WO1997020841A2 - New macrobicyclic compounds, methods of preparing them and pharmaceutical agents containing them - Google Patents

Abstract

The invention concerns new macrobicyclic compounds of general formula (I) in which R1-R6 are a -CH(R7)-CO2Y grouping, Y being a hydrogen atom and/or an equivalent of an ion of a metal of atomic number 20-29, 31, 32, 37-39, 42-44, 47, 49 or 57-83 and R7 being a hydrogen atom or a branched or unbranched C¿1?-C30 alkyl, C6-C10 aryl or C7-C30 aralkyl group which may be substituted by 1 to 6 hydroxy groups, whereby the carbon chain in the alkyl groups may also include 1 to 10 oxygen atoms and/or be substituted by 1 to 6 -CO2R?8¿ groups, and R8 being hydrogen or a branched or unbranched C¿1?-C4 alkyl or C7-C10 aralkyl group, plus salts of such compounds with inorganic and/or organic bases, aminoacids or aminoacid amines. The metal complexes of these compounds, or pharmaceutical agents containing them, are suitable for use in particular as contrast agents for NMR and X-ray examination purposes.

Description

 New macrobicyclic compounds, processes for their preparation and pharmaceutical compositions containing these macrobicyclic compounds

description

The invention relates to new macrobicyclic compounds, their metal complexes and complex salts, pharmaceutical compositions containing these compounds, their use in diagnostics and therapy and methods for producing these new compounds.

It is known that macropolycyclic compounds with metal ions can form stable mono- and multinuclear complexes with different binding, electrochemical and photophysical properties.

REPLACEMENT BLAπ (RULE 26) For example, de Mendoza et al in "Angewandte Chemie 103 (1991), No. 10 pp. 1365-1366" describe a macrobicyclic tris-2, 2'-bipyridine ligand and Cu2 (I) ^_ and Ag3 (I) - Complexes are described that are important in photochemistry and photophysics and for water splitting.

EP 0 321 353 describes cryptates with rare earth metals which can serve as fluorescent markers and are used for the detection of biological materials.

From "J. Chem. Soc, Chem. Commun., 1992, pp. 602-604" from Beer et al. Macrobicyclic tris-2,2'-bipyridine cryptands and zinc and copper cryptates are known therefrom, which additionally coordinated externally Ruthenium (II) cations included. The cryptates described are of spectro-electrochemical interest.

Macrobicyclic metal complexes are now also used as contrast agents in radio diagnostic techniques such as X-rays, magnetic resonance imaging and nuclear diagnostics.

Some metal complex compounds allow routine use, particularly in magnetic resonance imaging. For example, the dimeglumine salt of Gd DTPA (gadolinium III complex of diethylenetriaminepentaacetic acid) described in EP 0 071 564 and the meglumine salt of Gd DOTA (gadolinium III complex of 1, 4, 7, 10-tetracarboxymethyl-l, 4, 7, 10-tetraazacyclododecane) proven as a contrast agent for magnetic resonance imaging. They have been registered under the names Magnevist® and Dotarem®.

REPLACEMENT BLAπ (RULE 26) A major reason for their good applicability in the clinic is their high level of vigor in magnetic resonance imaging, especially in many brain tumors. You can therefore use 0.1 mmol / kg

Body weight are dosed much lower than, for example, X-ray contrast media in many X-ray examinations. However, these compounds are unsuitable as X-ray contrast agents and for NMR diagnosis of certain diseases outside the central nervous system because of their high osmomality.

EP 0 485 045 A2 describes macrocyclic metal complexes with reduced osmolality. These are tetraazacyclododecane compounds and their bis-gadolinium and bis-ytterbium complexes.

However, these compounds are also not optimal as X-ray contrast media with regard to the desired high metal atom density and the desired very good water solubility at the same time.

It was therefore an object of the invention to provide compounds which have a high metal atom density and, at the same time, very good water solubility, if possible> 1 g / ml of water, and are therefore also very suitable for use in NMR and X-ray diagnostics. In addition, the compounds should, of course, be well tolerated and, if possible, give rise to no or only extremely low cardiovascular or allergic side effects.

REPLACEMENT BLAπ (RULE 26) The object of the invention is achieved by new macrobicyclic compounds of the general formula I.

gelöst, in der

solved in the

R! -R ^{6 represent} the radical -CH (R ⁷ ) -CÜ2Y, where Y is a hydrogen atom and / or a metal ion equivalent of an element of atomic numbers 20-29, 31, 32, 37-39, 42-44, 47, 49 or 57-83 means and

R 'is a hydrogen atom or an optionally substituted with 1 to 6 hydroxyl groups, branched or unbranched Cχ-C3Q-alkyl, ^c 6 ~ ^c 10 ~ ^Ar y ^1- or C7-C3Q-aralkyl group, the alkyl groups optionally being 1 to 10 Oxygen atoms are interrupted and / or substituted by 1 to 6 -Cθ2R ⁸ groups, and

REPLACEMENT BLAπ (RULE 26) R ^{8 is} hydrogen or a branched or unbranched C] _- C4-alkyl or C7-C10 "aralkylyl group

and their salts with inorganic and / or organic bases, amino acids or amino acid amides.

