EP0357622A1 - Substituted complex-forming substances, complexes and complex salts, process for manufacture thereof and pharmaceutical agents which contain them - Google Patents

Abstract

Compounds of general formula (I), where n and m each represent the numbers 0, 1, 2, 3 and 4, X represents a hydrogen atom and / or an equivalent in metal ions of an element of ordinal numbers 21 -29, 31, 32, 37-39, 42-44, 49 or 57-83, R1 and R2 are different and each represents a hydrogen atom or a C0-C20 alkylene group with straight or branched chain, saturated or unsaturated , optionally containing one or more imino, phenyleneoxy, phenyleneimino, amido, hydrazido, ester, one or more oxygen, sulfur and / or nitrogen atoms, and optionally substituted by one or more hydroxy, mercapto, imino groups, epoxy, oxo, thioxo, and / or amino, said group having at its end a second molecule of general formula (IA) or (IB), a functional group or else, linked via this functional group, a bio- or macromolecule, provided that the sum of n and m is not more than 4 and that, when X represents an equivalent in metal ions, at least two of the X substituents have this notation, as well as their salts with inorganic or organic bases or amino acids are valuable diagnostic and therapeutic agents.

Description

SUBSTITUTED COMPLEX ILLUMINATORS, COMPLEX AND COMPLEX SALTS, METHOD FOR THE PRODUCTION THEREOF AND THEY CONTAIN PHARMACEUTICAL AGENTS

The invention relates to the subject matter characterized in the patent claims, that is to say new complexing agents, complexes and complex salts, agents containing these compounds, their use in diagnostics and therapy, and methods for producing these compounds and agents.

The use of complexing agents or complexes or their salts in medicine has long been known. Examples include:

Complexing agents as stabilizers of pharmaceutical preparations, complexes and their salts as auxiliaries for the administration of poorly soluble ions (eg iron), complexing agents and complexes (preferably calcium or zinc), optionally as salts with inorganic and / or organic bases, as antidotes for detoxification Accidental incorporation of heavy metals or their radioactive isotopes and complexing agents as tools in nuclear medicine using radioactive isotopes such as ^99m Tc for scintigraphy are known.

In the patent DE-OS 3401052 paramagnetic complex salts have recently been proposed as diagnostics, predominantly as NMR diagnostics.

All previously known complexes and their salts present problems with regard to the compatibility and / or selectivity of the binding and / or stability in their clinical use. These problems are more pronounced the higher the products derived from the complexing agents have to be dosed. The use of heavy elements as components of parenteral X-ray contrast media, which is useful per se, has hitherto failed due to the insufficient tolerance of such compounds. With the paramagnetic substances previously proposed or tested for magnetic resonance imaging, the distance between the effective dose and the dose which is toxic in animal experiments is relatively narrow, and / or they have a low organ specificity and / or stability and / or contrast-enhancing effect and / or their tolerance insufficient. The approach to at least some of these problems through the use of complexing agents, on the one hand by ionic binding to the appropriate metal (see below) and on the other hand by binding to a functional group or a non-toxic and possibly organ serving as carrier molecule specific macromolecule bound to solve, has so far been very limited.

If the functional groups of the complexing agent are used to bind the molecule to a biomolecule, the complex stability is weakened, i.e. a physiologically intolerable fraction of the metal ions of the macromolecule-metal ion complex is released [C.H. Paik et al., J. Radioanal. Chem. 57, 553 (1980), D.J. Hnatowich et al., J. Nucl. Med. 26.503 (1985)].

On the other hand, if the starting materials used are bifunctional complexing agents, that is to say complexing agents which carry both functional groups for the coordinative binding of the desired metal ion and one (other) functional group for binding the macromolecule, then according to the current state of the art (CF Meares et al. Radioimmunoimaging and Radioimmunotherapie 1983, 185, Canadian Patent No. 1 178 951) the various serious disadvantages: for example low stability of the complexes, multi-stage difficult synthesis of the complexes, little variation possibilities of the functional group required for binding to the macromolecule, risk of contamination the complexing agent during its synthesis with foreign metals, due to insufficient lipophilicity, only limited reaction possibilities of the complexing agent, necessary intermediate blockage of the functional groups of the complexing agent associated with reduction in yield and additional purification steps (e.g. example as an iron complex or protection of a phenolic hydroxyl group as methyl ether), necessity to work with highly purified solvents and equipment.

There is therefore a need for diverse purposes for stable, readily soluble, and sufficiently selective, but also better tolerated, easily accessible complex compounds which have as large a variety as possible of functional groups suitable for binding to macromolecules. The object of the invention is therefore to provide these compounds and agents and to create the simplest possible method for their production. This object is achieved by the invention. It has been found that compounds consisting of the anion of a monofunctionalized aminopolycarboxylic acid and one or more central ions of an element of atomic numbers 21-29, 31, 32, 37-39, 42-44 or 57-83 and optionally one or more Cations of an inorganic and / or organic base or amino acid exist, surprisingly excellent for the production of NMR, X-ray and radio diagnostics as well as radiotherapeutics.

The compounds according to the invention are described by the general formula I:

where n and m are each for the digits 0, 1, 2. 3 and 4.

X for a hydrogen atom and / or a metal ion equivalent of an element of atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 or 57-83, R ¹ and R ^{2 are} different and each for a hydrogen atom or an optionally Imino, phenyleneoxy, phenyleneimino, amido, hydrazido, ester group (s), oxygen, sulfur and / or nitrogen atom (s) containing de, optionally by hydroxy, mercapto, imino, epoxy , Oxo, thioxo and / or amino group (s) substituted straight-chain, branched, saturated or unsaturated C ₀ -C ₂₀ alkylene group, which in the end either a second

Molecule of the general formula I _A or I _B

a functional group or linked via this functional group

Has a bio or macromolecule, with the proviso that n and m together do not result in more than 4 and that if X represents a metal ion equivalent, at least two of the substituents X have this meaning.

Compounds of the general formula I with X in the meaning of hydrogen are referred to as complexing agents and with at least two of the substituents X in the meaning of a metal ion equivalent as metal complexes.

The element of the above-mentioned atomic number, which forms the central ion of the physiologically contractual complex salt, can of course also be radioactive for the intended use of the diagnostic agent according to the invention.

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, gadolinium (III), terbium (III) dysprosium (III), holmium (III), erbium (III) and iron (III) ions are particularly preferred. The central ion must be radioactive for the use of the agents according to the invention in nuclear medical diagnostics. For example, radioisotopes of the elements copper, cobalt, gallium, germanium, yttrium, strontium, technetium, indium, ytterbium, gadolinium, samarium and iridium are suitable. 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 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 of 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. The alkylene group contained in R ¹ or R ² can be straight-chain, branched, cyclic, aliphatic, aromatic or arylaliphatic and can have up to 20 carbon atoms. Straight-chain mono- to hexamethylene groups and C ₁ -C ₄ -alkylenephenyl groups are preferred. If the alkylene group contains a phenoxy group, this is preferably bonded in p-position to the -CH group of the basic structure of the compound of the general formula I via a methylene group.

Preferred functional groups which are located at the end of the R ¹ or R ² alkylene group are, for example, the benzyl ester, ethyl ester, t-butyl ester,

Amino, C ₁ -C ₆ alkylamino, aminocarbonyl, hydrazino, hydrazinocarbonyl,

Maleimido, methacrylamido, methacryloyl hydrazinocarbonyl, maleimidamidocarb onyl, halogeno, mercapto, hydrazinotrimethylene hydrazinocarbonyl, aminodimethylene amido carbonyl, bromocarbonyl, phenylenediazonium, isothiocyanate,

Semicarbazide, thiosemicarbazide group. A few selected R ¹ and R ² substituents are listed for clarification:

wherein R and R 'are the same or different and each represents a hydrogen atom, a saturated or unsaturated C ₁ -C ₂₀ -alkyl radical optionally substituted by a phenyl group or a phenyl group.

If not all acidic hydrogen atoms are substituted by the central ion, one, several or all remaining hydrogen atoms can be replaced by cations of inorganic and / or organic bases or amino acids. Suitable inorganic cations are, for example, lithium ion, potassium ion, calcium ion and in particular sodium ion. Suitable cations of organic bases include those of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine and in particular N-methylglucamine. Suitable cations of amino acids are, for example, those of lysine, arginine and ornithine.

The complexing agents according to the invention are prepared by saponification of compounds of the general formula II

wherein n and m have the meaning given above, R ^{1 '} and R ^{2' are} different and each represents a hydrogen atom or an optionally imino, phenylene oxy, phenyleneimino, amido, hydrazido, ester group (s), oxygen Straight-chain, branched, saturated or unsaturated C ₀ , containing sulfur and / or nitrogen atom (s), optionally substituted by hydroxy, mercapto, imino, epoxy, oxo, thioxo and / or amino group (s) -C ₂₀ alkylene group, which at the end is a second molecule of the general formula I ' _A or I " _B , or has a functional group, and R ^{3 represents} a C ₁ -C ₆ alkyl radical.

The saponification takes place according to the methods known to the person skilled in the art, for example in the case of tert-butyl esters with the aid of trifluoroacetic acid.

The starting materials are prepared by alkylation of monosubstituted polyamines of the general formula III

where n and m each represent the numbers 0, 1, 2, 3 and 4 and R ^{1 "} and R ^2" each represent a hydrogen atom or a substituent which can be converted into R ^{1 '} and R ^2' , respectively , with the proviso that n and m together do not result in more than 4, that the substituents R ^{1 ″} and R ^{2 ″} are different and one for a hydrogen atom and the other for a substituent which is in R ^{1 ′} or R ^{2 '} can be converted, with an ester of the general formula IV

HalCH ₂ COOR ³ (IV),

wherein shark represents chlorine, bromine or iodine, and R ^{3 has} the meaning given for the general formula II. The reaction is carried out in polar aprotic solvents such as, for example, dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric acid triamide in the presence of an acid trap, such as, for example, tertiary amine (for example triethylamine, trimethylamine, N, N-dimethylaminopyridine, 1.5 diazabicyclo [4.3.0] nonen-5 [DBN ], 1.5 diazabicyclo [5.4.0] undecene-5), alkali, alkaline earth carbonate or hydrogen carbonate (for example sodium, magnesium, calcium, barium, potassium carbonate and hydrogen carbonate) at temperatures between -10 ° C and 120 ° C, preferably between 0 ° C and 50 ° C.

The synthesis of dimers, ie of compounds of the general formula I, in which the C ₀ -C ₂₀ -alkylene group contained in R ¹ and R ^{2 is} bonded to a second molecule of the general formula I _A or I _B , is carried out according to the literature

Processes, for example via an addition / elimination reaction of an amine with a carbonyl compound (for example acid chloride, mixed anhydride, activated ester, aldehyde); two amine-substituted rings with a dicarbonyl compound (for example oxalyl chloride, glutardialdehyde); two rings, each having a nucleophilic group, with an alkylene compound carrying two leaving groups or, in the case of terminal acetyls, by oxidative coupling (Cadiot, Chodkiewicz in Viehe "Acetylenes", 597-647, Marcel Dekker, New York, 1969).

The chain linking the two halves of the molecule can then be modified by subsequent reactions (for example hydrogenation).

The substituents R ^{1 ″} and R ^{2 ″} include, among others, hydroxy and nitrobenzyl,

Hydroxy and carboxyalkyl as well as thioalkyl radicals with up to 10 carbon atoms are suitable. They are converted into the desired substituents (for example, with the amino-, for example with the literature method known to the skilled worker (Chem.-Pharm. Bull. 33.674 (1985). Compendium of Org. Synthesis Vol. 1-5, Wiley and Sons, Inc.) Hydrazino, hydrazinocarbonyl, methacryloylhydrazinocarbonyl, maleimidamido carbonyl, halogeno, halogenocarbonyl, mercapto group as functional group) converted, whereby in the case of the nitrobenzyl radical first a catalytic hydrogenation (for example according to PN Rylander, Catalytic Hydrogenation over Platinum Metals, Academic Press 1967) for the aminobenzyl derivative.

Examples of the conversion of hydroxyl or amino groups bound to aromatic or aliphatic radicals are those in anhydrous, aprotic solution agents like tetrahydrofuran. Dimethoxyethane or dimethyl sulfoxide in the presence of an acid trap such as sodium hydroxide. Sodium hydride or alkali or alkaline earth carbonates such as sodium, magnesium, potassium, calcium carbonate at temperatures between 0 ° C and the boiling point of the respective solvent, but preferably between 20 ° C and 60 ° C. carried out reactions with a substrate of the general formula V

Z-L-Fu (V),

where Z for a nucleofuge such as Cl. Br, J. CH ₃ C ₆ H ₄ SO ₃ , or CF ₃ SO ₃ ,

L for an aliphatic. Aromatic, arylaliphatic, branched, straight-chain or cyclic hydrocarbon radical having up to 20 carbon atoms and Fu for the desired terminal functional group, optionally in protected form, are available (DE-OS 34 17 413). Examples of compounds of the general formula V are mentioned

Conversions of carboxy groups can, for example, by the carbodiimide method (Fieser, Reagents for Organic Syntheses 10,142) over a mixed anhydride [Org. Prep. Proc. Int. 7.215 (1975)] or via an activated ester (Adv. Org. Chem. Part B. 472).

The amines of the general formula III required as starting substances are prepared analogously to methods known from the literature (for example Canad. Patent No. 1,178,951, Eui. I. Med. Chem. Chim Ther. 1985. 20, 509 and 1986. 21, 333 ). by starting from amino acids which are converted into amides optionally substituted with ethyleneamines [for example with N (2-aminoethyl) -carbamic acid benzyl ester] and then reduced to the desired aminone (preferably so with diborane or lithium aluminum hydride). If you want to synthesize compounds of general formula I with R ¹ in the meaning of a hydrogen atom, it is necessary to reduce such an amide before the reduction by reaction with, for example, ethyl oxamate in a polar solvent such as tetrahydrofuran, dimethyl sulfoxide or dimethoxyethane at a temperature between 50 ° C and 250 ° C, preferably 70 ° C to 150 ° C (optionally in a pressure vessel) at the α-amino group to substitute, so that a 3-aza-2-oxo-glutaric acid diamide derivative is obtained as an intermediate.

The complex-forming ligands (as well as the complexes) obtained in this way can also be linked to bio- or macromolecules, which are known to accumulate particularly well in the organ or organ part to be examined. Such molecules are, for example, enzymes, hormones, sugars, dextrans, lectins. Porphyrins, bleomycins, insulin, prostaglandins, steroid hormones, aminosugars, amino acids, peptides such as polylysine, proteins (such as immunoglobulins and monoclonal antibodies) or lipids (also in the form of liposomes). Of particular note are conjugates with albumins such as human serum albumin, antibodies such as monoclonal antibodies specific for tumor associated antigens, antimyosin or cholic acid. Instead of biomolecules, suitable synthetic polymers such as polyethyleneimines, polyamides, polyureas, polyethers and polythioureas can also be attached. The pharmaceutical agents formed therefrom are suitable, for example, for use in tumor and infarct diagnostics and tumor therapy. As monoclonal antibodies (for example Nature 256, 495, 1975), which have the advantage over the polyclonal antibodies that they are specific for an antigenic determinant, have a defined binding affinity, are homogeneous (this makes their purity much easier) and that in Cell cultures that can be produced in large quantities are particularly suitable for conjugation if they are directed against antigens predominantly in the cell membrane. As such, monoclonal antibodies or their fragments Fab and F (ab ') _{2 are} suitable for tumor imaging, for example, which are specific for human tumors of the gastrointestinal tract, breast, liver, bladder, gonads and melanomas ( Cancer Treatment Repts. 68, 317, 1984, Bio Sei 34, 150, 1984) or against carcinoembryonic antigen (CEA), human choriogonadotropin (β-HCG) or other tumorigenic antigens such as glycoproteins. (New Engl.J. Med. 298, 1384, 1973. U.S. Patent 4,331,647). Anti-myosin, anti-insulin and anti-fibrin antibodies are also suitable (UC-P 4,036,945).

Both the monomeric complexes and conjugates or inclusion compounds with liposomes (which are used, for example, as unila ellar or multilamellar phosphatidylcholine-cholesterol vesicles) are suitable for liver examinations and gallbladder diagnostics or for tumor diagnostics.

The bindings known from the prior art, for example of radioisotopes to immunoglobulins and their fragments, have the disadvantage of a lack of stability of the labeled antibody conjugates or of a lack of specificity (for example as a result of the use of a diethylenetriaminepentacetic acid = DTPA anhydride) (for example Diagnostic Imat ing 84, 56; ^* i> fιCe 220. f. '■ 3 1903; Car.i er [irug ι> ^« -lα vei y J .. 125. 1964).

