1.5 1 of water with good stirring. The mixture is extracted three times with 500 ml of toluene each time, and the combined organic phases are washed with water, clarified with tonsil, Celite and active carbon and concentrated completely. 147 g (90% of theory) of 3-benzyloxy-4-chloro-2-methylpyridine are obtained as a pale yellow oil which was further reacted without further purification.

For characterisation, a small part was converted into the hydrochloride in ethereal solution using hydrochloric-acid gas. A colourless crystallisate of m.p. 150-151°C was obtained. - 15 f) 3-Benzyloxy-2-methyl-4-[lHJpyridone 348 g of maltol are dissolved in 13 1 of acetone, 367 g of benzyl chloride and 2 g of potassium iodide are added and the mixture is heated to reflux temperature. 572 g of ground potassium carbonate are then metered in with intensive stirring in the course of 5 hours and the mixture is stirred under reflux for a further 20 hours. After filtration of inorganic salts, the filtrate is completely concentrated in vacuo and the pale yellow, oily residue (3-benzyloxy-2-methyl-4-pyrone) is treated with 2.7 1 of 25% strength ammonia solution. The mixture is heated cautiously to 60 °C in the course of 3 hours and a further 2.8 1 of ammonia solution are metered in in the course of 3 hours. The mixture is then stirred at 80°C for 20 hours, cooled and extracted 4 times with 2 1 of dichloromethane each time, the combined organic phases are washed with 1 1 of water and largely concentrated in a rotary evaporator, and the residue is crystallised by addition of 2 1 of diisopropyl ether. After cooling to °C, the mixture is filtered through a suction filter, and the crystals are washed with diisopropyl ether and dried to constant weight at 40°C in a vacuum drying oven. 421 g (71% of theory) of 3-benzyloxy-2-methyl-4[lHJpyridone are obtained as an ivory-coloured crystallisate of m.p. 168-170°C. . 3,4-Dimethoxypvridine-2-aldehyde According to the procedure described in Example 4a), 100 g of 2~hydroxymethyl-3,4-dimethoxypyridine and 150 g of active manganese dioxide gives, after crystal30 lisation from diisopropyl ether, 75.1 g (76% of theory) of the title compound of m.p. 64-66’C. 6. N-(3-Hvdroxv-4-rlHlPvridon-2-vlmethvl)ethvlenediamine-N,Ν'-diacetic acid dihydrochloride a) N-(3-Hydroxy-4-[1H]pyridon-2-ylmethyl)ethylenedi35 amine-Ν,Ν'-diacetic acid dihydrochloride N- [ (3,4-Bis-benzyloxy-2-pyridyl) methyl J ethylenediamine-Ν,Ν'-diacetic acid is hydrogenated with the addition of 2.1 equivalents of hydrochloric acid, as described in Example la). The title compound is obtained - 16 as a colourless solid of m.p. 226 - 228°C. b) N-[ ( 3,4-bis-benzyloxy-2-pyridyl)methyl]ethylenediamine-Ν,Ν'-diacetic acid 2.0 g (11.4 mmol) of ethylenediamine-N,N'-diace5 tic acid, dissolved in 20 ml of 4N sodium hydroxide