Compounds of general formula I with Y in the

The meaning of hydrogen is referred to as a complexing agent and with at least two of the substituents Y in the meaning of a metal ion equivalent as metal complexes.

It was found that the complexing agents of the general formula I according to the invention can complex up to 3 metal atoms and thus form homo- or heterotrinuclear metal complexes with a sufficiently high metal atom density. The good water solubility is achieved by the residues R ^ -R ^. Because of the high metal atom density and the water solubility of the compounds of general formula I according to the invention of 1 g / ml of water and more, galenical formulations of these compounds can also be used very well as in vivo contrast media, in particular for NMR and X-ray diagnostics.

In addition to the "simple" cage connections according to general formula I, two or more such cages can also be coupled to one another and used as contrast agents in conventional radio diagnostic techniques such as X-rays, magnetic resonance imaging and nuclear diagnostics.

REPLACEMENT BLAπ (RULE 26) It has been found that particularly suitable compounds are those in which at least two of the substituents Y are metal ion equivalents of at least one element of atomic numbers 20-29, 31, 32, 37-39, 42-44, 47, 49 or 57-83 or a radionuclide an element of atomic numbers 21, 26, 27, 29, 31, 32, 37-39, 43, 47, 49, 62-64, 67, 70, 71, 75, 77, 79 and 83. Particularly preferred compounds are those in which three of the substituents Y are metal ion equivalents of at least one element with the atomic numbers 21-29, 42-44 and 58-70.

According to the invention, the compounds are very particularly preferred in which at least two of the substituents Y by the metal ions Mn ²⁺ , Fe ³⁺ , Co ³⁺ , Ni ²⁺ , Cu ² +, Pr ³⁺ , Nd ³⁺ , Sm3 ⁺ , Yb ³⁺ , Eu ²⁺ , Eu ³⁺ , Gd ³⁺ , Tb ³⁺ , Dy ³⁺ , Ha ³⁺ or mixtures thereof. Such heterotrinuclear metal complexes of the general formula I with the metal ions Cu ²⁺ / Fe ³⁺ / Cu ²⁺ ' ^* Gd ³⁺ / Mn ²⁺ / Gd ³⁺ are particularly suitable; Fe ³⁺ / Mn ²⁺ / Fe ³⁺ ; Cu ²⁺ / Mn ²⁺ / cu ²⁺ ; Gd ³⁺ / Fe ^{3 + /} Gd ³⁺ .

The radical R ⁷ represents in the general formula I is preferably a Cι-C20 ^-A lkyl- or C7 ~ C20 ~ aralkyl group wherein the alkyl group branched, unbranched, may be saturated or unsaturated and optionally substituted by 1 to 6, preferably 1 to 3, hydroxy groups. The alkyl groups in the R ⁷ radical can also preferably be interrupted by 1 to 5 oxygen atoms and / or substituted by 1 to 3 -CO2R ⁸ groups, for example by -CO2CH3, - CO2C2H5, -Cθ2iProp, -Cθ2tBut or -CO2CH2C6H5.

REPLACEMENT BLAπ (RULE 26) Examples of preferred radicals R ⁷ are: -CH ₃ , -C ₂ H ₅ , -iC ₃ H ₇ , -C ₈ H ₁₇ , -C ₁₅ H ₃₁ , -C ₁₆ H ₃₃ , -C ₁₇ H ₃₅ , - CH ₂ OH, -CH ₂ CH ₂ OH, -CH (OH) CH ₂ OH, -C ₆ H ₅ , -CH ₂ C ₆ H ₅ , -CH (OH) CH (OH) CH ₂ OH, -OCH3, -OC ₂ H ₅ , -OCH ₂ C ₆ H ₅ , -OCH ₂ CH ₂ OCH ₃ ,

-OCH2CH2OCH2CH2OH, - (CH ₂ ) 5θH, -CH ₂ C0 ₂ H, - (CH ₂ ) 2C0 ₂ H, -0CH ₂ C0 ₂ H, -0 (CH ₂ ) 5CO2H, -CH ₂ C0 ₂ C ₂ H ₅ , -CH ₂ C0 ₂ iC ₃ H ₇ , -CH ₂ -0-CH (C02H) -CH ₂ C0 ₂ H, -0-CH ₂ -CH (OCH3) -CH ₂ -0CH ₃

Particularly preferred radicals for R ⁷ are hydrogen, -CH ₂ OH, -CH ₂ CH ₂ OH or -CH (OH) CH ₂ OH.