Dir ι-.r.-jι.gatL '.: l'i'ii;". u: '. ^• . • :. ';. jTi.iii 'invention occurs ageg ulier die am

1 2 End of the C _n -C „„ allene group. ran Cut_> stitυent '.- ^r ' P or R located uri'i ", i r.ι-li» - C.uppe. w «.i wfit * r • ..! ■ • ;. is defined. E-; can in the conjugation of acids with Bio-odf-r fa cromolecular r. Mr.ir ». • -" .aureres te- an di se gt '... urιc.er, wfj <- ^r ι. in diτ - * •: • ^■ ■ F., .. ";., t,., j» de 'surere ^ t ^ in Zeritralion

de Coupling the desired -! Macromolecules are made by eLienf.il U according to a known method, such as n- for example in Re ... Rou. Morptu.l. EmUryol. Physiö .. Physiologie- 19B ¹ , J_8. 241 and J. Pharm. £ 8. ^? 9 (1979) are described, for example by reacting the nucleophilic group of a macromolecule, such as the amino, phenol, sulfhydryl, aldehyde or imidazole group, with an activated derivative of the complexing agent. Examples of activated derivatives are monoanhydrides. Acid chlorides, acid hydrazides. mixed anhydrides ⁽ see for example GE Kre carek and Kl Tuckei. B löchern., Biophy: -. Res. Commun. 1977, 581). activated esters. Nitι * τιe or I sot hioeyanate into consideration. Conversely, it is also possible to add an activated macromolecule with the complex-forming acid u. Zui Kon _j uga'.ic with f-ut- .r. _t -. t-iπttr εict- also substituents for example the structure (H .- Ch NHCOn ¹ .. C _c H NHCS od C _C H, CCH_C0 ar b <• In the case of antibody conjugates, the binding of the antibody to the complexing agent (or to the metal complex; the production of the metal complex conjugate can be carried out both in the order of complexing agent, complexing agent conjugate, end product and in the order of complexing agent, metal Complex, end product occur) do not lead to the loss or reduction of the binding affinity and binding specificity of the antibody to the antigen. This can be done either by binding to the carbohydrate portion in the Fc part of the glycoprotein or in the Fab or F (ab ') ₂ fragments or by binding to sulfur atoms of the antibody or the antibody fragments.

In the first case, an oxidative cleavage of sugar units must be carried out to generate formyl groups capable of coupling. This oxidation can be done chemically with oxidizing agents such as periodic acid. Sodium metaperiodate or potassium metaperiodate according to methods known from the literature (for example J. Histochem and Cytochem. 22, 1084, 1974) in aqueous solution in concentrations of 1 to 100, preferably 1 to 20 mg / ml. and a concentration of the oxidizing agent between 0.001 to 10 mmol, preferably 1 to 10 mmol in a pH range of approximately 4 to 8 at a temperature between 0 to 37 ° C and a reaction time between 15 minutes and 24 hours. Oxidation can also occur enzymatically. for example with the help of galactose oxidase in an enzyme concentration of 10-100 units / ml, a substrate concentration of 1 to 20 mg / ml, at a pH of 5 to 8, a reaction time of 1 to 8 hours and a temperature between 20 and 40 ° C. be carried out (for example J. Biol. Chem. 234, 445, 1959).

Complexing agents (or metal complexes, see above) with suitable functional groups such as, for example, hydrazine, hydrazide, primary amine, hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide are reacted to the aldehydes generated by oxidation by reaction between 0 and 37 ° C. with a reaction time of 1 up to 65 hours, a pH between about 5.5 and 8. an antibody concentration of 0.5 to 20 mg / ml and a molar ratio of the complexing agent to the anti-coroaldehyde of 1: 1 to 1000: 1. The subsequent stabilization of the conjugate is carried out by reducing the double bond, for example with sodium borohydride or sodium cyanoborohydride; the reducing agent is used in a 10 to 100-fold excess (for example J. Biol. Chem. 254, 4359, 1979). The second possibility for the formation of antibody conjugates is based on a gentle reduction of the disulfide bridges of the immunoglobulin molecule; Here, the more sensitive disulfide bridges of the H chains of the antibody molecule are cleaved, while the SS bonds of the antigen-binding region remain intact, so that there is practically no reduction in the binding affinity and specificity of the antibody (Biochem. 18, 2226, 1979, Handbook of Experimental Immunology, Vol. 1. Second Edition, Blackwell Scientific Publications. London 1973. Chapter 10). These free sulfhydryl groups of the intra-H chain regions are then formed with suitable functional groups of complexing agents or metal complexes at 0 to 37 ° C., a pH of about 4 to 7, and a reaction time of 3 to 72 hours a covalent bond. which does not affect the antigen binding region of the antibody. Examples of suitable reactive groups are: haloalkyl, haloacetyl, p-mercuribenzoate groups and groups which undergo a Michael addition reaction. such as maleimides, methacrylic groups (e.g. J. Amer. Chem. Soc. 101, 3097, 1979).

Bonds of a non-covalent type can also be used for coupling, where both ionic and van der Waals and hydrogen bonds can contribute to the bond in varying proportions and strengths (key-lock principle) (for example avidin-biotin , Antibody antigen). Inclusion compounds (host-guest) of smaller complexes in larger cavities in the macromolecule are also possible.

The coupling principle consists in first producing a bifunctional macromolecule by either fusing an antibody hybridoma directed against a tumor antigen with a second antibody hybridoma directed against a complex according to the invention or by chemically combining the two antibodies via a linker (for example in the method described in J. Amer Chem. Soc. 101, 3097 (1979) as indicated) or binds the antibody directed against the tumor antigen, optionally via a linker, to avidin (or biotin) [DJ Hnatowich et al., J. Nucl. Med 28, 1294 (1987)] Instead of the Anticoipei, their corresponding F (ab) or F (ab ') ₂ fragments used again For pharmaceutical use, the bifunctional macrumulecule that accumulates at the target site is first injected, and then in time Lichen distance the complex compound according to the invention [optionally bound to biotin (or avidin)], which is coupled in vivo to the target location and can develop its diagnostic or therapeutic effect there. In addition, other coupling methods, such as that in Protein Tailoring Food Med. Uses [Am. Chem. Soc. Symp.] (1985). 349, described "Reversible Radio Labeling" are used.

A method that is particularly suitable for the production of conjugates of both antibody and antibody fragments is coupling to a solid phase. Here, the antibody or the corresponding F (ab) ₂ fragment is bound to a stationary phase (for example an ion exchanger), which is located in a temperature-controlled column with inflow and outflow. For oxidation in the Fc part of the antibody, the column must be protected from light by covering; To reduce disulfide bridges (for example when generating Fab fragments) it must be possible to work under argon as a protective gas. The actual coupling process then proceeds as follows:

After rinsing the column with a suitable buffer, a solution is used as the eluent which generates reactive groups on the bound protein (for example, periodate solution for the generation of aldehyde groups in the Fc part of monoclonal antibodies or mercaptoethylamine solution for the production of sulfhydryl groups in Fragments). After the reaction solution has completely displaced the previous eluent, the flow is stopped for a time sufficient for complete reaction, then rinsed sufficiently with buffer, then a solution is drawn with the coupling partner (for example the hydrazide or dithiopyridyl derivative of a complexing agent or a complex) opens and stops the flow again for a sufficiently long time. Instead of stopping the flow for a long time, a so-called recycle circuit can also be used; the eluate leaving the column is pumped directly onto the column by means of a loop circuit. Because of the better mixing, much shorter reaction times and better yields are achieved. This is followed by a rinse with buffer solution. If a free complexing agent is the coupling partner, complexing is carried out in a further cycle with a solution of the desired metal salt (for example a citrate solution) and a subsequent rinsing cycle. Finally, the conjugate is eluted with a pH or salt gradient ducks. Then, if necessary after desalting, lyophilization. After aquilibration with buffer solution, the column is ready for the next coupling step.

This method is far superior to the conventional methods both in terms of speed and in yield for the preparation of very small and very large amounts of conjugate, and also allows the continuous preparation of conjugates; this is the prerequisite for the economic production of large quantities.

The compounds formed in this way are then preferably purified chromatographically via ion exchangers on a fast protein liquid chromatography system.

The compounds of the general formula I thus obtained with X in the meaning of a hydrogen atom represent complexing agents. They can be isolated and purified or converted into metal complexes of the general formula I with at least two of the substituents X in the meaning of a metal ion equivalent without isolation.

The metal complexes according to the invention are prepared in the manner disclosed in DE-OS 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 21 -29, 31, 32, 38, 39, 42-44, 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 acid of general formula I with X in the meaning of a hydrogen atom and then, if desired, substituted acidic hydrogen atoms present by acid groups by cations of inorganic and / or organic bases or amino acids.

The neutralization is carried out with the aid of inorganic bases (for example hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium or lithium and / or organic bases such as, inter alia, primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N. -Methyl- and N, N-dimethylglucamine, as well as basic amino acids, such as lysine, arginine and ornithine. To produce the neutral complex compounds, for example, the acidic complex salts in aqueous solution or suspension can be added with as much of the desired base that the neutral point is reached. The solution obtained can then be evaporated to dryness in vacuo. It is often advantageous to neutralize the neutral 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.

If the acidic complex compounds contain several free acidic groups, it is often expedient to prepare neutral mixed salts which contain both inorganic and organic cations as counterions.

This can be done, for example, by reacting the complex-forming acid in aqueous suspension or solution with the oxide or salt of the element providing the central ion and half the amount of an organic base required for neutralization, isolating the complex salt formed, cleaning it if desired and then the required amount of inorganic base is added for complete neutralization. The order of base addition can also be reversed.

The antibody-complex conjugates are dialyzed prior to in vivo use after incubation with a weak complexing agent such as sodium citrate, sodium ethylenediaminetetraacetic acid to remove weakly bound metal atoms.

If complex compounds containing radioisotopes are used, their preparation can be carried out according to the methods described in "Radiotracers for Medical Applications", Volume 1, CRC-Press, Boca Raton, Florida. The pharmaceutical compositions according to the invention are likewise prepared in a manner known per se by suspending or dissolving the complex compounds according to the invention - optionally with the addition of the additives customary in galenics - in an aqueous medium and then, if appropriate, sterilizing the suspension or solution. Suitable additives are, for example, physiologically acceptable buffers (such as tromethamine), small additions of complexing agents (such as diethylenetriaminepentaacetic acid) or, if necessary, electrolytes such as 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 adjuvants (for example methyl cellulose, lactose, mannitol) and / or surfactant (en) (for

Example lecithins. Tween ^(R) Myrj ^(R) and / or flavoring (s) for flavor correction ⁽ for example essential oils) mixed.

In principle, it is also possible to produce the pharmaceutical compositions according to the invention without isolating the complex salts. In any case, special care must be taken to carry out the chelation 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 1 μmol - 1 mol / 1 of the complex salt and are generally dosed in amounts of 0.001–5 mmol / kg. They are intended for enteral and parenteral administration.

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 radio dioisotopes of the elements with atomic numbers 27, 29, 31, 32, 38, 39, 43, 49, 62, 64, 70 and 77.

The agents according to the invention meet the diverse requirements for their suitability as contrast agents for magnetic resonance imaging. After oral 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 of the agents according to the invention makes it possible to produce highly concentrated solutions, thus keeping the volume load of the circulation within reasonable limits and compensating for the dilution by the body fluid, i.e. NMR diagnostics must be 100-1000 times more water soluble than for NMR spectroscopy. Furthermore, the agents according to the invention not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that the release or exchange of the ions which are not covalently bound in the complexes and which are toxic per se within the time in which the new contrast agents are completely excreted again, is extremely slow.

In general, the agents according to the invention for use as NMR diagnostic agents are dosed in amounts of 0.001-5 mmol / kg, preferably 0.005-0.5 mmol / kg. Details of the application are, for example, in H.J. Weinmann et al., Am.

3rd of Roentgenology 142, 619 (1984).

Particularly low doses (below 1 mg / kg body weight) of organ-specific NMR diagnostics can be used, for example, to detect tumors and heart attacks. 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 contained in them, the agents according to the invention are also suitable as radio diagnostics. Details of their application 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 ⁴³ Sc, ⁴⁴ Sc, 5 ² Fe, ⁵⁵ Co and 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. This differs from the corresponding diagnostics only in the amount and type of radioactive isotope used. The goal is the destruction of tumor cells by high-energy short-wave radiation with the shortest possible range. The specificity of the antibody used is of crucial importance since unspecifically localized antibody conjugates lead to the destruction of healthy tissue.

The antibody or the antibody fragment of the antibody-metal complex according to the invention serves to transport the complex to the target organ in an immunospecific manner for the antigen in question, where the metal ion selected because of its cell-killing properties can emit rays which lethally damage the cells. Suitable β-emitting ions are, for example ⁴⁶ Sc, ⁴⁷ Sc, ⁴⁸ Sc, ⁷² Ga and ⁷³ Ga. Suitable α-emitting ions with short half-lives are, for example, ²¹¹ Bi, ²¹² Bi, ²¹³ Bi and ²¹⁴ Bi, where ²¹² Bi is preferred. A suitable photon and electron emitting ion is ¹⁵⁸ Gd, which can be obtained from ¹⁵⁷ Gd by neutron capture.

In the in vivo application of the therapeutic agents according to the invention, these can be used together with a suitable carrier such as serum or physiological saline and 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 imaging method.

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

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

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 examinations. They are particularly valuable for digital subtraction techniques due to their favorable absorption properties in areas with higher tube voltages.

In general, the agents according to the invention for use as X-ray contrast agents are dosed in analogy to, for example, meglumine diatrizoate in amounts of 0.1 -5 mmol / kg, preferably 0.25-1 mmol / kg.

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, 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 compounds of general formula I can also be used as haptens for the production of antibodies. Details of the registration of haptens for the production of antibodies are e.g. B. in S. Seil, Immunology, Immunopathology and Immunity, 372, Harper and Row Publ., 3rd ed.

The following examples serve to explain the subject of the invention in more detail. example 1

a) 3,6-Diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4-hy droxybenzyl) -suberic acid bis- (tert-butyl) diester

15.31 g (0.064 mol) of 4-hydroxybenzyl-1,2-ethane-diamine as dihydrochloride and 71.14 g (0.71 mol) of potassium hydrogen carbonate are placed in 380 ml of dimethylformamide (dried over sodium hydride) and 50 at 35 ° C g (0.26 mol) of bromoacetic acid tert-butyl ester in 80 ml of dirnethylformamide were added dropwise. The mixture is stirred for a further 2.5 hours at 35 ° C, after which no starting product can be detected by thin layer chromatography. Filtrated from potassium bromide which has precipitated out and the filtrate is concentrated. The residue is mixed with water and extracted several times with ether. After drying and concentrating, the ether extract is purified from unreacted tert-butyl bromoacetate via a silica gel column. 24.8 g (63% of theory) of a colorless oil are obtained.

analysis

Ber. : C 63, 64 H 8, 73 N 4, 49 0 23.12

Gef. : C 63 .78 H 8.69 N 4.41 b) 3,6-Diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- [4- (3-benzyloxycarbonylaminopropoxy) benzyl] -succinic acid bis- (tert-butyl) diester

1.0 g (1.61 mmol) of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) -succinic acid bis- (tert-butyl) diester (example 1a) are combined with 53 mg of NaH (80% in paraffin) (1.77 mmol) in 10 ml of dry tetrahydrofuran and slowly 440 mg of benzyl N- (3-bromopropyl) carbamate in 5 ml of tetrahydrofuran are added dropwise. After stirring overnight, the mixture is concentrated and separated from the paraffin oil on a silica gel column. After evaporation of the solvent, 920 mg (70.2% of theory) of colorless oil are obtained.

analysis

Ber. : C 64.92 H 8. 29 N 5.16 O 21.61

Gef. : C 64.99 H 8. 20 N 5. 07

c) 3,6-Diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- [4- (3-aminopropoxy) benzyl] -succinic acid bis- (tert-butyl) diester

0.92 g (1.13 mmol) of 3,6-diaza-3,6-bis (butoxycarbonylmethyl) -4- [4- (3-benzyloxycarbonylaminopropoxy) benzyl] - suberic acid bis (tert-butyl) diesters (Example 1b) (1.13 mmol) are dissolved in 20 ml of methanol and hydrogenated with 500 mg of 10% palladium-carbon until no further H ₂ uptake occurs. The catalyst is then filtered off. The remaining colorless oil weighs 680 mg (74% of theory)

analysis

Ber. : C 63, 59 H 9, 04 N 6. 180 21, 17

Gef. : C 63, 43 H 8. 99 N 6.15

3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- [4- (3- (maleimido) propoxy) benzyl] -suberic acid bis- (tert-butyl) diester

6.5 g of 3,6-diaza-3,6-bis- (tert-butoxycarbonylmethyl) -4- [4- (3-aminopropoxy) -benzyl] -suberic acid-bis- (tert-butyl) - a solution of 920 mg (9.4 mmol) of maleic anhydride in 50 ml of methylene chloride is added to diester (Example 1c) (9.4 mmol) in 200 ml of dry methylene chloride and the mixture is stirred at room temperature overnight. Then 1.27 g (9.4 mmol) of 1-hydroxybenzotriazole and 2.13 g (10.34 mmol) of dicyclohexylcarbodiimide are added. After 2 days, the urea which has separated out is filtered off and the product is purified by preparative medium pressure chromatography (methylene chloride / ether). Yield: 3.89 g (80% of theory)

analysis

Ber. : C 63 -22 H 8.09 N 5.52 O 23.15

Gef. : C 63 .19 H 8.15 N 5. 41

3,6-diaza-3,6-bis (carboxymethyl) -4- [4- (3- (maleimido) propoxy) benzyl] suberic acid

2.4 g (9.2 mmol) of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- [4- (3- (maleimido) propoxy) benzyl] -succinic acid-bis- (tert-Butyl) diester (Example 1d) are dissolved in 35 ml of trifluoroacetic acid and stirred at room temperature for 36 hours. Half of the trifluoroacetic acid is removed in vacuo and the remaining solution is poured into 100 ml of dry diethyl ether. The precipitated product is suctioned off and dried. 1.45 g (85%) of a white crystalline powder are obtained. Melting point> 145 ° (decomposition)

analysis

Calc .: C 53.82 H 5.45 N 7.84 O 32.56

Found: C 53.89 H 5.41 N 7.85

Gadolinium complex

7.25 g (13.55 mmol) of 3,6-diaza-3,6-bis- (carboxymethyl) -4- [4- (3- (maleimido) propoxy) benzyl] -succinic acid are dissolved in 120 ml 0.1 N ammonium acetate / water and slowly add 14 ml of an in gadolinium acetate solution in water. After 15 minutes, the pH is adjusted to about 7.5-8 with 0.1N ammonia solution, heated to 60 ° C. for 15 minutes and then centrifuged off. After freeze-drying, the supernatant gives 9.35 g of white crystalline mass (99% of theory)

analysis

Ber. : C 41.79 K 3.79 N 6. D9 O 25.51 Gd 22.79 Gef. : C 41.77 H 3.76 N 6. 11 Gd 22 .55

Gd (atomic absorption spectroscopy = A% AS): 22.72% Sodium salt of the gadolinium complex

The complex obtained as described above (3.63 g; 5.26 mmol) is dissolved in 10 times the amount of water and mixed with 5.26 ml of a 1N sodium hydroxide solution using a microbette. After freeze-drying, 3.74 g of white crystals are present.