solution, are metered into 3,4-bisbenzyloxy-2-chloromethylpyridinium chloride (4.27 g, 11.4 mmol, obtained by reaction of 3,4-bisbenzyloxy-2-hydroxymethylpyridine with thionyl chloride in dichloromethane according to the customary procedure, m.p. 141 - 142°C), dissolved in 40 ml of ethanol, at 60°C in the course of 4 hours. After a further 2 hours at 60°C, the mixture is concentrated, 100 ml of water are added to the residue, and the mixture is adjusted to pH 3 with hydrochloric acid and extracted several times with methylene chloride. After concentration of the organic phase, the product from Example lb) is obtained as a by-product. A colourless solid crystallises from the water phase. It is filtered and dried to constant weight. The title compound of m.p. 92-93°C is obtained. 7. N,N'-Bis (3-hydroxv-4-Γ1H1-pyridon-2-vlmethvl) ethvlenediamine monoacetic acid dihvdrochloride a) N,N'-Bis (3-hydroxy-4-[IH]-pyridon-2-ylmethyl)ethylenediamine monoacetic acid dihydrochloride According to the procedure described in Example la), 0.18 g of N,N'-bis[(3,4-bis-benzyloxy-2-pyridyl)methyljethylenediamine monoacetic acid gives, after crystallisation from methanol/acetone, 0.12 g of the title compound in the form of colourless crystals of m.p. 217-219°C (contains water of crystallisation). b) N,N'-Bis[(3,4-bis-benzyloxy-2-pyridyl)methyl]ethylenediamine monoacetic acid dihydrochloride 1.0 g (1.5 mmol) of N,N'-bis[(3,4-bis-benzyloxy2-pyridyl)methylJethylenediamine are reacted with 0.25 g (1.8 mmol) of bromoacetic acid according to the procedure described in Example lb) and the mixture is worked up. The amorphous residue is dissolved in acetone and treated with 2 equivalents of concentrated hydrochloric acid. The precipitated solid is filtered off with suction and - 17 recrystallised twice from acetone/methanol. 0.8 g of the title compound of m.p. 179-180°c is obtained. 8. N, Ν' -Bis ( 3-hydroxv-4-Γ1H1-pyridon-2-ylmethyl jethvlenediamine tetrahvdrochloride According to the procedure described in Example la), hydrogenation of 1.0 g of N,N'-bis[(3,4-bisbenzyloxy-2-pyridyl)methyl]ethylenediamine in 60 ml of methanol in the presence of 0.1 g of palladium/carbon and 1.5 ml (4 equivalents) of 4N hydrochloric acid gives 0.6 g (89% of theory) of the title compound of m.p. 166°C (dec.). 9. Gadolinium(III) monosodium N,Nr-bis (4-ΓlHlpyridon3-olato-2-ylmethyl)ethylenediamine diacetate tetrahydrate 0.53 g (1 mmol) of N,N'-bis(3-hydroxy-4-[lH]pyridon-2-ylmethyl)ethylenediamine diacetic acid dihydrochloride are dissolved in 5 ml of water. After addition of 1 equivalent of gadolinium trichloride x 6 H2O, the mixture is adjusted to pH 3 with 2N NaOH (4 equivalents) and stirred for 5 hours. The precipitated solid is filtered, washed with water and dried at 50C. 0.48 g of the title compound of m.p. >300°C is obtained.