The remaining acidic hydrogen atoms, that is to say those which have not been substituted by the central ion, can optionally be wholly or partly replaced by cations of inorganic and / or organic bases, amino acids or amino acid amides.

Suitable inorganic cations are, for example, lithium ion, potassium ion, calcium ion, magnesium ion, zinc ion and in particular sodium ion. Suitable cations of organic bases include those of primary, secondary or tertiary amines, such as ethanolamine, diethanolamine, morpholine, glucamine, N, N-

Dimethylglucamine and especially N-methylglucamine. Suitable cations of amino acids are, for example, those of lysine, arginine and ornithine and the amides of otherwise acidic or neutral amino acids such as e.g. Lysine methyl amide, glycine ethyl amide and serine methyl amide.

REPLACEMENT BLAπ (RULE 26) The macrobicyclic compounds of general formula I according to the invention are prepared by using the macrobicyclic polyamine of general formula II

in water or in water-miscible solvents or their mixtures with water with heating to 30-90 ° C. and after adding an inorganic and / or organic base with an ester compound of the general formula III

Hal-CH (R ⁷ ) -C0 ₂ R: II D

implements in the

R ^{7 has} the abovementioned meaning, hydroxyl groups which may be present in the radical R ^{7 being} optionally protected

REPLACEMENT BLAπ (RULE 26) R ^{9 represents} an acid protecting group and

Hal stands for Cl, Br or J, then splits off all protective groups and thus receives complexing agents (Y = H), if desired for the production of metal complexes with at least one metal oxide or metal salt of an element of atomic numbers 20-29, 31, 32, 37-39, 42-44, 47, 49 or 57-83 and then - if desired - existing acidic hydrogen atoms substituted by cations of inorganic and / or organic bases, amino acids or amino acid amides.

As water-miscible solvents, e.g. Acetonitrite, DMF, DMA, ethanol, methanol, dioxane, THF, DMSO, DME or a mixture thereof can be used.

Potassium, sodium, lithium, calcium, barium or magnesium oxide or sodium or potassium carbonate are suitable as inorganic bases. Triethyl-, tripropyl, tributylamine,

Pyridine, DMAP, Reillex®, Triton B® can be used.

Hydroxy protective groups R ⁹ are all those which are easy to introduce and later regress to the ultimately desired free ones

Allow the hydroxy group to be easily split off again. Preferred protecting groups are ether groups such as e.g. the benzyl, 4-methoxybenzyl, 4-nitrobenzyl, trityl, di and triphenylmethyl, trimethylsilyl, dimethyl-t-butylsilyl, diphenyl-t-butylsilyl group. However, the hydroxyl groups are preferably protected in the form of ketals with, for example, acetone, acetaldehyde, cyclohexanone or benzaldehyde.

REPLACEMENT BUIP (RULE 26) The hydroxyl protective groups are split off in a manner known per se, for example in the case of a benzyl ether by reductive cleavage with lithium ammonia or by hydrogenolytic cleavage in the presence of, for example, palladium-carbon and in the case of ether or ketal cleavage by acid treatment with the aid of, for example Cation exchangers, trifluoroacetic acid or mineral acids [see, for example, TW Greene "Protective Groups in Organic Synthesis", John Wiley and Sons (1991)].

Suitable acid protective groups are C 1 -C 6 -alkyl, Cg-Cig-aryl and C 6 -C 6 -ar (C1-C4) -alkyl groups and trialkylsilyl groups. The methyl, ethyl, propyl, ^ ^" propyl, n-butyl, - * ^" butyl and the ^{tert • "} butyl group are preferred.

The cleavage of this acid protective groups takes place according to known in the art methods, for example by hydrolysis, hydrogenolysis, alkaline saponification of esters with alkali in aqueous-alcoholic solution at temperatures of 0 to 50 ° C, acid saponification with mineral acids or in the case of ^tert - ^"butyl esters with the help of trifluoroacetic acid.

The compound of general formula II is prepared in a manner known per se - such as e.g. in "J. Chem. Soc, Chem Commun, 1992 pp. 602-603" - by reaction of TREN (tris (2-aminoethyl) amine), which is known as an excellent ligand for transition metal ions, with 5, 5 ' -Diformyl-2, 2'-bipyridine and subsequent hydrogenation to macrobicyclic polyamine II.