Analysis:

Calculated: C 40.44 H 3.67 N 5.89 O 24.69 Gd 22.06 Na 3.22

Found: C 40.32 H 3.60 N 5.95 O Gd 21.81 Na 3.33

N-methyl-D-glucamine salt of the gadolinium complex

7.85 g (11.36 mmol) of the gadolinium complex, dissolved in 80 ml of water, are mixed with 2.22 g (11.38 mmol) of N-methyl-D-glucamine in portions with stirring. After the base has completely dissolved, freeze-drying is carried out. 10.0 g of a colorless crystalline compound remain.

Analysis:

Calc .: C 42.07 H 4.89 N 6.53 O 28.92 Gd 17.76

Found: C 42.12 H 4.77 N 6.59 O Gd 17.77

Morpholine salt of the gadolinium complex

5.13 g (7.43 mmol) of the gadolinium complex, dissolved in 50 ml of water, mixed with 6.4 g of a solution which contains 10% by weight of morpholine and then freeze-dried. 5.76 g of colorless crystals are obtained.

Analysis:

Calc .: C 43.34 H 4.41 N 7.22 0 24.74 Gd 20.26

Found: C 43.40 H 4.32 N 7.41 0 Gd 20.22 Analogously to the regulation for the preparation of the gadolinium complex, one receives the

Yttrium complex

Calc .: C 46.31 H 4.21 N 6.75 O 28.28 Y 14.45

Found: C 46.45 H 4.19 N 6.78 O Y 14.07

Ytterbium complex

Calc .: C 40.86 H 3.71 N 5.96 O 24.95 Yb 24.53

Found: C 40.83 H 3.81 N 5.87 O Yb 24.41

Samarium complex

Calculated: C 42.21 H 3.84 N 6.16 O 25.77 Sm 22.02

Found: C 42.17 H 3.82 N 6.05 O Sm 22.13

Praseodymium complex

Calculated: C 42.81 H 3.89 N 6.24 O 26.14 Pr 20.92

Found: C 42.18 H 3.79 N 6.22 O Pr 20.97

Cobalt complex

Calcd .: C 48.74 H 4.43 N 7.11 O 29.76 Co 9.96

Found: C 48.73 H 4.71 N 7.33 O Co 10.07

Indium complex

Ber. : C 44.53 H 4.05 N 49.31 O 27.19 In 17.74

Found: C 44.56 H 3.98 N 49.27 In 17.82 Example 2

3,6-Diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- [4- (3- (methacrylamido) propoxy) benzyl] -suberic acid bis- (tert-butyl) diester

7.33 g (10.6 mmol) of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- [4- (3-aminopropoxy) -benzyl] -succinic acid bis- (tert. -butyl) diester (Example 1c), dissolved in 175 ml of dry ethyl acetate, 1.2 ml (11.7 mmol) of triethylamine are added and a solution of 1.2 g (11 mmol) of methacryloyl chloride in at 0 ° C 20 ml of dry ethyl acetate are added dropwise. The mixture is stirred overnight at room temperature, then filtered off from the precipitated triethylammonium chloride and concentrated. Column chromatography (toluene / ethyl acetate) gives 6.9 g (9.2 mmol; 87% of theory) of a colorless oil.

Analysis:

Calc .: C 64.23 H 8.75 N 5.61 O 21.39

Found: C 64.44 H 8.52 N 5.63

3,6-diaza-3,6-bis (carboxymethyl) -4- [4- (3- (methacrylamido) propoxy) benzyl] suberic acid

2.0 g (2.7 mmol) of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- [4- (3- (methacrylamido) propoxy) benzyl] -suberic acid -bis- (tert-butyl) diesters (Example 2a), as described in Example le, are converted into the free complexing agent with trifluoroacetic acid.

After drying, 1.3 g (2.5 mmol; 92%) of a colorless powder are obtained. Melting point: 133 ° C (decomposition)

analysis

Calc .: C 55.06 H 6.35 N 8.02. O 30.55

Found: C 55.01 H 6.23 N 8.13

Gadolinium complex

Analogously to the procedure in Example 1e, the gadolinium complex is obtained in almost quantitative yield.

analysis

Calc .: C 42.53 H 4.46 N 6.19 O 23.6 Gd 23.20 Found: C 42.38 H 4.30 N 6.25 Gd 23.02

Gd (AAS): 23.25% The following salts are obtained analogously to the regulation in 1 egg:

Sodium salt of the gadolinium complex

Calc .: C 41.13 H 4.31 N 5.99 O 22.83 Gd 22.44 Na 3.28 Found: C 41.20 H 4.39 N 5.89 O Gd 21.99 Na 3.27

Meglumine salt of the gadolinium complex

Calc .: C 43.96 H 5.13 N 7.32 O 23.00 Gd 20.55 Found: C 43.89 H 5.22 N 7.30 O Gd 21.01

Morpholine salt of the gadolinium complex

Calc .: C 42.60 H 5.53 N 6.41 O 27.45 Gd 17.99 Found: C 42.65 H 5.60 N 6.42 O Gd 17.79

Example 3

3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4-benzyloxycarbonylmethoxybenzyl) -suberic acid bis- (tert-butyl) diester

93.06 g of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) ¬-4- (4-hydroxy-benzyl) -succinic acid bis (tert-butyl) diester (Example 1a) ( 0.15 mol) are slowly combined with 4.48 g NaH (80% in paraffin) (0.15 mol) in 600 ml dry tetrahydrofuran with stirring and then at room temperature 34.4 g benzyl bromoacetate (0.15 mol) in 150 ml of dry tetrahydrofuran were added dropwise. After stirring overnight, the sodium bromide which has precipitated is filtered off, concentrated, taken up in diethyl ether and the remaining inorganic constituents are removed by washing with water. After drying with MgSO ₄ , the solvent is freed and purified on a silica gel column. 75.2 g (65% of theory) of a colorless oil are obtained.

analysis

Calc .: C 65.43 H 8.10 N 3.63 O 22.82

Found: C 65.23 H 8.17 N 3.58

3,6-diaza-3,6-bis (carboxymethyl) -4 - (- 4-benzyloxycarbo¬nylmethoxybenzyl) -suberinsäure

5.49 g of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4-benzyloxycarbonylmethoxybenzyl) -succinic acid bis- (tert-butyl) diester (Example 3a) (8, 1 mmol) are warmed to 50 ° C in 50 ml of trifluoroacetic acid and left overnight at room temperature. Then the clear solution is poured into 500 ml of dry ether and the precipitate is filtered off with suction. After drying, 2.4 g of white crystals (54.5% of theory) are obtained, which decompose at 150 ° C. with the evolution of gas.

analysis

Ber. : C 57.13 H 5.53 N 5.12 O 32.20

Gef. : C 57.21 H 5.51 N 4.98

The gadolinium complex is prepared according to the procedure described under example le.

analysis

Calc .: C 44.56 H 3.88 N 3.99 O 25.11 Gd 22.43 Found: C 44.42 H 3.85 N 4.05 Gd 21.93

Gd (AAS) 22.38%

The following salts are also obtained by the procedure described under le:

Sodium salt of the gadolinium complex

Analysis:

Calc .: C 43.20 H 3.62 N 3.87 O 24.35 Gd 21.75 Na 3.18

Found: C 43.14 H 3.66 N 3.85 O Gd 21.15 Na 3.09

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 44.28 H 4.84 N 4.69 O 28.60 Gd 17.57

Found: C 44.30 H 4.81 N 4.75 O Gd 17.23

Morpholine salt of the gadolinium complex

Analysis:

Calc .: C 45.79 H 4.48 N 5.34 O 24.39 Gd 19.98

Found: C 45.81 H 4.41 N 5.37 O GdG 19.59

Example 4

3,6-diaza-3,6-bis- (tert-butoxycarbonylmethyl-4- (4-hy¬drazinocarbonylmethoxybenzyl) -succinic acid-bis- (tert-butyl) diester

6.8 g of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4-benzyloxycarbonylmethoxybenzyl) -succinic acid bis- (tert-butyl) diester (Example 3a) (8, 82 mmol), dissolved in 25 ml of absolute ethanol, are added dropwise to a solution of 1.1 ml of hydrazine hydrate (22.3 mmol) in 50 ml of ethanol at 5 ° C.-10 ° C. and stirred at room temperature overnight. The mixture is then concentrated to half, poured into 400 ml of H ₂ O and extracted several times with ether. After drying and stripping off the organic phase, it is purified on a silica gel column. 5.85 g (95.4% of theory) of colorless oil are obtained.

analysis

Calc .: C 60.49 H 8.41 N 8.06 O 23.02

Found: C 60.60 H 8.31 N 8.07

3,6-diaza-3,6-bis (carboxymethyl) -4- (4-hydrazinocarbo¬nylmethoxybenzyl) suberic acid

7.7 g (10.9 mmol) of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4-hydrazinocarbonylmethoxybenzyl) -succinic acid-bis- (tert-butyl) diester ( Example 4a) are left to stand in 80 ml of trifluoroacetic acid for 2 hours at room temperature. Then pour into dry ether and decant. The mixture is then stirred for a further 1/2 hour with 100 ml of a 10% ether-triethylamine solution, filtered off with suction and dried in vacuo: 4.5 g of white crystals with a melting point of 185 ° C. (decomposition). Yield 4.5 g (89% of theory).

analysis

Calc .: C 48.50 H 5.57 N 11.90 O 34.0 Found: C 48.27 H 5.56 N 11.93

The gadolinium complex is prepared according to the procedure described under example le.

analysis

Calc .: C 36.53 H 3.71 N 8.96 O 25.61 Gd 25.17 Found: C 36.60 H 3.68 N 8.89 Gd 24.51

Gd (AAS): 25.26%

The following salts are obtained analogously to the procedure in Example 1e:

Sodium salt of the gadolinium complex

Analysis:

Calculated: C 35.29 H 3.42 N 8.66 O 24.74 Gd 24.31 Na 3.55

Found: C 35.33 H 3.40 N 8.71 O Gd 24.01 Na 3.59

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 38.08 H 4.91 N 6.54 O 29.27 Gd 19.17

Found: C 38.12 H 4.90 N 8.49 O Gd 19.20

Morpholine salt of the gadolinium complex

Analysis:

Ber. : C 38.86 H 4.39 N 9.85 O 24.76 Gd 22.12

Found: C 38.82 H 4.48 N 9.89 O Gd 22.16

Example 5

3,6-diaza-3,6-bis- (tert-butoxycarbonylmethyl) -4- (4-benzyloxycarbonylpentamethyleneoxybenzyl) -succinic acid bis- (tert-butyl) diester

According to the procedure given for example 3a, 3.5 g (5.6 mmol) of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) -suberic acid-bis are obtained - (tert-Butyl) diester (Example 1a) and 1.6 g (5.6 mmol) of benzyl 6-bromcaproate 3.6 g (78% of theory) of a colorless oil

analysis

Calc .: C 66.80 H 8.53 N 3.38 0 21.27

Found: C 66.72 H 8.49 N 3.40

3,6-diaza-3,6-bis (carboxymethyl) -4- (4-benzyloxycarbonyl pentamethyleneoxybenzyl) suberic acid

According to the procedure given for Example 3b, 12.3 g (14.8 mmol) of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4-benzyloxycarbonylpentamethyleneoxybenzyl) -succinic acid-bis are obtained - (tert.-butyl) diester (Example 5a) 8.25 g (92% of theory) of a white crystalline product Melting point: 188 ° C. (decomposition)

analysis

Ber. : C 59.79 H 6.35 N 4.64 O 29.20

Found: C 55.92 H 6.41 N 4.74

Gadolinium complex

The gadolinium complex is obtained in almost quantitative yield in the manner described in Example le

analysis

Calc .: C 47.60 H 4.66 N 3.70 O 23.25 Gd 20.77 Found: C 47.38 H 4.67 N 3.52 Gd 20.65

The following salts are obtained analogously to the procedure in Example 1e:

Sodium salt of the gadolinium complex

Analysis:

Calculated: C 46.26 H 4.40 N 3.59 O 22.29 Gd 20.19 Na 2.95

Found: C 46.25 H 4.36 N 3.60 O Gd 20.09 Na 2.99

Meglumine salt of the gadolinium complex

Analysis:

Calculated: C 47.47 H 5.59 N 4.48 O 25.63 Gd 16.79

Found: C 47.39 H 5.57 N 4.49 O Gd 16.63

Morpholine salt of the gadolinium complex

Analysis:

Calc .: C 48.44 H 5.14 N 4.98 O 22.77 Gd 18.65

Found: C 48.38 H 5.17 N 4.93 O GdG 18.37

Example 6

3,6-diaza-3,6-bis- (tert-butoxycarbonylmethyl) -4- (4-hydrazinocarbonylpentamethyleneoxybenzyl) -suberic acid-bis- (tert-butyl) diester

According to the procedure given for Example 4a, 6.35 g (7.68 mmol) of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4-benzyloxycarbonylpentamethyleneoxybenzyl) -succinic acid are obtained bis (tert-butyl) diester (Example 5a) 5.07 g (88% of theory) of a colorless oil

analysis

Calc .: C 62.37 H 8.85 N 7.46 O 22.30

Found: 62.28 H 8.84 N 7.51

3,6-diaza-3,6-bis (carboxymethyl) -4- (4-hydrazinocarbonylpentamethyleneoxybenzyl) suberic acid

According to the procedure given for Example 4b, from 2.66 g (3.54 mmol) of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl-4- (4- (hydrazinocarbonylpentame¬thylene-oxybenzyl) -suberic acid) bis (tert-butyl) diester (Example 6a) 1.69 g (91% of theory) of a white crystalline product Melting point: 210 ° C. (decomposition)

analysis

Ber. : C 52.46 H 6.50 N 10.64 O 30.38

Found: C 52.51 H 6.39 N 10.70

Gadolinium complex

The gadolinium complex is obtained in almost quantitative yield in the manner described in Example le

analysis

Ber. : C 40.57 H 4.59 N 8.22 O 23.50 Gd 23.09 Found: C 40.60 H 4.52 N 8.21 Gd 23.0

The following salts are obtained analogously to the regulation in 1e:

Sodium salt of the gadolinium complex

Analysis:

Calc .: C 39.31 H 4.30 N 7.97 O 22.76 Gd 22.37 Na 3.27

Found: C 39.26 H 4.31 N 7.90 O Gd 21.97 Na 3.27

Meglum salt of the gadolinium complex

Analysis:

Calc .: C 41.13 H 5.52 N 7.99 O 27.39 Gd 17.95

Found: C 41.20 H 5.55 N 7.87 O Gd 17.81

Moroholin salt of the Gadolinium complex

Analysis:

Calculated: C 42.28 H 5.12 N 9.13 O 22.94 Gd 20.50

Found: C 42.31 H 5.07 N 9.14 O GdG 20.11

a) Example 7

3,6-Diaza-3,6-bis (tert-butoxycarbonylmethyl-4- [4- (methacryloyl) hydrazinocarbonylpentamethyleneoxybenz yl) -suberic acid bis- (tert-butyl) diester

4.17 g (5.56 mmol) of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4-hydrazinocarbonylpentamethyleneoxybenzyl) -succinic acid-bis- (tert-butyl) diester (Example 6a) are dissolved in 50 ml of dry dichloromethane and mixed with 0.6 ml of triethylamine. A solution of 0.6 g of methacryloyl chloride in 10 ml of dichloromethane is then added dropwise at 0.degree. C., the mixture is stirred overnight at room temperature and the precipitated triethylammonium chloride is filtered off. After filtration over silica gel with ethyl acetate, 3.14 g (69% of theory) of a colorless oil are obtained after stripping off the solvent.

analysis

Ber. : C 63 .05 H 8. 61 N 6.84 O 22. 48

Gef. : C 62. 98 H 8.70 N 6. 82

3,6-diaza-3,6-bis (carboxymethyl) -4- [4- (methacryloyl) hydrazinocarbonylpentamethyleneoxybenzyl) suberic acid

According to the procedure given for Example 3b, 3.0 g (3.66 mmol) of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4- (methacryloyl) hydrazinocarbonylpentamethyleneoxybenzyl) -succinic acid bis (tert-butyl) diester (Example 7a). 1.92 g (88% of theory) of a white crystal melting point: 135 ° C (decomposition)

analysis

Calc .: C 54.53 H 6.44 N 9.42 O 29.59

Found: C 54.60 H 6.31 N 9.51

Gadolinium complex

The gadolinium complex is obtained in almost quantitative yield in the manner described in Example le

analysis

Ber. : C 43. 30 H 4.71 N 7. 48 O 23. 50 Gd 20.99 Gef. : C 43. 24 H 4. 69 N 7.43 Gd 21.20

The following salts are obtained analogously to regulation 1e:

Sodium salt of the gadolinium complex

Analysis:

Calculated: C 42.01 H 4.57 N 7.25 O 22.80 Gd 20.37 Na 2.97

Found: C 41.96 H 4.55 N 7.30 O Gd 20.03 Na 3.01

Heglumin salt of the gadolinium complex

Analysis:

Calculated: C 43.21 H 5.65 N 7.41 O 27.08 Gd 16.63

Found: C 43.20 H 5.70 N 7.38 O Gd 16.33

Morpholine salt of the gadolinium complex

Analysis:

Calc .: C 44.54 H 5.30 N 8.37 O 22.96 Gd 18.81

Found: C 44.45 H 5.38 N 8.34 O Gd 18.80

Example 8

3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4-carboxymethoxybenzyl) -suberic acid bis- (tert-butyl) diester

9.5 g of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4-benzyloxycarbonylmethoxybenzyl) -succinic acid bis- (tert-butyl) diester (Example 3a) (0.012 mol ) are dissolved in 100 ml of dry tetrahydrofuran and hydrogenated in the presence of 2 g of 10% Pd / C until no further hydrogen uptake takes place. After suction, the solvent is removed on a rotary evaporator and the substance is dried further at 0.01 torr. The viscous oil obtained weighs 8.33 g (99% of theory)

analysis

Ber. : C 61.74 H 8. 29 N 4.11 O 25.84

Gef. : C 61. 82 H 8.17 N 4.12

b) 3.6-Dιaza-3,6-bιs (tert-butoxycarbony] methyl) -4- [4- ((2,3,4, 5,6-pentahydroxyhexyl) methylamino) carbonylmethoxybenzyl] -succinic acid-bis- (tert-butyl) diester

1.36 g of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4-carboxymethoxybenzyl) -succinic acid-bis- (tert-butyl) diester are dissolved in 50 ml of tetrahydrofuran and 0.3 g (3 mmol) of triethylamine were added. At -5 ° C, 0.25 g (2.02 mmol) of isobutyl chloroformate in 20 ml of tetrahydrofuran are carefully added and finally 5 ml of an aqueous solution of 430 mg (2.2 mmol) of N-methyl-D-glucamine are added. After stirring for 30 minutes at below 0 ° C., the cold bath is removed and the mixture is allowed to warm to room temperature. After the solvent has been stripped off, the residue is purified by chromatography on silica gel. 1.43 g of white, crystalline substance (83% of theory) is obtained, which decomposes with a brown color from 52 ° C.