Analysis; Calculated: C 32.24 H 3.91 N.8.35 Found: C 32.87 H 3.82 N 8.50

Claims (16)

1. Patent Claims

1. Complexing agents of the general formula I Rl — (CH?) —N z n . N—(CH ) —R2 t z n (I), (H 2 C)q (CH 2 )q R3 R4 in which Rl, R2, R3 and R4 are identical or different and stand for H, COOH, C(0)NHR5, where R5 denotes H and ClC4-alkyl, PO 3 H 2 , SOjH and the radical 3-hydroxy-l-(R6)-4-[ 1H]pyridon-2-yl, where R6 denotes H and Cl-C4-alkyl, with the proviso that at least one of the radicals Rl, R2, R3 and R4 has the meaning 3-hydroxy-1-(R6) 4-[1H]pyridon-2-yl where R6 = H and Cl-C4-alkyl, X stands for a single bond, (CH 2 ) n and NR7, where R7 denotes H, Cl-C4-alkyl and (CH 2 ) n Rl and m denotes 1 and 2, n and q stand for integers from 0 to 2, where n and q are identical or different and their sum is at least 1, and p stands for an integer from 1 to 3, but not for 1 when X has the meaning NR7, and their salts with organic and inorganic bases and acids .

2. Complexing agents according to Claim 1, characterised in that in the general formula I Rl, R2, R3 and R4 are identical or different and stand for H, COOH, C(0)NHR5, where R5 denotes H, methyl and ethyl, and the radical 3-hydroxy-4-[lH]-pyridon2- yl, with the proviso that at least one of the radicals Rl, R2, R3 and R4 stands for the meaning

3. - hydroxy-

4. -[1H]pyridon-2-yl, stands for a single bond, CH Z and NR7, where R7 denotes H and (CH 2 ) n Rl, - 19 n and q stand for 1 and p stands for 1 and 2, but not for 1 when X has the meaning NR7 , and not for 2 when X denotes a single bond, 5. And their salts with organic and inorganic bases and acids . 3. Complexing agents according to Claim 1, characterised in that in the general formula I RI, R2, R3 and R4 are identical or different and stand 10 for H, COOH and the radical 3-hydroxy-4-[ 1H]pyridon2- yl, with the proviso that at least one of the radicals RI, R2, R3 and R4 stands for the radical 3- hydroxy-4-[lH]pyridon-2-yl, X stands for a single bond, 15 n stands for 1, q stands for 0 and 1 and P stands for 1, and their salts with organic and inorganic bases and acids. 20 4. Complexing agents according to Claim 1, characterised in that in the general formula I RI, R2, R3 and R4 are identical or different and stand for H, COOH and the radical 3-hydroxy-4-[ lHJpyridon2-yl, with the proviso that at least one of the 25 radicals RI, R2, R3 and R4 stands for the radical 3-hydroxy-4-[1H]pyridon-2-yl, X n q stands for NR7, where R7 denotes (CH 2 ) n Rl, stands for 1, stands for 0 and 1 and 30 P stands for 2, and their salts with organic and inorganic bases and acids .

5. N, N' -bis (3-hydroxy-4 - [ lH]pyridon-2-ylmethyl) ethylenediamine-N,Ν'-diacetic acid, N,N'-bis (3-hydroxy35 4-[lH]pyridon-2-ylmethyl)ethylenediaminemonoacetic acid, N,N' -bis ( 3-hydroxy-4- [ 1H]pyridon-2-ylmethyl) ethylenediamine, N,N-bis(3-hydroxy-4-[lH]pyridon-2-ylmethyl)diethylenetriamine-N,N',N-triacetic acid, N-(3-hydroxy4-[ lH]pyridon-2-ylmethyl)ethylenediamine-N,N',N'-triaceIE 920409 tic acid, N'-(3-hydroxy-4-[lH]pyridon-2-ylmethyl)diethylenetriamine-Ν,Ν,Ν,N-tetraacetic acid and N-(3-hydroxy4-[lH]pyridon-2-ylmethyl)ethylenediamine-N,N'-diacetic acid and their salts with organic and inorganic bases and 5 acids.

6. Complexing agents according to Claim 1, characterised in that one or two of the radicals Rl, R2, R3 and R4 have the meaning H and one or two of the radicals Rl, R2, R3 and R4 have the meaning 3-hydroxy-4-[IH]pyridon10 2-yl, and their salts with organic and inorganic bases and acids .

7. Complexes of paramagnetic metal ions with complexing agents according to Claims 1 to 6 and their salts.

8. Complexes according to Claim 7, characterised in 15 that the paramagnetic metal ions are iron(III), manganese(II) and gadolinium(III).

9. Complexes according to Claim 7, characterised in that they are present as sodium or N-methylglucamine salts. 20

10. Contrast agents for MR diagnosis containing complexes according to Claims 7, 8 and 9.

11. Process for the preparation of complexes, characterised in that compounds of the general formula I, in which Rl, R2, R3, R4, R5, R6, R7, X, m, n, p and q have 25 the meanings given in Claim 1, are reacted with paramagnetic metal ions and, if desired, the complexes obtained are converted into the salts with the aid of strong bases.

12. Process for the preparation of the complexing agents 30 of the general formula I, characterised in that a compound of the general formula I, in which the 3hydroxy-4-[IH]pyridon-2-yl radicals are replaced by 3,4-dihydroxypyridin-2-yl radicals whose hydroxyl groups are protected by protective groups customary for hydroxyl 35 groups, preferably benzyl and methyl, are reacted under conditions which remove the protective groups and, if desired, the 3-hydroxy-4-[IH]pyridon-2-yl radicals are Cl-C4-alkylated in the 1-position. -20a

13. Complexing agents substantially as hereinbefore described with reference to the Examples.

14. Complexes substantially as hereinbefore described with reference to the Examples.

15. A process substantially as hereinbefore described with reference to the Examples.

16. Contrast agents substantially as hereinbefore described with reference to the Examples.