REPLACEMENT BLAπ (RULE 26) The metal complexes according to the invention are prepared in the manner disclosed in German Offenlegungsschrift 34 01 052 by adding the metal oxide or a metal salt (for example the nitrate, acetate, carbonate, chloride or sulfate of the element of atomic numbers 20-29), 31, 32, 37-39, 42-44, 47, 49, 57-83) dissolved or suspended in water and / or a lower alcohol (such as methanol, ethanol or isopropanol) and with the solution or suspension of the equivalent amount of the complexing Reacts ligands and then - if desired - substitute existing acidic hydrogen atoms with cations of inorganic and / or organic bases or amino acids.

The desired metal ions can be introduced either before or after the hydroxyl protective groups are split off.

Any free carboxy groups still present are neutralized with the aid of inorganic bases (for example hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium, lithium, magnesium or calcium and / or organic bases, such as primary, secondary and tertiary amines, such as Example ethanolamine, morpholine, glucamine, N-methyl and N, N-dimethylglucamine, as well as basic amino acids, such as lysine, arginine and ornithine or amides of originally neutral or acidic amino acids.

To prepare the neutral complex compounds, for example, the acidic complex salts in aqueous solution or suspension can contain as much of the desired bases

REPLACEMENT BLAπ (RULE 26) add that the neutral point is reached. The solution obtained can then be evaporated to dryness in vacuo. It is often advantageous to neutralize the formed salts by adding water-miscible solvents such as lower alcohols (methanol, ethanol, isopropanol and others), lower ketones (acetone and others), polar ethers (tetrahydrofuran, dioxane, 1,2) -Dimethoxyethane and others) to precipitate and to obtain crystals that are easy to isolate and easy to clean. It has proven to be particularly advantageous to add the desired base already during the complex formation of the reaction mixture and thereby to save one process step.

Another possibility of obtaining neutral complex compounds is to convert all or part of the remaining acid groups in the complex into, for example, esters or amides. This can be done by subsequent reaction on the finished complex (e.g. by exhaustive reaction of the free carboxy groups with dimethyl sulfate).

According to the invention, the compounds of general formula I or their pharmaceutical agents are preferably used as in vivo contrast agents for MRI (magnetic resonance images) and as in vivo x-ray contrast agents. Furthermore, they are used as contrast agents for nuclear diagnostics, the metal ions of the elements being present as radioactive isotopes, or as susceptibility reagents in NMR diagnostics. The compounds according to the invention can also be used in neutron capture therapy, in positron

REPLACEMENT BLAπ (RULE 26) Emission tomography (PET), and used as a luminescence marker in biology and medicine. Compounds with the metal ions Eu ³⁺ , Tb ³⁺ , Gd ³⁺ are particularly preferably used as luminescence markers.

The invention also relates to pharmaceutical compositions which contain at least one physiologically tolerable compound of the general formula I, if appropriate with the additives customary in galenics.

In particular, the pharmaceutical compositions are suitable for enteral and parenteral use. The pharmaceutical compositions are prepared by bringing a metal complex of the general formula I, dissolved or suspended in water, physiological salt or protein solution, optionally with the additives customary in galenics, into a form suitable for enteral or parenteral administration.

Suitable additives are, for example, physiologically acceptable buffers (such as tromethamine), additives of complexing agents (such as diethylenetriaminepentaacetic acid) or - if necessary - electrolytes such as e.g. Sodium chloride - or if necessary - antioxidants such as Ascorbic acid.

If suspensions or solutions of the agents according to the invention in water or physiological saline solution are desired for enteral administration or other purposes, they are combined with one or more auxiliary substances (e.g. methyl cellulose, lactose, mannitol) and / or surfactants (e.g. lecithins) , Tween®,

ERSATZBUπ (RULE 26) Myrij® and / or flavoring (s) mixed for flavor correction (e.g. essential oils).

In principle, it is also possible to use the pharmaceutical compositions according to the invention without isolating the

To produce complex salt. In any case, special care must be taken to carry out the complex formation so that the salts and salt solutions according to the invention are practically free of non-complexed toxic metal ions.

This can be ensured, for example, with the help of color indicators such as xylenol orange through control titrations during the manufacturing process. The invention therefore also relates to processes for the preparation of the complex compounds and their salts. The final security is cleaning the isolated complex salt.

The pharmaceutical compositions according to the invention preferably contain 0.1 μmol-3 mol / l of the complex salt and are generally metered in amounts of 0.1 μmol / kg. They are intended for enteral and parenteral administration.

If the agent according to the invention is intended for use in NMR diagnostics, the central ion of the complex salt must be paramagnetic. These are in particular the divalent and trivalent ions of the elements of atomic numbers 21-29-42, 44 and 58-70. Suitable ions are, for example, chromium (III), manganese (II), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III ) -, samarium (III) - and ytterbium (III) ion. Because of their very strong magnetic moment are particularly preferred

REPLACEMENT BUIP (RULE 26) the gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III) and iron (III) ions.