Analyst:

Calculated: C 58.79 H 8.34 N 4.89 O 27.96

Found: C 58.62 H 8.32 N 4.7H

c) 3,6-Diaza-3,6-bis (carboxymethyl) -4- [4 - ((2,3,4,5,6-pentahydroxyhexyl) meth ylamino) carbonylmethoxybenzyl] -suberic acid

As described in Example 1e, 0.78 g (0.91 mmol) of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- [4 - ((2,3,4,5,6- pentahydroxyhexyl) - methylamino) -carbonylmethoxybenzyl] -succinic acid-bis- (tert-butyl) diester 432 mg (75% of theory) of the title compound of melting point 132 ° (decomposition).

Analysis:

Calculated: C 49.28 H 6.20 N 6.63 O 37.87

Found: C 49.19 H 6.21 N 6.46 Gadolinium complex

Analogous to the instruction in 1e, the gadolinium complex is obtained in almost quantitative yield:

Analysis:

Calc .: C 39.63 H 4.6 N 5.33 O 30.46 Gd 19.95

Found: C 39.72 H 4.66 N 5.32 6d 19.75

Gd (AAS) 20.01% by weight

The following are also obtained analogously to the regulation of 1e:

Sodium salt of the gadolinium complex

Analysis:

Calc .: C 38.56 H 4.35 N 5.18 O 29.63 Gd 19.41 Na 2.83

Found: C 38.50 H 4.34 N 5.09 Gd 19.50 Na 2.81

Meolumin salt of the gadolinium complex

Analysis:

Calc .: C 40.31 H 5.43 N 5.69 O 32.55 Gd 15.99

Found: C 40.29 H 5.40 N 5.67 Gd 15.80

Horolin salt of the gadolinium complex

Analysis:

Calc .: C 41.23 H 5.07 N 6.41 O 22.29 Gd 17.99

Found: C 41.20 H 4.98 N 6.37 Gd 17.69 Example 9

O-benzyl-N-trifluoroacetyltyrosine

112.5 g (0.41 mmol) of O-benzyltyrosine are suspended in 1 l of dry methanol and 58.9 ml (0.42 mol) of triethylamine are added at room temperature. After the addition of 67 ml (0.53 mol) of ethyl trifluoroacetate, the mixture is stirred for 130 h at room temperature with the exclusion of water. It is separated from unreacted starting material and volatile components are removed by shaking with ethyl acetate / aqueous hydrochloric acid. The ethyl acetate phase is decolorized with activated carbon. After evaporation of the solvents, 120.7 g (80% of theory) of colorless crystals are obtained. Melting point: 149-150 ° C

analysis

Calc .: C 58.85 H 4.39 N 3.81 O 17.42 F 15.51 Found: C 58.78 H 4.29 N 3.79 F 15.57

O-benzyl-N-trifluoroacetyltyrosine (2-carbobenzoxyaminoethylene) amide

18.5 g (50.4 mmol) of O-benzyl-N-trifluoroacetyltyrosine (Example 9a) are dissolved in 200 ml of dry tetrahydrofuran, mixed with 7 ml of Et ₃ N and then dropwise 4.8 ml (50.8 mmol) of ethyl chloroformate added keeping the temperature below -10 ° C. After the addition has ended, the mixture is stirred at this temperature for 30 minutes, the same amount of precooled triethylamine is added, and an ice-cold solution of 11.6 g (50.4 mmol) of N- (2-aminooethyl) -carbamic acid benzyl ester hydrochloride in 100 ml Dimethylformamide added dropwise. The mixture is stirred for a further 30 minutes at -10 ° C., then allowed to come to room temperature with stirring and then warmed to 30 ° C. for 10 minutes. The solvent is then removed on a rotary evaporator and poured onto 750 ml of ice water. The crystals are filtered off, washed with ice water and dried. The yield is 26.9 g (94% of theory). Melting point: 189-190 ° C

analysis

Ber. : C 61.87 H 5.19 N 7.73 O 14.71 F 10.48 Gef. : C 61.90 H 5.08 N 7.77 F 10.43

O-benzyltyrosine (2-carbobenzoxyaminoethylene) amide

25.9 g (47.8 mmol) of O-benzyl-N-trifluoroacetyltyrosine (2-carbobenzoxyaminoethylene) -amide (Example 9b) are suspended in 300 ml of EtOH and 7.2 g (191 mmol) of sodium borohydride are added in portions. After stirring overnight at room temperature, 50 ml of acetone are added, the solvent is removed, 500 ml of H ₂ O are added and the mixture is extracted several times with ethyl acetate. After drying and concentrating, the organic phase gave 18.8 g (88% of theory) of white crystals with a melting point of 145 ° C.

analysis

Ber. : C 69.77 H 6.53 N 9.38 O 1 4.29

Gef. : C 69.79 H 6.53 N 9 .35

d) tyrosine (2-aminoethylene) amide

42.3 g (94.6 mmol) of O-benzyltyrosine (2-carbobenzoxyamioethylene) -amide (Example 9c) are dissolved in 1.1 l of methanol, 2 g of 10% palladium-carbon are added and the mixture is hydrogenated with stirring until none further hydrogen uptake occurs. The catalyst is filtered off and the solvent is evaporated off. It is dissolved in methanol in the heat and precipitated with ether: 17 g (86% of theory) of colorless crystals. Melting point: 138-141 ° C

analysis

Ber. : C 59.17 H 7.67 N 18.81 O 14.33

Gef. : C 59.23 H 7.51 N 18.90

3-aza-1- (4-hydroxybenzyl) pentane-1,5-diamine · trihydrochloride

6.55 g (29.3 mmol) of tyrosine (2-aminoethylene) -amide (Example 9d) are suspended in 130 ml of dry tetrahydrofuran and a slow stream of B ₂ H ₆ (from 5.8 g of NaBH ₄ in 75 ml Diethylene glycol dimethyl ether and 54 ml boron trifluoride etherate complex) with dry nitrogen with constant stirring through the solution. The mixture is stirred overnight at 60 ° C., then 30 ml of methanol are added dropwise at 20 ° C. and hydrogen chloride is passed in with ice cooling. Then boil briefly and suction. The trihydrochloride is obtained in the form of colorless crystals (8.04 g; 86% of theory). Melting point: 250 ° C (decomposition)

analysis

Calc .: C 41.45 H 6.95 N 13.18 O 5.02 Cl 33.37 Found: C 41.37 H 6.89 N 13.14 Cl 33.51

f) 3,6,9-triaza-4- (4-hydroxybenzyl) -3,6,9-tris- (tert-butoxycarbonylmethyl) -undecanedioic acid bis- (tert-butyl) diester

2.07 g (6.5 mmol) of 3-aza-1- (4-hydroxybenzyl) pentane-1,5-diamine · trihydrochloride (Example 9e) are mixed with 5.2 g of sodium hydrogen carbonate and 6.34 g (82, 2 mmol) tert-butyl bromoacetic acid according to the instructions for 3,6-diaza-bis- (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) -suberic acid-bis- (tert-butyl) diester (example 1a) manufactured. 3.54 g (68.8%) of a colorless oil are obtained.

analysis

Ber. : C 63 .13 H 8 .91 N 5.38 O 22.56

Gef. : C 63.21 H 8.90 N 5.42

3,6,9-Triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- [4- (3-benzyloxycarbonylaminopropoxy) benzyl)] - undecanedioic acid bis (tert-butyl) diester .

From 4.6 g (5.90 mmol) 3, 6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) -undecanedioic acid-bis- (tert.- Butyl) diester (Example 9f) is obtained according to the procedure given for Example 1b 4.2 g of a colorless oil (yield 74% of theory)

analysis

Calc .: C 64.30 H 8.51 N 5.76 O 22.41

Found: C 64.20 H 8.65 N 5.82

3,6,9-Triaza-3,6,9-tris (tert-butoxycarbonylmethyl-4- [4- (3-aminopropoxy) benzyl] undecanedioic acid bis (tert-butyl) diester

According to the method described in Example 1c, 3.9 g (4.8 mmol) of 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl-4- [4- (3-benzyloxycarbonylaminopropoxy) -benzyl-undecanedioic acid-bis- (tert-butyl) diester (Example 9g) is hydrogenated. A colorless viscous oil is obtained. Yield: 3.17 g (97.3% of theory)

analysis

Ber. : C 63 .13 H 9.15 N 6.69 O 22.02

Gef. : C 62.97 H 9.01 N 6.62

i) 3,6,9-Triaza-3,6,9-tris (tert-butoxycarbonylmethyl) 4- [4- (3- (maleimido) propoxy) benzyl] -undecanedioic acid bis- (tert.- butyl) diesters

According to the method described in Example 1d, the maleimide is obtained in 91% yield starting from 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl-4- [4- (3-aminopropoxyl-benzyl] -undecanedioic acid-bis- (tert-butyl) diester (Example 9h) obtained (colorless, viscous oil)

analysis

Ber. : C 62.86 H 8.35 N 6. 10 O 22.62

Gef. : C 62.71 H 8.33 N 6.10

j) 3,6,9-Triaza-3,6,9-tris (carboxymethyl) -4 [4- (3- (maleimido) propoxy) benzyl] undecanedioic acid

As described in Example le, the free penta acid is obtained in 89% yield starting from 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl-4- [4- (3- (maleimido) -propoxy) -benzyl] -undecanedioic acid-bis- (tert-butyl) diester (Example 9i) as a white powder. Melting point:> 161 ° C (decomposition)

analysis

Calc .: C 52.82 H 5.69 N 8.80 O 32.67 Found: C 52, 72 H 5.63 N 8.86

Gadolinium complex

Analysis of the regulation in example le, the gadolinium complex is obtained in almost quantitative yield.

analysis

Calc .: C 42.52 H 4.20 N 7.08 O 26.30 Gd 19.88

Found: C 42.58 H 4.29 N 7.83 O Gd 19.89

Gd (AAS): 73.73%

The following salts are obtained as described under 1e:

Sodium salt of the gadolinium complex

Analysis:

Calculated: C 40.28 H 3.74 N 6.71 O 24.91 Gd 18.83 Na 5.50

Found: C 40.23 H 3.77 N 6.90 O Gd 18.58 Na 5.47

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 42.70 H 5.85 N 7.28 O 30.52 Gd 13.63

Found: C 42.58 H 5.69 N 7.35 Gd 13.51

Moroholin salt of the Gadolinium complex

Analysis:

Calc .: C 44.89 H 5.12 N 8.72 O 24.91 Gd 16.32

Found: C 44.93 H 5.15 N 8.77 Gd 16.15

Analogously to the instructions for the preparation of the gadolinium complex, the

Indium complex

Calc .: C 44.93 H 4.44 N 7.49 O 27.79 In 15.34 Found: C 44.94 H 4.61 N 7.44 In 15.32

Yttrium complex

Ber. : C 46.48 H 4.59 N 7.75 O 28.75 Y 12.43 Found: C 46.50 H 4.62 N 7.61 Y 12.45 Ytterbium complex

Calc .: C 41.68 H 4.12 N 6.95 O 25.79 Yb 21.45 Found: C 41.55 H 4.17 N 6.81 Yb 21.32

Samarium complex

Calc .: C 42.89 H 4.24 N 7.15 O 26.53 Sm 19.18 Found: C 42.81 H 4.23 N 7.20 Sm 19.31

Praseodymium complex

Calc .: C 43.42 H 4.29 N 7.24 O 26.86 Pr 18.19 Found: C 43.32 H 4.43 N 7.31 Pr 18.20

Cobalt complex

Calc .: C 48.56 H 4.80 N 8.09 O 30.04 Co 8.51 Found: C 48.58 H 4.73 N 8.18 Co 8.36

Example 10

3,6,9-Triaza-4- (4-benzyloxycarbonylmethoxybenzyl) -3,6,9-tris- (tert-butoxycarbonylmethyl) -undecanedioic acid-bis- (tert-butyl) diester

From 1.98 g (2.54 mmol) of 3,6,9-triaza-4- (4-hydroxybenzyl) -3,6,9-tris (tert-butoxycarbonylmethyl) -undecanedioic acid-bis- (tert.- butyl) diesters (Example 9f) and 0.54 g of benzyl bromoacetate (2.54 mmol) are obtained according to the procedure given in Example 3a, 1.35 g (1.45 mmol) of a colorless syrup (62% of theory)

analysis

Ber. : C 64.70 H 8.36 N 4.52 O 22.4

Found: C 64.91 H 8.31 N 4.55

3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-benzyloxycarbonylmethoxybenzyl) -undecanedioic acid

From 5.3 g (5.71 mmol) of 3,6,9-triaza-4- (4-benzyloxycarbonylmethoxy-benzyl-3,6,9-tris (tert-butoxycarbonylmethyl) - undecanedioic acid-bis- (tert. -butyl) diester (Example 10a) 3.0 g (82% of theory) of a white solid are obtained according to the instructions given for Example 3b melting point: 145 ° C. (decomposition)

analysis

Calc .: C 55.63 H 5.75 N 6.48 O 32.11 Found: C 55.69 H 5.70 N 6.43

The gadolinium complex was prepared according to the procedure described in Example 1e

analysis

Calc .: C 44.93 H 4.27 N 5.24 O 25.93 Gd 19.61 Found: C 44.87 H 4.14 N 5.30 Gd 19.41

Gd (AAS): 19.62%

The following salts are obtained analogously to the instruction given under 1e:

Sodium salt of the gadolinium complex

Analysis:

Calculated: C 42.60 H 3.81 N 4.96 O 24.59 Gd 18.59 Na 5.43

6ef .: C 42.54 H 3.87 N 4.99 Gd 18.38 Na 5.47

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 44.32 H 5.74 N 5.87 O 30.86 Gd 13.18

Found: C 44.50 H 5.65 N 5.88 Gd 13.07

Morpholine salt of the gadolinium complex

Analysis:

Calculated: C 46.85 H 5.17 N 7.18 O 24.63 Gd 16.14

Found: C 46.57 H 5.15 N 7.25 Gd 15.97

Example 11

3,6,9-triaza-4- (4-hydrazinocarbonyl-methoxybenzyl) -3,6,9-tris- (tert-butoxycarbonylmethyl) -undecanedioic acid-bis- (tert-butyl) diester

From 12.6 g (13.57 mmol) of 3,6,9-triaza-4- (4-benzyloxycarbonylmethoxybenzyl) -3,6,9-tris- (tert-butoxycarbonylmethyl) -undecanedioic acid-bis- (tert.- Butyl) diester (Example 10a) is obtained according to the procedure given in Example 4a, 9.6 g (83% of theory) of a colorless oil which is highly viscous at room temperature.

analysis

Calc .: C 60.61 H 8.63 N 8.21 O 22.533

Found: C 60.47 H 8.70 N 8.12

3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-hydrazinocarbonylmethoxybenzyl) undecanedioic acid

6.8 g (7.9 mmol) of 3,6,9-triaza-4- (4-hydrazinocarbonylmethoxybenzyl) -3,6,9-tris- (tert-butoxycarbonylmethyl) undecanedioic acid-bis- (tert-butyl) diesters (example a) are reacted with trifluoroacetic acid according to the instructions given for example 4b. After working up, 3.1 g of white crystals (67% of theory) are obtained. Melting point: 180 ° C. (decomposition)

analysis

Calc .: C 48.33 H 5.81 N 12.25 O 33.59 Found: C 48.46 H 5.79 N 12.30

The gadolinium complex was prepared according to the procedure described in Example 8

analysis

Calc .: C 33.06 H 4.16 N 9.64 O 26.45 Gd 21.66 Found: C 32.98 H 4.08 N 9.55 Gd 21.03

Gd (AAS) 21.57%

The following salts are obtained analogously to the instruction given under 1e:

Sodium salt of the gadolinium complex

Analysis:

Calcd .: C 35.88 H 3.66 N 9.09 O 24.94 Gd 20.42 Na 5.97

Found: C 35.78 H 3.57 N 9.00 Gd 20.23 Na 5.96

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 39.85 H 5.69 N 8.79 O 31.56 Gd 14.10

Found: C 39.81 H 5.70 N 8.73 Gd 14.00

Morpholine salt of the gadolinium complex

Analysis:

Ber. : C 41.46 H 5.16 N 10.91 O 24.94 Gd 17.51

Found: C 41.41 H 5.17 N 10.99 Gd 17.48

Example 12

3,6,9-Triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-benzyloxycarbonylpentamethyleneoxybenzyl) -undecanedioic acid bis- (tert-butyl) diester

According to the instructions given for example 3a, from 7.3 g (9.36 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) -undecanedioic acid bis (tert-butyl) diester (Example 9f) and 2.67 g (9.36 mmol) of benzyl 6-bromcaproate 7.19 g (78% of theory) of a colorless oil

analysis

Ber. : C 65.89 H 8.70 N 4.26 O 21.13

Found: C 65.76 H 8.62 N 4.30

3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-benzyloxy¬carbonylpentamethyleneoxybenzyl) -undecanedioic acid

According to the procedure given for Example 3b, 6.93 g (7.04 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-benzyloxycarbonylpentamethyleneoxybenzyl) -undecanedioic acid bis (tert-butyl) diester (Example a) 4.30 g (87% of theory) of a white crystalline product Melting point: 173 ° C (decomposition)

analysis

Calc .: C 58.02 H 6.44 N 5.97 O 29.55 Found: C 58.02 H 6.34 N 5.96

Gadolinium complex

The gadolinium complex is obtained in almost quantitative yield in the manner described in Example le

analysis

Calc .: C 47.59 H 4.93 N 4.89 O 24.24 Gd 18.32 Found: C 47.50 H 4.83 N 4.98 Gd 18.22

The following salts are obtained analogously to the instruction given under 1e:

Sodium salt of the gadolinium complex

Analysis:

Calc .: C 45.27 H 4.47 N 4.65 O 23.06 Gd 17.43 Na 5.09

Found: C 45.33 H 4.45 N 4.61 Gd 17.51 Na 5.11

Megluminsal of the Gadolinium complex

Analysis:

Calculated: C 46.18 H 6.13 N 5.60 O 29.47 Gd 12.59

Found: C 46.17 H 6.14 N 5.51 Gd 12.61

Moroholin salt of the Gadolinium complex

Analysis:

Calc .: C 48.96 H 5.67 N 6.79 O 23.29 Gd 15.26

Found: C 48.99 H 5.61 N 6.78 Gd 15.17

Example 13

a) 3,6,9-Triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- (4-hydrazinocarbonylpentamethyleneoxybenzyl) -undecanedioic acid bis- (tert-butyl) diester

According to the procedure given for example 4a, 16.95 g (16.61 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxyycarbonylmethyl) -4- (4-benzyloxycarbonylpentamethyleneoxybenzyl) -undecanedioic acid bis (tert-butyl) diester (Example 12a) 14.03 g (93% of theory) of a colorless oil

analysis

Ber. : C 62.15 H 8 .99 N 7.71 O 21. 14

Gef. : C 62.01 H 8.72 N 7.78

3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-hydrazinocarbonylpentamethyleneoxybenzyl) undecanedioic acid

According to the procedure given for example 4b, 6.2.9 g (6.88 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl-4- (4-hydrazinocarbonylpentamethyleneoxybenzyl-undecanedioic acid) is obtained bis (tert-butyl) diester (Example a) 3.86 g (87% of theory) of a white crystalline product Melting point: 225 ° C (decomposition)

analysis

Calc .: C 51.66 H 6.58 N 11.15 O 30.58 Found: C 51.52 H 6.57 N 11.20

Gadolinium complex

The gadolinium complex is obtained in almost quantitative yield in the manner described in Example le

Analysis

Calc .: C 41.47 H 4.89 N 8.95 O 24.55 Gd 20.11 Found: C 41.41 H 4.90 N 9.01 Gd 20.12

The following salts are obtained analogously to the instruction given under 1e:

Sodium salt of the Gadolinium Komolex

Analysis:

Calc .: C 39.26 H 4.39 N 8.48 O 23.24 Gd 19.04 Na 5.56

Found: C 39.18 H 4.33 N 8.40 Gd 19.00 Na 5.53

Meglumine salt of the gadolinium complex

Analysis:

Calculated: C 42.00 H 6.19 N 8.36 O 30.02 Gd 13.41

Found: C 42.10 H 6.15 N 8.33 Gd 13.20

Moroholin salt of the Gadolinium complex

Analysis:

Calc .: C 44.06 H 5.70 N 10.27 O 23.47 Gd 16.48

Found: C 43.95 H 5.71 N 10.23 Gd 16.42

Example 14

a) 3,6,9-Triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- [4- (methacryloyl) -hydrazinocarbonylpentamethyleneoxybenzyl) -undecanedioic acid bis- (tert-butyl) diester

According to the procedure given for Example 7a, 7.78 g (8.56 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-hydrazinocarbonylpentamethyleneoxybenzyl) -undecanedioic acid bis (tert-butyl) diester (Example 13 a) 6.02 g (72% of theory) of a colorless oil

analysis

Calc .: C 62.74 H 8 .77 N 7.17 O 21.3

Found: C 62.51 H 8 .80 N 7.20

b 3,6,9-Triaza-3,6,9-tris (carboxymethyl) -4- [4- (methacryloyl) hydrazinocarbonylpentamethyleneoxybenzyl) undecanedioic acid

According to the procedure given for Example 3b, 1.98 g (2.02 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4-E4- (methacryloyl) is obtained -hydrazinocarbonylpentamethyleneoxybenzyl) -undecanedioic acid bis (tert-butyl) diester (Example a) 1.38 g (98% of theory) of a white crystalline product Melting point: 162 ° C (decomposition)

analysis

Ber. : C 53 .51 H 6.51 N 10.06 O 29.89

Gef. : C 53. 60 H 6.72 N 10.10

Gadolinium complex

The gadolinium complex is obtained in almost quantitative yield in the manner described in Example le

analysis

Calc .: C 43.80 H 4.98 N 8.23 O 24.47 Gd 18.50 Found: C 43.71 H 4.81 N 8.09 Gd 18.41

The following salts are obtained analogously to the instruction given under 1e:

Sodium salt of the gadolinium complex

Analysis:

Calculated: C 41.60 H 4.61 N 7.82 O 23.24 Gd 17.57 Na 5.13

Found: C 41.55 H 4.62 N 7.78 Gd 17.50 Na 5.12

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 43.53 H 6.25 N 7.89 O 29.64 Gd 12.66

Found: C 43.49 H 6.27 N 7.87 Gd 12.51

Moroholin salt of the Gadolinium complex

Analysis:

Calc .: C 45.78 H 5.81 N 9.58 O 23.45 Gd 15.36

Found: C 45.77 H 5.80 N 9.53 Gd 15.31

Example 15

3,6,9-Triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- [4- (3- (methacrylamido) propoxy) benzyl] -undecanedioic acid bis- (tert-butyl ) -diester

According to the method described in Example 2a, starting from 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl-4- [4- (3-aminopropoxy) -benzyl] -undecanedioic acid-bis - (tert-Butyl) diester (Example 9H) the title compound in 89% yield.

Analysis:

Ber. : C 63 .69 H 8.90 N 6.18 O 21.21

Gef. : C 63.61 H 8.71 N 6.22

b)

3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- [4- (3- (methacrylamido) propoxy) benzyl] undecanedioic acid

According to the procedure given for Example 2b, starting from 3,6,9-triaza-3,6,9-tris- (tert-bu toxycarbonylmethyl) -4- [4- (3-methacrylamido) propoxy) - benzyl] -undecanedioic acid bis (tert-butyl) diester (in game a), the title compound in 90% yield.

analysis

Calc .: C 53.83 H 6.45 N 8.96 O 30.73 Found: C 53.75 H 6.25 N 8.90

Gadolinium complex

The gadolinium complex is obtained in 98% yield in the manner described in Example le.

analysis

Calc .: C 43.17 H 4.78 N 7.19 O 24.65 Gd 20.18 Found: C 43.30 H 4.70 N 7.17 Gd 20.22

GD (AAS): 20.25%

The following salts are obtained analogously to the instruction given under 1e:

Sodium salt of the gadolinium complex

Analysis:

Calculated: C 40.87 H 4.28 N 6.80 O 23.33 Gd 19.11 Na 5.58

Found: C 40.85 H 4.23 N 6.74 Gd 19.01 Na 5.55

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 43.10 H 6.20 N 7.18 O 30.07 Gd 13.43

Found: C 41.15 H 6.19 N 7.20 Gd 13.28

Moroholin salt of the Gadolinium complex

Analysis:

Calc .: C 45.41 H 5.71 N 8.82 O 23.52 Gd 16.51

Found: C 45.36 H 5.84 N 8.78 Gd 16.39

EXAMPLE 16

a) 3,6,9-Triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- (4-carboxymethoxybenzyl) -undecanedioic acid bis- (tert-butyl) diester.

From 7.83 g (8.43 mmol) 3, 6,9-triaza-4- (4-benzyloxycarbonylmethoxybenzyl) - 3,6,9-tris- (tert-butoxycarbonylmethyl) -undecanedioic acid-bis- (tert.- butyl) diester (Example 10a) is obtained according to the procedure given for Example 8a 4.2 g of a colorless oil (yield 74% of theory)

Analysis:

Calc .: C 61, 62 H 8.53 N 5.01 O 24.81

Found: C 61, 73 H 8.53 N 5.10

b) 3,6,9-Triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- [4- (2,3,4,5,6-pen tahydroxyhexyl) methylamino-carbonylmethoxybenzyl] -undecanedioic acid- bis (tert-butyl) diester

4.56 g (5.4 mmol) 3, 6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-carboxymethoxybenzyl) -undecanedioic acid bis- (tert-butyl ) diesters are dissolved in 100 ml of tetrahydrofuran and mixed with 0.5 g (8 mmol) of triethylamine. At -5 ° C., 0.73 g (5.5 mmol) of isobutyl chloroformate in 40 ml of tetrahydrofuran are carefully added and finally 10 ml of an aqueous solution of 1.08 g (5.5 mmol) of N-methyl-D-glucamine are added. After stirring for 30 minutes below 0 ° C., the cooling bath is removed and the mixture is allowed to warm to room temperature. After the solvent has been stripped off, the residue is purified by chromatography on silica gel. 4.17 g of white, crystalline substance are obtained (76% of theory), which decomposes at 50 ° C. with a brown color.

Analysis:

Calc .: C 59.15 H 8.53 N 5.51 O 26.79

Found: C 59.07 H 8.56 N 5.50 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- [4- (2,3,4,5,6-pentahydroxyhexyl) methylaminocarbonylmethoxybenzyl] undecanedioic acid

As described in Example le, 3.25 g (3.2 mmol) of 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- [4- (2,3,4, 5,6-pentahydroxyhexyl) -methylamino -carbonylmethoxybenzyl] -undecanedioic acid-bis- (tert.butyl) -diester 1.86 g (79% of theory) of the title compound of melting point 132 ° C. (decomposition)

Analysis:

Calc .: C 49.04 H 6.31 N 7.62 O 37.01

Found: C 49.19 H 6.21 N 7.46

Gadolinium complex

Analogous to the instruction in 1e, the gadolinium complex is obtained in almost quantitative yield:

Analysis:

Calc .: C 40.53 H 4.87 N 6.30 O 30.59 Gd 17.68

Found: C 40.72 H 4.65 N 6.32 Gd 17.75

Gd (AAS) 17.51% by weight

The following salts are obtained analogously to the instruction given under 1e:

Sodium salt of the gadolinium complex

Analysis:

Calc .: C 38.62 H 4.42 N 6.00 O 29.15 Gd 16.85 Na 4.92

Found: C 38.68 H 4.48 N 5.93 Gd 16.54 Na 4.98

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 41.30 H 6.06 N 6.56 O 33.76 Gd 12.29

Found: C 41.27 H 5.98 N 6.69 Gd 11.90

Morpholine salt of the gadolinium complex

Analysis:

Calc .: C 43.01 H 5.60 N 7.91 O 28.64 Gd 14.81

Found: C 43.06 H 5.62 N 7.98 Gd 14.88

Example 17

3-aza-2- (4-benzyloxybenzyl) -4-oxoglutaric acid diamide (method A).

3.62 g (13.3 mmol) of O-benzyltyrosinamide are refluxed with 2.7 g of ethyl oxamate (23 mmol) in dimethoxyethane for 14 h. After the solvent has been stripped off, it is washed successively with water, ethanol and ether. After drying, 2.73 g of white crystals (60% of theory) are obtained. Melting point: 270 ° C.

analysis

Ber. : C 63.33 H 5.61 N 12.30 O 18.74

Gef. : C 63 .24 H 5.52 N 12.14

or according to method B: 3-aza-2- (4-benzyloxybenzyl) -4-oxoglutaric acid-5-ethyl ester-1-amide

3 g (11.1 mmol) of O-benzyltyrosinamide are dissolved in 30 ml of dimethoxyethane, mixed with 1.56 ml of triethylamine and 1.53 g (11.1 mmol) of ethyl oxalate chloride are added dropwise at 0 ° C. After 30 minutes at 0 °, the mixture is poured onto 100 ml of ice, suction filtered and dried. The yield is 3.87 g (94% of theory) melting point: 142 ° C.

analysis

Calc .: C 64.85 H 5.98 N 7.56 O 21.59

Found: C 64.71 H 6.11 N 7.46

3.6 g (9.72 mmol) of 3-aza-2- (4-benzyloxybenzyl) -4-oxoglutaric acid-5-ethyl ester-1-amide (Example aα) are mixed with 40 ml of a solution of 1 mol of NH ₃ / l Poured methanol. After 1 hour, the precipitated product is filtered off. After drying, 3.13 g (95% of theory) of the title compound are obtained in the form of colorless crystals. Melting point: 269 ° C

analysis

Calc .: C 63.33 H 5.61 N 12.30 O 18.74

Found: C 63.25 H 5.63 N 12.17

3-aza-2- (4-hydroxybenzyl) -4-oxoglutaric acid diamide

1 g (2.9 mmol) of 3-aza-2- (4-benzyloxybenzyl) -4-oxoglutaric acid diamide Example a) is suspended with 100 mg of 10% palladium-carbon and a few drops of concentrated hydrochloric acid in 20 ml of methanol and until the end of Hydrogen uptake hydrogenated. After filtering off the catalyst, 690 mg of colorless crystals (93% of theory) are obtained. Melting point: 245-250 ° C. (decomposition)

analysis

Ber. : C 52.58 H 5.21 N 16.72 O 22.47

Found: C 52.83 H 5.19 N 16.84

3-aza-2- (4-hydroxybenzyl) pentane-1,5-diamine · trihydrochloride

1 g (4.0 mmol) of 3-aza-2- (4-hydroxybenzyl) -4-oxoglutaric acid diamide (Example b) are reacted according to the instructions given for Example 9e. The colorless crystals obtained weigh 1.19 g (93.7% of theory). Melting point: 238 ° C.

analysis

Calculated: C 41.61 H 6.98 N 13.23 O 5.03 Cl 33.13

Found: C 41.60 H 6.95 N 13.17 Cl 33.33

3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -5- (4-hydroxybenzyl) -undecanedioic acid bis- (tert-butyl) diester

According to the instructions given for example 1a, 5.19 g (16.3 mmol) of 3-aza-2- (4-hydroxyybenzyl) pentane-1,5-diamine · trihydrochloride (example c) are made into 7.75 g (61 % of theory) of the title compound in the form of a viscous, clear liquid.

analysis

Calc .: C 63.13 H 8.91 N 5.38 O 22.56 Found: C 63.00 H 8.92 N 5.29

3,6,9-triaza-5- (4-benzyloxycarbonylmethoxybenzyl)

3,6,9-tris (tert-butoxycarbonylmethyl) -undecanedioic acid bis- (tert-butyl) diester

5.0 g (6.4 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl-5- (4-hydroxybenzyl) -undecanedioic acid-bis- (tert-butyl) diesters (example d) are reacted with benzyl bromoacetate according to the instructions for example 3a to give 4.6 g (74.8% of theory) of a colorless, viscous oil.

analysis

Calc .: C 64.70 H 8.36 N 4.52 O 22.40

Found: C 64.46 H 8.30 N 4.49

3,6,9-triaza-3,6,9-tris (carboxymethyl) -5- (4-benzyloxycarbonylmethoxybenzyl) -undecanedioic acid

From 3.6 g (5.7 mmol) 3, 6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -5- (4-benzyloxycarbonylmethoxybenzyl) -undecanedioic acid-bis- (tert-butyl) diester (Example 17e) is obtained according to the instructions given for Example 3b 3.9 g (82% of theory) of a white dye. Melting point 145 ° C (decomposition)

Analysis:

Calc .: C 55.63 H 5.75 N 6.48 O 32.11

Found: C 55.67 H 5, 54 N 6.65

The gadolinium complex was prepared according to the procedure described in Example 1e

Analysis:

Calcd .: C 44.93 H 4.27 N 5.24 O 25.93 Gd 19.61

Found: C 45.01 H 4.21 N 5.15 Gd 19.70

Gd (AAS): 19.61%

The following salts are obtained analogously to the instruction given under 1e:

Sodium salt of the gadolinium complex

Analysis:

Calculated: C 42.60 H 3.81 N 4.96 O 24.59 Gd 18.59 Na 5.43

Found: C 42.61 H 3.82 N 4.90 Gd 18.40 Na 5.45

Meglumine salt of the gadolinium complex

Analysis:

Calcd .: C 44.32 H 5.74 N 5.87 O 30.86 Gd 13.18

Found: C 44.31 H 5.59 N 5.74 Gd 13.12

Moroholin salt of the Gadolinium complex

Analysis:

Calculated: C 46.85 H 5.17 N 7.18 O 24.63 Gd 16.14

Found: C 46.72 H 5.21 N 7.18 Gd 16.16

Example 18: 3,6,9-Triaza-3,6,9-tris (tert-butoxycarbonylmethyl) - [4- (3-benzyloxycarbonylaminopropxy) benzyl] -undecanedioic acid bis (tert-butyl) diester .