The central ion must be radioactive for the use of the agents according to the invention in nuclear medicine. For example, radioisotopes of the elements copper, cobalt, gallium, germanium, yttrium, strontium, technetium, indium, ytterbium, gadolinium, samarium, silver, gold, rhenium and iridium are suitable.

If the agent according to the invention is intended for use in X-ray diagnostics, the central ion must be derived from an element with a higher atomic number in order to achieve sufficient absorption of the X-rays. It has been found that diagnostic agents containing a physiologically compatible complex salt with central ions of elements of atomic numbers between 21-29, 42, 44, 57-83 are suitable for this purpose; these are, for example, the lanthanum (III) ion and the above-mentioned ions of the lanthanide series.

To summarize:

The complex compounds according to the invention are used

1.) for NMR and X-ray diagnostics in the form of their complexes with the ions of the elements with atomic numbers 21-29, 42, 44 and 57-83;

2.) for radio diagnostics and radiotherapy in the form of their complexes with the radioisotopes of elements with atomic numbers 21, 26, 27, 29, 31, 32, 37-

REPLACEMENT BUIP (RULE 26) 39, 43, 47, 49, 62-64, 67, 70, 71, 75, 77, 79 and 83.

The agents according to the invention meet the diverse requirements for their suitability as contrast agents for magnetic resonance imaging. After enteral or parenteral application, they are ideally suited to improve the meaningfulness of the image obtained with the aid of an MRI scanner by increasing the signal intensity. They also show the high effectiveness that is necessary to burden the body with the smallest possible amount of foreign substances and the good tolerance that is necessary to maintain the non-invasive character of the examinations.

The good water solubility and low osmolality of the agents according to the invention make it possible to produce highly concentrated solutions, so that the volume load of the circulation is kept within reasonable limits and the dilution is compensated for by the body fluid, i.e. NMR diagnostics have to be 100 to 100 times more soluble in water than for NMR - spectroscopy. Furthermore, the agents according to the invention not only have high stability in vitro, but also surprisingly high stability in vivo.

In general, the agents according to the invention for use as NMR diagnostic agents are dosed in amounts of 0.0001-5 mmol / kg, preferably 0.005-0.5 mmol / kg. Details of the application are e.g. in H.J. Weinmann et al .; At the. J. of Roentgenology 142, 619 (1984).

REPLACEMENT BUIP (RULE 26) Furthermore, the complex compounds according to the invention can advantageously be used as susceptibility reagents and as shift reagents for in vivo NMR spectroscopy.

Because of their favorable radioactive properties and the good stability of the complex compounds they contain, the agents according to the invention are also suitable as radio diagnostic agents. Details of the use of radio diagnostics and dosage are e.g. in "Radiotracers for Medical Applications", CRC Press, Boca Raton, Florida.

Another imaging method with radioisotopes is positron emission tomography, which uses positron-emitting isotopes such as ^ ³ Ξc, ^ Sc, 52 _{Fθ /} 55 _{Co unc} j 68 _Ga (Heiss. WD: Phelps, ME; Positron Emission Tomography of Brain , Springer Verlag Berlin, Heidelberg, New York 1983).

The compounds according to the invention can also be used in radioimmunotherapy or radiation therapy. This differs from the corresponding diagnostics only in the amount and type of isotope used. The goal is the destruction of tumor cells by high-energy short-wave radiation with the shortest possible range. Suitable β-emitting ions are, for example, ⁴⁶ Sc, ⁴⁷ Sc, ⁴⁸ Sc, ⁷² Ga, ⁷³ Ga and ⁹⁰ Y. Suitable α-emitting ions with short half-lives are, for example, ²¹¹ Bi, ²¹² Bi, ²¹³ Bi, and ² ^ ⁴ Bi , ² ^ ² Bi being preferred. A suitable photon and electron emitting ion is I ^ Q ^ which can be obtained from ¹⁵⁷ Gd by neutron capture.

REPLACEMENT BUIP (RULE 26) Is the agent according to the invention for use in the RL Mills et al. [Nature Vol. 336, (1988), p. 787] proposed variant of radiation therapy, the central ion must be derived from a Mössbauer isotope such as ^ Fe or l ^^ Eu.

In the in vivo application of the therapeutic agents according to the invention, these can be used together with a suitable carrier such as e.g. Serum or physiological saline and can be administered together with another protein such as human serum albumin. The dosage depends on the type of cellular disorder, the metal ion used and the type of method, e.g. Brachytherapy.

The therapeutic agents according to the invention are preferably administered parenterally.

Details of the use of radiotherapeutics are e.g. in R.W. Kozak et al. TIBTEC, October 1986, 262 discussed.

The agents according to the invention are outstandingly suitable as X-ray contrast agents, and it should be emphasized in particular that they show no signs of the anaphylaxis-like reactions known from the iodine-containing contrast agents in biochemical-pharmacological studies. They are particularly valuable because of the favorable absorption properties in areas of higher

Tube voltages for digital subtraction techniques. In general, the agents according to the invention are used for use as X-ray contrast agents in analogy to e.g. Meglumine diatrizoate in amounts of 0.1-5 mmol / kg, preferably 0.25-1 mmol / kg.

REPLACEMENT BUIP (RULE 26) Details of the use of X-ray contrast media are discussed, for example, in Barke, X-ray contrast media, G. Thieme, Leipzig (1970) and P. Thurn, E. Bücheier - "Introduction to X-ray diagnostics", G. Thieme, Stuttgart, New York (1977).

Overall, it has been possible to synthesize new complexing agents, metal complexes and metal complex salts with the macrobicyclic compounds of the formula I, which open up new possibilities in diagnostic and therapeutic medicine. In particular, the development of new imaging methods in medical diagnostics makes this development appear desirable.

The following examples serve to explain the subject of the invention in more detail without restricting it:

Embodiment 1

Preparation of a complexing agent according to the general formula I with R ^ -Rg in each case -CH ₂ -COOH

a) Preparation of the macro cycle

A solution of TREN (tris (2-aminoethyl) amine) in dry acetonitrile is added to a suspension of the dialdehyde at room temperature under an argon atmosphere

REPLACEMENT BUIP (RULE 26) 5,5'-Diformyl-2,2'-bipyridine added dropwise in acetonitrile. The orange-colored precipitate obtained is filtered off and recrystallized from methanol to form colorless crystals.

b) hydrogenation to the starting compound II

The macrobicyclic sixfold Schiff base (21.6 g corresponding to 26 mmol) prepared under a) is dissolved in 750 ml of methanol. The solution is heated to 40 ° C. and solid NaBH4 (21.5 g corresponding to 570 mmol) is carefully added with stirring. A strong gas development is observed. After the addition has ended, the mixture is stirred at 40 ° C. for one hour and then filtered. The methanol is removed in vacuo on a rotary evaporator. 133 ml of water and 860 ml of dichloromethane are added to the solid. The mixture is stirred until the solid has dissolved. The aqueous phase is discarded, the dichloromethane is removed in vacuo and the colorless solid obtained is dried in a high vacuum.

Yield: 20 g (92%) colorless powder

c) reaction of II with ester compound III

II (20 g = 24 mmol) is dissolved in a mixture of 49 ml of water and 400 ml of dioxane while heating to 80 ° C. After the addition of LiOH (4.4 g = 186 mmol), the mixture is allowed to cool to 40 ° C. and the tert-butyl bromoacetic acid (33.7 g £ 173.7 mmol, corresponding to 25.3 ml) is added dropwise within 30 min. The mixture is stirred at this temperature for about 12 hours, a yellowish solution with suspended white solid being obtained. The solvent is in a vacuum

REPLACEMENT BUIP (RULE 26) removed on a rotary evaporator at approx. 40 ° C. and the residue extracted with a mixture of 160 ml of water and 800 ml of dichloromethane. It is filtered and the phases are separated. The aqueous phase is discarded, the solvent is removed from the organic phase in vacuo using a rotary evaporator. The slightly yellowish glassy solid is then dried under high vacuum for 12 hours.

Yield: 21 g corresponding to 58%

Elimination of the hydroxyl protective groups

Then the one produced under c)

Compound (16.7 g corresponding to 11 mmol) dissolved in 130 ml trifluoroacetic acid and the mixture stirred at 25 ° C for 28 hours. The acid is then removed in vacuo at 40 ° C. 30 ml of water are added 3 times and the water is removed in vacuo each time at 40.degree. The residue is dissolved in 130 ml of water and extracted with 3 times 55 ml of toluene at 70 ° C. The organic phase is discarded and the aqueous mixture is stirred at 80 ° C. for 1 hour with about 1 g of activated carbon. The mixture is then filtered, the solution is concentrated in vacuo on a rotary evaporator at 40 ° C. and the residue is then dried in a high vacuum for 12 hours.

Further cleaning is carried out using a weakly basic ion exchanger (Reilex, polyvinylpyridine). To do this, the crude product is dissolved in 60 ml of water and chromatographed on a 3.5 by 6.5 cm column of the ion exchanger, of which 10 g are used. You elute with water for so long

REPLACEMENT BUIP (RULE 26) (approx. 0.5 1) until the solution runs colorless or until a test with Fe ²⁺ reacts only weakly. The water is removed in vacuo on a rotary evaporator and the glassy red solid which remains is dried for 12 hours under high vacuum. It is then largely crushed and dried again at 10 ^~ 6 mbar for 36 hours.