From 9.6 g (5.90 mmol) 3, 6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -5- (4-hydroxybenzyl) -undecanedioic acid-bis- (tert.- Butyl) diester (Example 17d) is obtained according to the procedure given for Example 1b 4.2 g of a colorless oil (yield 74% of theory)

analysis

Calc .: C 64.30 H 8.51 N 5.76 O 21.41 Found: C 64.45 H 8.55 N 5.76

3,6,9-Triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -5- [4- (3-aminopropoxybenzyl) -undecanedioic acid bis- (tert-butyl) diester

According to the method described in Example 1c, 2.8 g (1.25 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl-5- [4- (3-benzyloxycarbonylaminopropoxy) benzyl] -undecanedioic acid bis (tert-butyl) diester (Example a) is hydrogenated. A colorless viscous oil is obtained. Yield: 2.28 g (95% of theory)

analysis

Calc .: C 63.13 H 9.15 N 6.69 O 21.02

Found: C 63.22 H 9.14 N 6.66

c) 3,6,9-Triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -5- [4- (3- (maleimido-propoxy) -benzyl] -undecanedioic acid-bis- (tert.- butyl) - diester

According to the method described in Example 1d, starting from 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- [4- (3-aminopropoxybenzyl] -undecanedioic acid bis- (tert .-Butyl) diester (Example b), the maleimide obtained in 90% of the yield (colorless, viscous oil).

analysis

Calc .: C 62.86 H 8.35 N 6.10 O 22.62 Found: C 62.75 H 8, 41 N 6.01

d) 3,6,9-Triaza-3,6,9-tris (carboxymethyl) -5- [4- (3- (malei mido-propoxy) benzyl] undecanedioic acid

As described in Example le, starting from 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- [4- (3-maleimido-propoxy) -benzyl] -undecanedioic acid bis (tert-butyl) diester (Example c), the free penta acid in 96% yield as a white powder Melting point: 285 ° C. (decomposition)

analysis

Calc .: C 52.82 H 5.69 N 8.80 O 32.67 Found: C 52.70 H 5.82 N 8.74

Gadolinium complex

As already described in example le, the gadolinium complex is obtained in quantitative yield.

analysis

Calc .: C 42.52 H 4.20 N 7.08 O 26.30 Gd 19.88 Found: C 42.39 H 4.21 N 7.19 Gd 19.55

Gd (AAS): 18.63%

The following salts are obtained analogously to the instruction given under le:

Sodium salt of the gadolinium complex

Analysis:

Calculated: C 40.28 H 3.74 N 6.71 O 24.91 Gd 18.23 Na 5.50

Found: C 40.18 H 3.87 N 6.69 Gd 18.68 Na 5.57

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 42.70 H 5.85 N 7.28 O 30.52 Gd 13.63

Found: C 42.60 H 5.70 N 7.36 Gd 13.61

Morpholine salt of the gadolinium complex

Analysis:

Calc .: C 44.89 H 5.12 N 8.72 O 24.91 Gd 16.32

Found: C 44.90 H 5.11 N 8.63 Gd 15.98

analogous to the instructions for the preparation of the gadolinium complex, the

Indium Komolex

Calculated: C 44.93 H 4.44 N 7.49 O 27.79 In 15.34

Found: C 44.99 H 4.50 N 7.38 In 15.41

Yttrium complex

Ber. : C 46.48 H 4.59 N 7.75 O 28.75 Y 12.43

Found: C 46.46 H 4.48 N 7.58 Y 12.15

Ytterbium complex

Calculated: C 41.68 H 4.12 N 6.95 O 25.79 Yb 21.45

Found: C 41.75 H 4.08 N 6.92 Yb 21.32

Samarium complex

Calculated: C 42.89 H 4.24 N 7.15 O 26.53 Sm 19.18

Found: C 42.88 H 4.36 N 7.22 Sm 19.15

Praseodvm complex

Calculated: C 43.42 H 4.29 N 7.24 O 26.86 Pr 18.19

Found: C 43.43 H 4.24 N 7.30 Pr 18.32

Cobalt Komolex

Calc .: C 48.56 H 4.80 N 8.09 O 30.04 Co 8.51

Found: C 48.55 H 4.49 N 8.12 Co 8.55 Example 19

3,6,9-Triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5¬- (4-hydrazinocarbonylmethoxybenzyl) -undecanedioic acid bis- (tert-butyl) diester

From 15.2 g (13.57 mmol) of 3,6,9-triaza-5- (4-benzyloxycarbonylmethoxybenzyl) -3,6,9-tris- (tert-butoxycarbonylmethyl) -undecanedioic acid-bis- (tert.- Butyl) diester (Example 17e) is obtained according to the procedure given in Example 4a, 9.6 g (83% of theory) of an oil which is highly viscous at room temperature.

analysis

Calc .: C 60.61 H 8.63 N 8.21 O 22.53

Found: C 60.49 H 8.52 N 8.23

b) 3,6,9-Triaza-3,6,9-tris (carboxymethyl) -5- (4-hydrazinocarbonylmethoxybenzyl) -undecanedioic acid

2.1 g (7.9 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- (4-hydrazinocarbonylmethoxybenzyl) - undecanedioic acid bis- (tert-butyl ) diesters (example a) are reacted with trifluoroacetic acid according to the instructions given for example 4b. After working up, 3.1 g of white crystals (67% of theory) are obtained. Melting point: 180 ° C. (decomposition)

analysis

Calc .: C 48.33 H 5.8 N 12.25 O 33.59

Found: C 48.15 H 5.83 N 12.31

The gadolinium complex was prepared according to the procedure described in Example 1e

analysis

Calc .: C 33.06 H 4.16 N 9.64 O 26.45 Gd 21.66 Found: C 32.97 H 4.17 N 9.70 Gd 21.65

Gd (AAS): 21.63%

The following salts are obtained analogously to the instruction given under le:

Sodium salt of the gadolinium complex

Analysis:

Calcd .: C 35.88 H 3.66 N 9.09 O 24.94 Gd 20.42 Na 5.97

Found: C 35.76 H 3.68 N 9.11 Gd 20.19 Na 6.00

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 39.85 H 5.69 N 8.79 O 31.56 Gd 14.10

Found: C 39.80 H 5.72 N 8.71 Gd 14.02

Moroholin salt of the Gadolinium complex

Analysis:

Calculated: C 41.46 H 5.16 N 10.91 O 24.94 Gd 17.51

Found: C 41.51 H 5, 15 N 10.78 Gd 17.363

Example 20

a) 3,6,9-Triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- (4-benzyloxycarbonylpentamethyleneoxybenzyl) -undecanedioic acid bis- (tert-butyl) diester

According to the instructions given for example 3a, 3.8.9 (4.87 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- (4-hydroxybenzyl) - undecanedioic acid bis (tert-butyl) diester (Example 17d) 3.69 g (77% of theory) of a colorless oil

analysis

Ber. : C 65. 89 H 8 .70 N 4.26 O 22.13

Gef. : C 65. 66 H 8. 63 N 4.38

3,6,9-triaza-3,6,9-tris (carboxymethyl) -5- (4-benzyloxycarbonylpentamethyleneoxybenzyl) undecanedioic acid

According to the procedure given for Example 3b, 8.3.9 (8.43 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- (4-benzyloxycarbonylpentamethyleneoxybenzyl) is obtained -undecanedioic acid-bis- (tert-butyl) diester (Example a) 5.51 g (93% of theory) of a white crystalline product Melting point: 183 ° C (decomposition)

analysis

Calc .: C 58.02 H 6.44 N 5.97 O 29.55 Found: C 58.09 H 6, 31 N 6.03

Gadolinium complex

The gadolinium complex is obtained in almost quantitative yield in the manner described in Example le

analysis

Calc .: C 47.59 H 4.93 N 4.89 O 24.24 Gd 18.32 Found: C 47.70 H 4.70 N 4.82 Gd 18.50

The following salts are obtained analogously to the instruction given under le:

Sodium salt of the gadolinium complex

Analysis:

Calc .: C 45.27 H 4.47 N 4.65 O 23.06 Gd 17.43 Na 5.09

Found: C 45.30 H 4.48 N 4.62 Gd 17.28 Na 5.01

Meolumin salt of the gadolinium complex

Analysis:

Calculated: C 46.18 H 6.13 N 5.60 O 29.47 Gd 12.59

Found: C 46.19 H 6.09 N 5.71 Gd 12.52

Moroholin salt of the Gadolinium complex

Analysis:

Calc .: C 48.96 H 5.67 N 6.79 O 23.29 Gd 15.26

Found: C 49.03 H 5.66 N 6.80 Gd 15.11

Example 21

3,6,9-Triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- (4-hydrazinocarbonylpentamethyleneoxybenzyl) -undecanedioic acid bis- (tert-butyl) diester

According to the procedure given for Example 4a, 13.05 g (13.26 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- (4-benzyloxycarbonylpentamethyleneoxybenzyl) is obtained -undecanedioic acid bis (tert-butyl) diester (Example 20a) 10.72 g (89% of theory) of a colorless oil.

analysis

Ber. : C 62.25 H 8.99 N 7.71 O 21.14

Gef. : C 62.16 N 9.01 N 7.75

3,6,9-triaza-3,6,9-tris (carboxylmethyl) -5- (4-hydrazinocarbonylpentamethyleneoxybenzyl) undecanedioic acid

According to the procedure given for example 4b, 4.5.9 (4.95 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl-5- (4-hydrazinocarbonylpentamethyleneoxybenzyl) -undecanedioic acid are obtained -bis- (tert-butyl) diester

(Example a) 2.80 g (90% of theory) of a white

Crystals

Melting point: 217 ° C (decomposition)

analysis

Calc .: C 51.66 H 6.58 N 11.15 O 30.58

Found: C 51.49 H 6.55 N 11.12

Gadolinium complex

The gadolinium complex is obtained in almost quantitative yield in the manner described in Example le

analysis

Calc .: C 41.47 H 4.89 N 8.95 O 24.55 Gd 20.11 Found: C 41.50 H 4.85 N 8.80 Gd 20.01

The following salts are obtained analogously to the instruction given under le:

Sodium salt of the gadolinium complex

Analysis:

Calc .: C 39.26 H 4.39 N 8.48 O 23.24 Gd 19.04 Na 5.56

Found: C 39.18 H 4.33 N 8.40 Gd 19.00 Na 5.53

Meglumine salt of the gadolinium complex

Analysis:

Calculated: C 42.00 H 6.19 N 8.36 O 30.02 Gd 13.41

Found: C 42.10 H 6.15 N 8.33 Gd 13.20

Moroholin salt of the Gadolinium complex

Analysis:

Calc .: C 44.06 H 5.70 N 10.27 O 23.47 Gd 16.48

Found: C 43.95 H 5.71 N 10.23 Gd 16.42

Example 22

3,6,9-Triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- [4- (methacryloyl) hydrazinocarbonylpentamethyleneoxybenzyl] -undecanedioic acid bis- (tert-butyl) diester

According to the procedure given for Example 7a, 9.9 g (9.9 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- (4-hydrazinocarbonylpentamethyleneoxybenzyl) -undecanedioic acid are obtained bis (tert-butyl) diester (Example 21a) 6.58 g (68% of theory) of a colorless oil

analysis

Calc .: C 62.74 H 8.77 N 7.17 O 21.3 Found: C 62.63 H 8.72 N 7.21

3,6,9-triaza-3,6,9-tris (carboxymethyl) -5- [4- (methacryloyl) hydrazinocarbonylpentamethyleneoxybenzyl] undecanedioic acid

According to the procedure given for example 3b, 2.25 g (2.3 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- [4- (methacryloyl) -hydrazinocarbonylpentamethyleneoxybenzyl are obtained ) -undecanedioic acid-bis- (tert-butyl) diester Example a) 1.41 g (88% of theory) of a white crystalline product Melting point: 139 ° C (decomposition)

analysis

Ber. : C 53.51 H 6.51 N 10.06 O 29.89

Found: C 53.52 H 6.50 N 10.13

Gadolinium complex

The gadolinium complex is obtained in almost quantitative yield in the manner described in Example le

analysis

Calc .: C 43.80 H 4.98 N 8.23 O 24.47 Gd 18.50 Found: C 43.71 H 4.86 N 8.31 Gd 18.38

The following salts are obtained analogously to the instruction given under le:

Sodium salt of the gadolinium complex

Analysis:

Calculated: C 41.60 H 4.61 N 7.82 O 23.24 Gd 17.57 Na 5.13

Found: C 41.61 H 4.58 N 7.80 Gd 17.39 Na 5.08

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 43.53 H 6.25 N 7.89 O 29.64 Gd 12.66

Found: C 43.53 H 6.20 N 7.88 Gd 12.45

Moroholin salt of the Gadolinium complex

Analysis:

Calc .: C 45.78 H 5.81 N 9.58 O 23.45 Gd 15.36

Found: C 45.79 H 5.77 N 9.55 Gd 15.20

Example 23

3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- [4- (3- (methacrylamido) propoxy) benzyl) -undecanedioic acid bis- (tert-butyl ) -diester

According to the method described in Example 2a, starting from 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -5- [4- (3-aminopropoxybenzyl] -undecanedioic acid bis- ( tert-butyl) diester (Example 18b) title compound obtained in 86% yield as an oil.

analysis

Calc .: C 63.69 H 8.90 N 6.18 O 21.21

Found: C 63.80 H 8.74 N 6.25

3,6,9-triaza-3,6,9-tris (carboxymethyl) -5- [4- (3- (methacrylamido) propoxy) benzyl] undecanedioic acid

Starting from 3,6,9-triaza-tris (tert-butoxycarbonylmethyl) -5- [4- (3- (methacrylamido) propoxy) benzyl] -undecanedioic acid bis (tert-butyl) diester ( Example a) gives the title compound analogously to the procedure described in Example 2b in 91% yield.

Analysis:

Calc .: C 53.83 H 6.45 N 8.96 O 30.73 Found: C 53.78 H 6.31 N 8.95

Gadolinium complex

Analogously to the procedure in Example 1e, the gadolinium complex is obtained in 98% yield.

Analysis:

Calc .: C 43.17 H 4.78 N 7.19 O 24.65 Gd 20.18

Found: C 43.33 H 4.60 N 7.15 Gd 20.12

Gd (AAS): 20 2%

The following salts are obtained analogously to the instruction given under le:

Sodium salt of the gadolinium complex

Analysis:

Calculated: C 40.87 H 4.28 N 6.80 O 23.33 Gd 19.11 Na 5.58

Found: C 40.88 H 4.25 N 6.78 Gd 19.05 Na 5.59

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 43.10 H 6.20 N 7.18 O 30.07 Gd 13.43

Found: C 43.01 H 6.15 N 7.14 Gd 13.40

Moroholin salt of the Gadolinium complex

Analysis:

Calc .: C 45.41 H 5.71 N 8.82 O 23.52 Gd 16.51

Found: C 45.38 H 5.77 N 8.80 Gd 16.41

EXAMPLE 24

a) 3,6,9-Triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- (4-carboxymethoxybenzyl) -undecanedioic acid-bis- (tert-butyl) diester

From 4.9 g (5.16 mmol) of 3,6,9-triaza-5- (4-benzyloxycarbonylmethoxybenzyl) - 3,6,9-tris (tert-butoxycarbonylmethyl) -undecanedioic acid bis- (tert.- butyl) diesters (Example 17e) 4.1 g of a colorless viscous oil are obtained according to the procedure given in Example 8a (93.2% of theory)

Analysis:

Calc .: C 61.62 H 8.53 N 5.01 O 24.81

Found: C 61.66, H 8.45 N 5.15

b) 3,6,9-Triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -5- [4 - {(2,3,4,5,6-pentahydroxyhexyl) methylamino} carbonylmethoxybenzyl] -undecanedioic acid bis (tert-butyl) diester

3.90 g (4.6 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- (4-carboxymethoxybenzyl) -undecanedioic acid bis- (tert-butyl ) diesters are dissolved in 80 ml of tetrahydrofuran and mixed with 0.43 g (6.8 mmol) of triethylamine. At -5 ° C, 0.62 g (4.70 mmol) of isobutyl chloroformate in 30 ml of tetrahydrofuran are carefully added and finally 10 ml of an aqueous solution of 920 mg (4.7 mmol) of N-methyl-D-glucamine are added. After stirring for 30 minutes below 0 ° C., the cooling bath is removed and the mixture is allowed to warm to room temperature. After the solvent has been stripped off, the residue is purified by chromatography on silica gel. 3.73 g of white, crystalline substance (80% of theory) are obtained, which decomposes with a brown color from 50 ° C.

Analysis:

Calc .: C 59.15 H 8.53 N 5.51 O 26.79

Found: C 59.18 H 8.60 N 5.55 3,6,9-Triaza-3,6,9-tris (carboxymethyl) -5- [4 - {(2,3,4,5,6-pentahydroxyhexyl) methylamino} carbonylmethoxybenzyl] undecanedioic acid

As described in Example le, 1.77 g (1.7 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- [4 - {(2nd , 3,4,5,6-pentahydroxyhexyl) methylamino} carbonylmethoxybenzyl] -undecanedioic acid bis (tert-butyl) diester 1.04 g (83% of theory) of the title compound of melting point 132 ° C (decomposition) ..