Yield of compound I: about 14 g corresponding to about 90 '

ERSATZBUπ (RULE 26) e) NMR spectroscopic characterization of the complexing agent I obtained in step d)

^X H-NMR spectrum (500 MHz) in D ₂ 0 / Me ₃ Si (CH ₂ ) ₃ Na (80 ° C) pH 6-7

δ (ppm) integral

8, 90-8, 30 m 6 H bipyridine H-6

8, 30-7, 40 m 12 H bipyridine H-3, H-4

4, 80-2, 60 m 55 H aliphatic protons, HDO

intense signals in the aliphatic range

4.45 s approx. 6 h

3.93 s (br)

3.51 s (br)

3.17 m (br)

2.99 m (br)

"C ^ H) NMR spectrum (125.7 MHz) in D ₂ 0 (80 ^C C) pH 6-7

δ (ppm) APT

177.5 Cq COOH

157.6 cq bipyridine

153.3 bipyridine

142.1 bipyridine

135.0 bipyridine

124.5 bipyridine

60.5 CH ₂ ethano and methylene groups

59.6 CH ₂ ethano and methylene groups

53.0 CH ₂ ethano and methylene groups

52.2 CH ₂ ethano and methylene groups

All signals are greatly broadened

ERS _A TZBUπ (RULE 26) Example 2:

Production of a metal complex with three gadolinium ions

130 mg (corresponding to l, lxl0 ^{~ 4} mol) of compound I from Example 1 are boiled in 15 ml of acetonitrile / methanol solution (1: 2) with 5 ml of trimethyl orthoformate under a nitrogen atmosphere under reflux for 2 hours. 132.6 mg of GdCl3xH ₂ 0 are also refluxed in 15 ml of methanol with 5 ml of trimethyl orthoformate in a nitrogen atmosphere for 2 hours. The gadolinium salt solution is added dropwise to the solution of I with stirring and boiled under reflux for 24 hours.

The solvent is then removed in vacuo.

Yield: 150 mg

Example 3:

Production of a metal complex with Mn ²⁺ Gd ³⁺ Mn ²⁺ ions

The gadolinium complex of I is prepared analogously to Example 2. The gadolinium complex is then dissolved in 15 ml of water and heated to 80 ° C. with stirring.

25.3 mg (corresponding to 2.2 × 10 ^-4 mol) of manganese carbonate is dissolved in 10 ml of water with stirring, if necessary with heating. This solution is slowly dripped into the gadolinium complex solution in the heat,

REPLACEMENT BUILD (RULE 2 » then stirred for 24 hours at 80 ° C and then freeze-dried.

Yield: 117 mg

Embodiment 4

Production of a metal complex with Cu ²⁺ Gd ³⁺ Cu ²⁺ ions

The gadolinium complex obtained in Example 2 is dissolved in water and heated to 80 ° C., then 35 mg of copper sulfate, dissolved in 10 ml of water, are added, and the mixture is then stirred at 80 ° C. for 24 hours. The solution obtained is passed through an ion exchanger. The aqueous solution obtained is then freeze-dried to obtain the corresponding heterometal complex.

The lanthanide complex obtained in this way has high magnetic properties, which indicate molecular ferromagnets.

Example 5:

Production of a metal complex with Mn ²⁺ Fe ³⁺ Mn ²⁺ ions

130 mg (corresponding to 1, lxl0 ^{~ 4} mol) of compound I from Example 1 are dissolved in 15 ml of water with stirring and heated to 80 ° C. With stirring, an iron III chloride solution (l, lxl0 ^{~ 4} mol) in 10 ml of water

REPLACEMENT BUIP (RULE 26) solved. The resulting solution with dark red color is then stirred at 80 ° C for 12 hours. 25.3 mg of manganese carbonate, dissolved in 10 ml of water, are then slowly added to the iron solution. The mixture obtained is stirred for a further 24 hours at 80 ° C. and then freeze-dried.

Embodiment 6

Production of a metal complex with three iron ions

In analogy to example 2, I is complexed with 3 iron ions.

The complex has the following physical properties: Solubility in water:> 1 g / g susceptibility in water: χ> 0, i.e. paramagnetic behavior can be observed,

Embodiment 7

Preparation of a pharmaceutical formulation of the metal complex from compound I with three gadolinium ions (I Gd3> from example 2 for NMR and X-ray diagnostics

A formulation of the following composition per ml is produced:

I Gd ₃ 1181.00 mg

I 2.36 mg

Trometamol 1.21 mg

REPLACEMENT BUIP (RULE 26) pH adjusted to 7.2 with HCl ad 1 ml with water pi

The aqueous formulation thus obtained can be prepared pharmaceutically in a conventional manner and can be autoclaved in the final container.

ERSATZBUπ (REGEL26)

Claims

 Claims 1. Macrobicyclic compounds of the general formula I

in the Ri-R ^{6 represent} the radical -CH (R ⁷ ) -C0 ₂ Y, where Y represents a hydrogen atom and / or a metal ion equivalent of an element of atomic numbers 20-29, 31, 32, 37-39, 42-44, 47, 49 or 57-83 and R is a hydrogen atom or a branched or unbranched one which is optionally substituted by 1 to 6 hydroxyl groups

C6 ~ ^C 10 ^-Ar yl ~ or C ₇ -C3o-aralkyl group, the alkyl groups optionally interrupted by 1 to 10 oxygen atoms ERS _A TZBUπ (RULE 26) and / or are substituted by 1 to 6 -C0 ₂ R ⁸ groups, and R ^{8 is} hydrogen or a branched or unbranched C 1 -C ₄ -alkyl or C ₇ -CIQ ^~ aralkylyl group and their salts with inorganic and / or organic bases, amino acids or amino acid amides. 2. Compounds according to claim 1, characterized in that R ^{7 is} a Cχ-C ₂ o ~ ^A l ^k yl "'C ₇ -C ₂ o ^~ aralkyl or Cg-Cιo ^_Arv l9 ^ru PP ^e , which is by 1 to 3 OH groups is substituted. 3. Compounds according to claim 1 or 2, characterized in that the alkyl groups in the radical R ^{7 are} interrupted by 1 to 5 oxygen atoms and / or are substituted by 1 to 3 -C0 ₂ R ⁸ groups. 4. Compounds according to claim 1, characterized in that R ^{7 is} a hydrogen atom. Compounds according to one of Claims 1 to 4, characterized in that Y represents hydrogen atoms. REPLACEMENT BUIP (RULE 26) 6. Compounds according to any one of claims 1 to 5, characterized in that at least two of the substituents Y metal ion equivalents of at least one element of the atomic numbers 20-29, 31, 32, 37-39, 42-44, 47, 49 or 57-83 or a radionuclide of an element of atomic numbers 21, 26, 27, 29, 31, 32, 37- 39, 43, 47, 49, 62-64, 67, 70, 71, 75, 77, 79 and 83 mean. 7. Compounds according to claim 6, characterized in that three of the substituents Y are metal ion equivalents of at least one element with the atomic numbers 21-29, 42-44 and 58-70. 8. Compounds according to any one of claims 1 to 7, characterized in that at least two of the substituents Y equivalents of the ions Mn ²⁺ , Fe ³⁺ , Co ³⁺ , Ni ²⁺ , Cu ² +, Pr ³⁺ , Nd ³⁺ , Sm ³⁺ , Yb ³⁺ , Eu ²⁺ , Eu ³⁺ , Gd ³⁺ , Tb ³⁺ , Dy ³⁺ , Ho ³⁺ or mixtures thereof are. REPLACEMENT BUIP (RULE 26) 9. Compounds according to claim 7 or 8, characterized in that three of the substituents Y are replaced by equivalents of the following metal ion combinations: _Cu 2+ _Fe 3+ _Cu 2+ _or Gd ³⁺ Mn ²⁺ Gd ³⁺ or Fe ³⁺ Mn ²⁺ Fe ³⁺ or Cu ²⁺ Mn ²⁺ Cu ²⁺ or _Gd 3+ _Fe 3+ _G d ³ +. ERSATZBUπ (RULE 26) 10. Process for the preparation of macrobicyclic compounds of the general formula I,

characterized in that the macrobicyclic polyamine of the general formula II REPLACEMENT BUIP (RULE 26)

in water or in water-miscible solvents or their mixtures with water with heating to 30-90 ° C and after adding an inorganic and / or organic base with an ester compound of general formula III Hal-CH (R ⁷ ) -C0 ₂ R in: in the R has the abovementioned meaning, hydroxyl groups which may be present in the R ⁷ radical being optionally protected R9 represents a hydroxy protecting group and Hal is Cl, Br or J, REPLACEMENT BUIP (RULE 26) reacted, then split off the hydroxyl protective groups and thus obtain complexing agents (Y = H), if desired for the production of metal complexes with at least one metal oxide or metal salt of an element of atomic numbers 20-29, 31, 32, 37-39, 42-44, 47, 49 or 57-83 and then - if desired - substitute existing acidic hydrogen atoms with cations of inorganic and / or organic bases, amino acids or amino acid amides. 11. Use of at least one physiologically compatible compound according to claims 1 to 9 in NMR, X-ray or radio diagnostics, in radioimmunotherapy, radiation or neutron capture therapy. 12. Use according to claim 11 as in-vivo Contrast agent for NMR or X-ray diagnostics. ERSATZBUπ (REGEL26)