Analysis:

Calc .: C 49.04 H 6.31 N 7.62 O 37.01

Found: C 49.12 H 6.35 N 7.50

Gadolinium complex

Analogously to the procedure in Example 1e, the gadolinium complex is obtained in 98% yield.

Analysis:

Calc .: C 40.53 H 4.87 N 6.30 O 30.59 Gd 17.68

Found: C 40.61 H 4.71 N 6.35 Gd 17.92

Gd (AAS) 17.86% by weight

The following salts are obtained analogously to the instruction given under le:

Sodium salt of the gadolinium complex

Analysis:

Calc .: C 38.62 H 4.42 N 6.00 O 29.15 Gd 16.85 Na 4.92

Found: C 38.57 H 4.43 N 6.03 Gd 16.54 Na 4.88

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 41.30 H 6.06 N 6.56 O 33.76 Gd 12.29

Found: C 41.17 H 5.98 N 6.59 Gd 11.97

Morpholine salt of the gadolinium complex

Analysis:

Ber. : C 43.01 H 5.60 N 7.91 O 28.64 Gd 14.81

Found: C 42.96 H 5.52 N 7.97 Gd 14.85

EXAMPLE 25

a)

3,6-diaza-3,6-bis- (tert-butoxycarbonylmethyl) -4- [4- (2-propynyloxy) -benzyl] -succinic acid-bis- (tert-butyl) diester

To a suspension of 390 mg sodium hydride (80% in paraffin) (13.3 mmol) in 50 ml toluene, a solution of 3.77 g (6.05 mmol) 3,6-diaza-3,6-bis- ( tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) -succinic acid bis (tert-butyl) diester (Example 1a) in 20 ml of toluene and a solution of 750 mg (6.3 mmol) of 3-bromopropyne in 20 ml of toluene. After 2 hours, filter, wash with water and, after evaporation, chromatograph on silica gel. 3.02 g of oil (75.5% of theory) are obtained.

Analysis:

Calculated: C 65.43 H 8.54 N 4.23 O 21.78

Found: C 65.33 H 8.60 N 4.30

b) 3,6-Diaza-3,6-bis (carboxymethyl) -4- [4- (2-propynyloxy) benzyl] suberic acid

1.35 g (2 mmol) of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- [4- (2-propynyloxy) benzyl] -suberic acid bis- (tert-butyl ) diesters are implemented according to the instructions given for example 1e. A white powder (740 mg, 83% of theory) is obtained, which melts at 140 ° C. with decomposition.

Analysis:

Calc .: C 55.04 H 5.54 N 6.41 O 32.99

Found: C 55.13 H 5.59 N 6.40

Gadolinium Komolex

The gadolinium complex is obtained as described under 1e.

Analysis.

Calc .: C 40.67 H 3.58 N 4.74 O 24.37 Gd 26.62

Found: C 40.80 H 3.60 N 4.70 Gd 26.36 The following salts are obtained analogously to the instruction given under le:

Sodium salt of the gadolinium complex

Analysis:

Calc .: C 39.21 H 3.29 N 4.57 O 23.50 Gd 25.66 Na 3.75

Found: C 39.22 H 3.22 N 4.60 Gd 25.36 Na 3.74

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 41.26 H 4.87 N 5.34 O 28.50 Gd 20.00

Found: C 41.22 H 4.89 N 5.32 Gd 20.31

Morpholine salt of the gadolinium complex

Analysis:

Calc .: C 42.59 H 4.31 N 6.20 O 23.64 Gd 23.23

Found: C 42.48 H 4.30 N 6.15 Gd 23.15

EXAMPLE 26

a) 3,6,9-Triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- [4- (2-propynyloxy) -benzyl] -undecanedioic acid-bis- (tert-butyl) - diester

5.36 g (6.87 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) -undecanedioic acid-bis- (tert-butyl ) diesters (Example 9f) are dissolved in 70 ml of toluene and 363 mg of sodium hydride (15.1 mmol) are carefully added. 858 mg of 3-bromopropine (7.2 mmol) in 30 ml of toluene are added dropwise.

After 2 hours, the solution is filtered, the organic phase is washed twice with water and the solvent is removed. After chromatography on silica gel, 4.89 g of a colorless oil (87% of theory) are obtained.

Analysis:

Calc .: C 64.60 H 8.74 N 5.13 O 21.51

Found: C 64.57 H 8.64 N 5.15

b) 3,6,9-Triaza-3,6,9-tris (carboxymethyl) -4- [4- (2-propynyloxy) benzyl] undecanedioic acid

4.35 g (5.32 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- [4- (2-propynyloxy) benzyl] undecanedioic acid bis - (Tert-butyl) diesters are reacted according to the instructions given for example le. A white powder (2.42 mg. 85% of theory) is obtained, which melts at 142 ° C. with decomposition.

Analysis:

Calc .: C 53.62 H 5.81 N 7.81 O 32.74

Found: C 53.66 H 5.85 N 7.82 Gadolinium complex

The gadolinium complex is obtained as described under le.

Analysis:

Calcd .: C 41.67 H 4.07 N 6.07 O 25.44 Gd 22.73

Found: C 41.42 H 4.12 N 6.27 Gd 22.59

The following salts are obtained analogously to the instruction given under 1e:

Sodium salt of the gadolinium complex

Analysis:

Calc .: C 39.18 H 3.56 N 5.71 O 23.92 Gd 21.37 Na 6.24

Found: C 38.97 H 3.55 N 5.65 O 23.90 Gd 21.53 Na 6.25

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 42.17 H 5.77 N 6.47 O 31.04 Gd 14.53

Found: C 42.01 H 5.63 N 6.50 O 30.98 Gd 14.55

Moroholin salt of the Gadolinium complex

Analysis:

Calc .: C 44.48 H 5, 13 N 8.10 O 24.07 Gd 18.20

Found: C 44.51 H 5.08 N 8.12 O 24.10 Gd 18.07 EXAMPLE 27

a) 3,6,9-Triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -5- [4- (2-propynyloxy) -benzyl] -undecanedioic acid-bis- (tert-butyl) - diester

4.57 g (5.8 mmol) 3, 6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -5- [4-hydroxybenzyl] -undecanedioic acid bis- (tert-butyl ) diesters (Example 17d) are reacted as described for Example 26a with 310 mg of sodium hydride and 730 mg of 3-bromopropine to give the title compound.

The title compound is obtained as a colorless oil with a yield of 4.07 g (74% of theory).

Analysis:

Calc .: C 64.60 H 8.74 N 5.13 O 21.51

Found: C 64.64 H 8.70 N 5.20

b) 3,6,9-Triaza-3,6,9-tris (carboxymethyl) -5- [4- (2-propynyloxy) benzyl] undecanedioic acid

4.69 g (5.7 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- [4- (2-propynyloxy) benzyl] -undecanedioic acid bis- ( Tert-butyl) diesters are reacted according to the instructions given for Example 1e. A white powder is obtained which melts at 135 ° C. with decomposition.

Analysis:

Calcd .: C 53.62 H 5.81 N 7.81 O 32.74

Found: C 53.66 H 5.90 N 7.75

Gadolinium complex

The gadolinium complex is obtained as described under 1e.

Analysis:

Calcd .: C 41.67 H 4.07 N 6.07 O 25.44 Gd 22.73

Found: C 41.66 H 4.11 N 6.04 Gd 22.51 The following salts are obtained analogously to the instruction given under le:

Sodium salt of the gadolinium complex

Analysis:

Calc .: C 39.18 H 3.56 N 5.71 O 23.92 Gd 21.37 Na 6.24

Found: C 39.32 H 3.55 N 5.80 O 23.81 Gd 21.50 Na 6.27

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 42.17 H 5.77 N 6.47 O 31.04 Gd 14.53

Found: C 42.15 H 5.60 N 6.51 O 31.05 Gd 14.37

Horolin salt of the gadolinium complex

Analysis:

Calculated: C 44.48 H 5.13 N 8.10 O 24.07 Gd 18.20

Found: C 44.45 H 5.15 N 8.11 O 24.17 Gd 18.19

EXAMPLE 28

a) 11- {4- [N, N, N ', N'-tetrakis (tert-butoxycarbonylmethyl) -2,3-diaminopropyl] phenoxyacetyl} aminoundecanoic acid- [2- (tert-butoxycarbonyl) hydrazide ]

To a solution of 18.23 g (26.78 mmol) 3, 6-diaza-3,6-bis- (tert-butoxy carbonylmethyl) -4- (4-carboxymethoxybenzyl) -succinic acid-bis- (tert.- butyl) diester (Example 8a) and 2.7 g (26.8 mmol) of triethylamine in 200 ml of dry tetrahydrofuran are added dropwise with constant cooling to below 5 ° C. 30 ml of a solution of 3.65 g (26.8 mmol) Isobutyl chloroformate in tetrahydrofuran. Half an hour after the end of the addition, while cooling and stirring are continued, a solution of 8.44 g (26.8 mmol) of 11-aminoundecanoic acid 2- (tert-butoxycarbonyl) hydrazide is slowly added. The mixture is then allowed to warm to room temperature with stirring and the solvent is evaporated off. The residue is taken up in 400 ml of toluene and water-soluble fractions are extracted with saturated sodium chloride solution. After washing with water and drying, the solvent is stripped off and the oil is subjected to purification by chromatography on silica gel. This gives 20.1 g (79% of theory) of colorless oil.

Analysis:

Calc .: C 63.19 H 9.22 N 7.36 O 20.2

Found: C 63.17 H 9.25 N 7.31

b) 11- {4- [N, N, N ', N'-tetrakis (carboxymethyl) -2,3-diaminopropyl] phenoxyacetyl} - aminoundecanoic acid hydrazide

As described for example le, the tert-butyl esters can be split off with trifluoroacetic acid at room temperature. Under these conditions, 11- {4- [N, N, N ', N'-tetrakis (tert-butoxycarbonylmethyl) -2,3-diaminopropyl] phenoxyacetyl] aminoundecanoic acid- [2- (tert-butoxycarbonyl ) hydrazide] also cleaved the tert-butoxycarbonyl protective group of the acid hydrazide and in the procedure described in Example 1e, 6.68 g of white crystalline substance is obtained from 12.56 g of starting material (13.2 mmol) in 77.3% yield, which begins to melt at 115 ° C. with decomposition.

Analysis:

Calc .: C 55.11 H 7.24 N 10.71 O 26.92

Found: C 54.98 H 7.30 N 10.77

Gadolinium Komolex

Analysis:

Calcd .: C 44.59 H 5.48 N 8.66 O 21.78 Gd 19.46

Found: C 44.55 H 5.49 N 8.71 Gd 19.21

The following salts are obtained analogously to the instruction given under 1e:

Sodium salt of the gadolinium complex

Analysis:

Calculated: C 43.41 H 5.22 N 8.43 O 21.20 Gd 18.94 Na 2.77

Found: C 43.36 H 5.19 N 8.47 Gd 18.59 Na 2.76

Meolumin salt of the gadolinium complex

Analysis:

Calc .: C 44.30 H 6.12 N 8.57 O 25.51 Gd 15.67

Found: C 44.33 H 6.15 N 8.51 Gd 15.76

Morpholine salt of the gadolinium complex

Analysis:

Calc .: C 45.67 H 5.86 N 9.39 O 21.47 Gd 17.58

Found: C 45.77 H 5.80 N 9.28 Gd 17.38 EXAMPLE 29

a) 11 - {- (4- (4- (tert-Butoxycarbonylmethyl) -4-aza-2,6-di- [bis- (tert-butoxycarbonylmethyl) amino] hexyl) phenoxyacetyl} aminoundecanoic acid - [2- (tert-bu toxycarbonyl) hydrazide]

8.4 g (10 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-carboxymethoxybenzyl) -undecanoic acid-bis- (tert-butyl) - diesters (Example 16a) are reacted according to the instructions for Example 28a with the equivalent amounts of triethylamine, isobutyl chloroformate and 2- (tert-butoxycarbonyl) hydrazide 11-aminoundecanoic acid. After purification by column chromatography, 8.74 g (77% of theory) of colorless oil are present.

Analysis:

Calculated: C 62.40 H 9.05 N 7.40 O 21.13

Found: C 62.31 H 9.10 N 7.36

b) 11- {4- (4- (Carboxymethyl) -4-aza-2,6-di- [bis- (carboxymethyl) amino] hexyl) phenoxyacetyl} aminoundecanoic acid hydrazide

As described for Examples 1e and 28b, 6.32 g (5.6 mmol) of 11-} 4- (4- (tert-butoxycarbonylmethyl) -4-aza-2,6-di- [bis- ( tert-butoxycarbonylmethyl) amino] hexyl) phenoxyacetyl} aminoundecanoic acid- [2- (tert-butoxycarbonyl) hydrazide] in 76% yield the title compound in the form of colorless crystals. Melting point: 185 ° C (decomposition)

Analysis:

Calc .: C 54.10 H 7.21 N 11.13 O 27, 55

Found: C 53.98 H 7.23 N 11.10 Gadolinium complex

Analysis:

Calc .: C 44.92 H 5.65 N 9.24 O 22.87 Gd 17.29

6ef .: C 44.95 H 5.60 N 9.26 Gd 17.33

The following salts are obtained analogously to the instruction given under 1e:

Sodium salt of the gadolinium complex

Analysis:

Calculated: C 42.85 H 5.18 N 8.81 O 21.82 Gd 16.50 Na 4.82

Found: C 42.69 H 5.12 N 8.80 Gd 16.25 Na 4.83

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 44.36 H 6.59 N 8.62 O 28.31 Gd 12.10

Found: C 44.35 H 6.50 N 8.63 Gd 12.15

Morpholine salt of the gadolinium complex

Analysis:

Calculated: C 46.65 H 6.24 N 10.36 O 22.19 Gd 15.54

Found: C 46.66 H 6.30 N 10.24 Gd 15.32 EXAMPLE 30

a) 11 - {4 - (3 - [(tert-butoxycarbonylmethyl) -3-aza] -2 - [[bis- (tert-butoxycarbonylmethyl) amino] methyl) -5- [bis- (tert. -butoxycarbonylmethyl) -amino] -pentyl-) phenoxyacetyl} -aminoundecanoic acid- [2- (tert-butoxycarbonyl) hydrazide]

6.13 g (7.3 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -5- (4-carboxymethoxybenzyl) -undecanoic acid bis- (tert-butyl ) diesters (Example 24a) are reacted according to the instructions for Example 28a with the equivalent amounts of triethylamine, isobutyl chloroformate and 2- (tert-butoxycarbonyl) hydrazide 11-aminoundecanoic acid. After purification by column chromatography, 7.04 g (85% of theory) of colorless oil are present.

Analysis:

Calculated: C 62.4 H 9.05 N 7.40 O 21.13

Found: C 62.31 H 9.17 N 7.56

b) 11- {4- (3 - [(carboxymethyl) -3-aza] -2 - [[bis- (carboxymethyl) amino] methyl] -5- [bis- (carboxymethyl) amino] pentyl) -phenoxyacetyl} -aminoundecanoic acid hydrazide

From 5.38 g (4.7 mmol) of 11- {4- (3 - [(tert-butoxycarbonylmethyl-3-aza] -2 - [(bis- (tert-butoxycarbonylmethyl) amino] methyl] - 5- [bis- (tert-butoxycarbonylmethyl) amino] pentyl) phenoxyacetyl} aminoundecanoic acid [2- (tert-butoxycarbonyl) hydrazide] is obtained according to the procedure described for Examples 1e and 28b, 2.93 g (82% of theory) colorless crystals, melting point: 192 ° C. (decomposition)

Analysis:

Calculated: C 54.1 H 7.21 N 11.13 O 27.55

Found: C 54.09 H 7.28 N 11, 11 Gadolinium complex

Analysis:

Calc .: C 44.92 H 5.65 N 9.24 O 22.87 Gd 17.29

Found: C 44.80 H 5.66 N 9.22 Gd 17.03

The following salts are obtained analogously to the instruction given under 1e:

Sodium salt of the Gadolinium Komolex

Analysis:

Calculated: C 42.85 H 5.18 N 8.81 O 21.82 Gd 16.50 Na 4.82

Found: C 42.88 H 5.12 N 8.83 Gd 16.91 Na 4.88

Meglumine salt of the gadolinium comolex

Analysis:

Calc .: C 44.36 H 6.59 N 8.62 O 28.31 Gd 12.10

Found: C 44.32 H 6.30 N 8.71 Gd 12.12

Horolin salt of the Gadolinium Komolex

Analysis:

Calculated: C 46.65 H 6.24 N 10.36 O 22.19 Gd 15.54

Found: C 46.39 H 6.26 N 10.32 Gd 15.61 EXAMPLE 31

a) 3,6-Diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4-oxiranylmethoxy) -benzylsuberinsäure-bis- (tert-butyl) diester

17.38 g (27.9 mMol) of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) -suberic acid-bis- (tert-butyl) diester (Example 1a ) are dissolved with 900 mg (30 mmol) of 80% sodium hydride in paraffin in 300 ml of toluene with stirring and a solution of 2.6 g (28 mmol) of epichlorohydrin is added dropwise at 40 ° C. After one hour, 100 ml of water is carefully added. After shaking, the phases are separated and then the organic phase is concentrated after drying. After chromatographic cleaning 15.5 g (22.8 mmol, 82% of theory) are present as a colorless oil.

Analysis:

Calculated: C 63.69 H 8.61 N 4.12 O 23.56

Found: C 63.57 H 8.62 N 4.07

b) 15- {4- [N, N, N ', N'-tetrakis (tert-butoxycarbonylmethyl) -2,3-diaminopropyl] phenoxy} -12-aza-14-hydroxy-pentadecanoic acid 2- ( butoxycarbonyl) hydrazide

7.35 g (10.8 mmol) of 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- (4-oκiranylmethoxy) -benzyl-suberic acid-bis- (tert-butyl) - diesters, dissolved in 100 ml of diethyl ether, are mixed with 3.41 g (10.8 mmol) of 11-aminoundecanoic acid 2- (tert-butoxycarbonyl) hydrazide in 100 ml of tetrahydrofuran and heated to reflux for 2 hours. After the solvent has been stripped off, the substance is present as pure colorless oil. Yield 9.54 g (88.5% of theory).

Analysis:

8: C 62.81 H 9.22 N 7.04 O 20.91

Found: C 62.65 H 9.23 N 7.15 c) 15- {4- [N, N, N ', N', - tetrakis (carboxymethyl) -2,3-diaminopropyl] phenoxy} -12- aza-14-hydroxy-pentadecanoic acid hydrazide

4.36 g (4.3 mmol) 15- (4- [2,3-N, N, N ', N', - tetrakis (tert-butoxycarbonylmethyl) -2,3-diaminopropyl] phenoxy] -12-aza- 14-hydroxy-pentadecanoic acid- [2- (butoxycarbonyl) hydrazide] are dissolved in 50 ml of trifluoroacetic acid at room temperature and worked up after 5 hours as described for Example 1e, giving 2.86 g (3.2 mmol); 73% of theory) colorless Crystals. Melting point: 145 ° C (decomposition) Analysis: Calc .: C 55.59 H 7.62 N 10.45 O 26.27 Found: C 55.60 H 7.49 N 10.55

Gadolinium complex:

Calc .: C 45.18 H 5.87 N 8.49 O 21.35 Gd 19.08

Found: C 45.20 H 5.88 N 8.62 Gd 19.09

The following salts are obtained analogously to the instruction given under le:

Sodium salt of the gadolinium complex

Analysis:

Calculated: C 44.01 H 5.59 N 8.27 O 20.80 Gd 18.58 Na 2.71

Found: C 43.95 H 5.61 N 8.23 Gd 18.38 Na 2.77

Meolumin salt of the Gadolinium Komolex

Analysis:

Calcd .: C 44.82 H 6.33 N 8.25 O 28.14 Gd 15.44

Found: C 44.69 H 6.43 N 8.20 Gd 15.40

Morolin salt of the Gadolinium Komolex

Analysis:

Calculated: C 46.24 H 6.09 N 9.24 O 21.11 Gd 17.29

Found: C 46.23 H 6.11 N 9.28 Gd 17.17

EXAMPLE 32

a) 3,6,9-Triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- (4-oxiranylmethoxy-benzyl) -undecanedioate-bis- (tert-butyl) diester

16.35 g (21.0 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-hydroxybenzyl) -undecanedioic acid-bis- (tert-butyl ) diesters (Example 9f) are dissolved with 630 mg (21 mmol) of sodium hydride (80% in paraffin) in 300 ml of toluene with stirring and at 40 ° C. dropwise with a solution of 1.95 g (21 mmol) of epichlorohydrin in 20 ml of toluene are added. After working up as described for Example 31 a, 15.4 g (88% of theory) of colorless oil are present.

Analysis:

Calc .: C 63.20 H 8.80 N 5.02 O 22.96

Found: C 63.35 H 8.76 N 5.09

b) 15- 4- [4-aza-2,6-diamino-N, N, N ', N ", N" -pentakis (tert-butoxycarbonylmethyl) hexyl] phenoxy -12-aza-14- hydroxy pentadecanoic acid (2-tert-butoxycarbonyl) hydrazide

7.5 g (9.0 mmol) of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-oxiranylmethoxybenzyl) -undecanedioic acid-bis- (tert-butyl) - diester, dissolved in 100 ml of dry diethyl ether, mixed with 2.85 g (9.0 mmol) of 11-aminoundecanoic acid (2-tert-butoxycarbonyl) hydrazide in 50 ml of dry tetrahydrofuran and heated under reflux for 2 hours. After stripping off the solvent and chromatography on silica gel, 9.12 g (88% of theory) of a colorless oil are obtained.

Analysis:

Calculated: C 62.58 H 9.27 N 7.29 O 20.84

Found: C 62.83 H 9.30 N 7.28 15- {4- [4-Aza-2,6-diamino-N, N.N ', N ", N" -pentakis (carboxymethyl) hexyl] phenoxy} -12-aza-14-hydroxy-pentadecanoic acid -hydrazide

As described for Example 1e, the title compound is obtained in 80% yield in the form of white crystals with a melting point above 135 ° C. (decomposition).

Analysis:

Calc .: C 54.53 H 7.58 N 10.90 O 26.88

Found: C 54.62 H 7.48 N 10.88

Gadolinium complex

Calc .: C 45.44 H 5.99 N 9.08 O 22.48 Cd 16.99 Found: C 45.38 H 6.02 N 9.05 Cd 16.76

The following salts are obtained analogously to the instruction given under 1e:

Sodium salt of the gadolinium complex

Analysis:

Calculated: C 43.38 H 5.51 N 8.67 O 21.46 Gd 16.22 Na 4.74

Found: C 43.42 H 5.49 N 8.70 Gd 16.03 Na 4.77

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 44.80 H 6.67 N 8.53 O 28.01 Gd 11.97

Found: C 44.84 H 6.70 N 8.51 Gd 11.88

Morpholine salt of the gadolinium complex

Analysis:

Calc .: C 47.15 H 6.34 N 10.23 O 21.91 Gd 14.35

Found: C 47.14 H 6.20 N 10.25 Gd 14.50 EXAMPLE 33

a) 3,6,9-Triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -5- (4-oxiranylmethoxybenzyl) -undecanedioic acid-bis- (tert-butyl) diester

Analogously to Example 32 a, the title compound is obtained from the compound described in Example 17 d in 82% yield as a colorless oil.

Analysis:

Calc .: C 63.20 H 8.80 N 5.02 O 22.96

Found: C 63.15 H 8.69 N 4.93

b) 15- {4- (3-Aza-3- (tert-butoxycarbonylmethyl) -2 - [[bis- (tert-butoxycarbonylmethyl) amino] methyl] -5- [bis- (tert-butoxycarbonylmethyl) ) -amino] -pentyl) -phenoxy} -12-aza-14-hydroxy-pentadecanoic acid- [2- (tert-butoxycarbonyl) hydrazide

As described for Example 32b, the title compound is obtained in 81% yield as a clear oil from the compound described in 33a.

Analysis:

Calculated: C 62.58 H 9.27 N 7.29 O 20.84

Found: C 62.47 H 9.30 N 7.30

c) 15- {4- (3-Aza-3- (carboxymethyl) -2 - [[bis- (carboxymethyl) amino] methyl] -5- [bis- (carboxymethyl) amino] pentyl) phenoxy } -12-aza-14-hydroxy-pentadecane acid hydrazide

As described for Example 32c, the title compound is obtained from the compound described in 32b as a colorless oil in 83% yield.

Analysis: Calc .: C 54.53 H 7.58 N 10.90 O 26.88 Found: C 54.60 H 7.55 N 10.95

Gadolinium complex: Calc .: C 45.44 H 5.99 N 9.08 O 22.48 Gd 16.99

Found: C 45.43 H 5.70 N 9.21 Gd 17.01 The following salts are obtained analogously to the instruction given under le:

Sodium salt of the Gadolinium Komolex

Analysis:

Calculated: C 43.38 H 5.51 N 8.67 O 21.46 Gd 16.22 Na 4.74

6ef .: C 43.45 H 5.30 N 8.76 Gd 15.90 Na 4.73

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 44.80 H 6.67 N 8.53 O 28.01 Gd 11.97

Found: C 44.95 H 6.66 N 6.50 Gd 11.51

Morpholine salt of the gadolinium complex

Analysis:

Ber .; C 47.15 H 6.34 N 10.23 O 21.91 Gd 14.35

Found: C 47.16 H 6.32 N 10.31 Gd 14.39

EXAMPLE 34

a) 3,6-Diaza-2,7-dioxo-4- (4-hydroxybenzyl) -suberic acid diethyl ester

23 g (96.4 mmol) of 1,2-diamino-1- (4-hydroxybenzyl) ethane dihydrochloride are stirred with 21.4 g (212 mmol) of triethylamine in 300 ml of dry tetrahydrofuran (THF) for one hour at 50 ° C and then at 5-10 ° C dropwise with a cooled solution of oxalic acid ethyl ester chloride (28.96, 212 mmol) with 21.4 g (212 mmol) triethylamine in 200 ml THF dropwise. After the addition, the mixture is stirred for a further hour at room temperature, heated to reflux for 15 minutes and the solvent is evaporated off. It is slurried in 500 ml of toluene. washes thoroughly with water and concentrates the organic phase again after drying. The analytically pure product remains in the form of colorless crystals in 86% (33.9 g) yield.

Melting point: 176 ° C (decomposition)

Analysis:

Calc .: C 55.73 H 6.05 N 7.64 O 30.56

Found: C 55.61 H 6.15 N 7.63

b) 3,6-Diaza-2,7-dioxo-4- (4-hydroxybenzyl) suberic acid diamide

17.32 g (47.2 mmol) of diethyl 3,6-diaza-2,7-dioxo-4- (4-hydroxybenzyl) -succinate are converted to the amide by the method described for Example 170. 14.28 g of white crystals are obtained in 98% yield, which melt from 285 ° C. with a brown color

Analysis:

Calculated: C 50.64 H 5.23 N 18.17 O 25.94

6ef .: C 50.66 H 5.20 N 18.23 c) 3,6-diaza-1,8-diamino-4- (4-hydroxybenzyl) octane (hydrochloride)

6.16 g (20 mmol) of 3,6-diaza-2,7-dioxo-4- (4-hydroxybenzyl) -succinic acid diamide are slurried in 200 ml of absolute THF and a slow stream of diborane (22.6 g NaBH ₄ and 205 ml of boron trifluoride etherate) passed through with stirring. The mixture is refluxed for 96 hours, half the original amount of diborane is introduced again and the mixture is boiled for a further 2 days. Then work on as described in Example 9e. The yield is 5.65 g (71% of theory) of colorless crystals which decompose at 90 ° C.

Analysis:

Calc .: C 39.36 H 7.11 N 14.12 O 4.03 Cl 35.36

Found: C 39.42 H 7.13 N 14.03 Cl 35.31

d) 3,6,9,12-tetraaza-3,6,9,12-tetrakis (tert-butoxycarbonylmethyl) -7- (4-hydroxybenzyl) tetradecanedicarboxylic acid bis- (tert-butyl) diester

13.21 g (33.1 mmol) of 3,6-diaza-1,8-diamino-4- (4-hydroxybenzyl) octane tetrahydrochloride are mixed with 38.7 g (198.6 mmol) of bromoacetic acid tert-butyl ester and 17.2 g (204.7 mmol) of NaHCO ₃ in 500 ml of dimethylformamide according to the instructions given for Example 1a to 26.11 g (84% of theory) of a colorless oil.

Analysis:

Calculated: C 62.79 H 9.03 N 5.97 O 22.19

Found: C 62.78 H 8.87 N 5.96 e) 3,6,9,12-tetraaza-3,6,9,12-tetrakis (tert-butoxycarbonylmethyl) -7- [4- (3-amino) -propoxybenzyl] -tetradecanedicarboxylic acid-bis- (tert. -butyl) -diester

The 4-hydroxybenzyl compound obtained according to d) is alkylated according to the procedure given for 1b. The product obtained in this way (in a yield of 72%) is used without isolation in the next reaction stage (cleavage of the amine protecting group according to the procedure given in 1c). The title compound is obtained in 82% yield analytically pure as a colorless oil.

Analysis: Calc .: C 62.75 H 9.31 N 7.03 O 20.89 Found: C 62.70 H 9.28 N 7.13

f) 3,6,9,12-tetraaza-3,6,9,12-tetrakis (carboxymethyl) -7- [4- (3-amino) propoxybenzyl] tetradecanedicarboxylic acid

2.56 g (2.5 mmol) of the ester obtained according to e) are stirred in 30 ml of trifluoroacetic acid (anhydrous) for 2 hours at room temperature. It is then poured into 300 ml of ether. sucks off, suspended twice with 100 ml of ether and dried. 1.4 g of colorless crystals (85% of theory) remain.

Melting point: above 135 ° C (decomposition)

Analysis:

Calc .: C 51.13 H 6.59 N 10.64 O 31.62

Found: C 51.25 H 6.62 N 10.50

The gadolinium complex is obtained as indicated under 1e:

Gadolinium complex:

Calcd .: C 41.42 H 4.96 N 6.62 O 25.61 Cd 19.36

Found: C 41.53 H 5.01 N 8.39 Cd 19.09 The following salts are obtained analogously to the instruction given under le:

Sodium salt of the gadolinium complex

Analysis:

Calc .: C 38.31 H 4.24 N 7.97 O 23.69 Gd 17.91 Na 7.85

Found: C 38.25 H 4.11 N 7.56 Gd 18.05 Na 7.86

Meglumine salt of the gadolinium complex

Analysis:

Calc .: C 42.11 H 6.56 N 8.01 O 32.05 Gd 11.25

Found: C 42.25 H 6.70 N 8.09 Gd 11.13

EXAMPLE 35

1 ¹¹ indium complex of conjugate of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4- [3- (meleimido) propoxy] benzyl) undecanedioic acid with Fab- Fragments of the 7B10D11 monoclonal antibody

a) Production of F (ab ') ₂ fragments:

16 mg (100 nmol) of the antibody 7B10D11 are dissolved in 1 ml of a mixture of 0.1 m acetate buffer (pH 4.5) and 0.1 M saline solution and after addition of 0.3 mg pepsin for 20 hours at 37 ° C incubated. After purification via Ultragel AcA 44 (LKB) at pH 7.0 and after freeze-drying, 6.3 mg (63% of theory) of the desired fragments are obtained.

b) Production and coupling of Fab fragments:

15 mg (150 nmol) of the fragments obtained according to a) are dissolved in 14.5 m] 0.1 M phosphate buffer (pH 6.0) and 0.15 ml of a 0.1 M mercaptoethylamine solution in 0.1 M phosphate buffer (pH 6.0) with the addition of 15 mmol of ethylenediaminetetraacetic acid. After incubation at 37 ° C. for 2 hours, the mixture is separated off under argon protection on a Sephadex G 25 column. Determination of the sulfhydryl groups gives 238 nmoles of SH-6 groups in the reaction mixture.

0.7 mg (2.15 μmol) of the complexing agent described in Example 9j are dissolved in 10 ml of 0.1 M phosphate buffer (pH 6.0). For this, the solution of the Fab fragment prepared above is added at 4 ° C. and the mixture is allowed to react overnight with gentle shaking (at a maximum of 4 ° C.). Then eluted over a cation exchanger, dialyzed against 0.1 M ammonium acetate solution and lyophilized. 14.1 mg of a white powder are obtained.

1 ml of ¹¹¹ InCl ₃ solution (pH 5.5 83 mCi / ml) are added to a solution of the conjugate in 25 ml of buffer (20 mmol, sodium acetate; 150 mmol sodium chloride) and incubated for 4 hours. Then you add another 5 ml of 0.1 M sodium acetate solution, dialyzed and lyophilized. 13.82 mg of white powder with a specific activity of 5 mCi / mg are obtained. EXAMPLE 36

1 ¹¹ -indium complex of the conjugate of the monoclonal antibody 7B10D11 with 15- {4- [4-aza-2,6-diamino-N, N, N ', N ", N" -pentakis (carboxymethyl) hexyl] -phenoxy} -12-aza-14-hydroxy-pentadecanoic acid hydrazide.

30 nmoles of the antibody are bound to a macroporous, strongly acidic cation exchanger, which was previously equilibrated with a 0.1 M sodium acetate buffer (pH 5) and is located in a column protected from light by aluminum foil. Then rinsed with 0.03 M sodium periodate in acetate buffer until the periodate appears in the eluate. The rinsing is interrupted for 30 minutes, then washed with acetate buffer and then a solution is drawn up which is 0.03 m of the above hydrazide (Example 32) and 0.1 m of sodium cyanoborohydride. After 2 hours, the non-coupled complexing agent is eluted with acetate buffer; the conjugate is eluted with a saline gradient. After desalting, freeze-drying is carried out. 4.5 mg of conjugate are obtained, which is converted into the indium complex as described in Example 35.

EXAMPLE 37

a) N-Carbobenzoxyserin- (2-carbobenzoxyaminoethylene) amide

7.34 g (30.7 mmol) of N-carbobenzoxyserine are reacted and worked up according to the instructions given for Example 9b with the corresponding amounts of ethyl chloroformate, triethylamine and N- (2-aminoethyl) carbamate benzyl ester hydrochloride. 10.33 g (81%) of colorless crystal lisate are obtained.

Melting point: 167 ° C

Analysis:

Calc .: C 60.71 H 6.06 N 10.11 O 23.1

Found: C 60.75 H 5.98 N 10, 15 b) (2-Aminoethyl) -serinamide

13.46 g (N-carbobenzoxyserin- (2-carbobenzoxyaminoethylene) -amide are hydrogenated in 200 ml of methanol in the presence of 1.37 g of 10% palladium-carbon until no more hydrogen is absorbed. The catalyst is filtered off and removed all volatile parts of the oil pump, leaving a viscous, partially crystalline oil.

Yield 4.67 g (98%)

Analysis:

Calc .: C 40.80 H 8.89 N 28.55 O 21.74

Found: C 40.71 H 8.85 N 28.30

c) 1-Hydroχymethyl-1,3,5-tnazapentane trihydrochloride

Analogously to the procedure for Example 9e, the title compound is obtained in 67% yield from the amide described above as a white, crystalline powder.

Melting point: 236 ° C (decomposition)

Analysis:

Calc .: C 24.75 H 7.47 N 17.32 O 6.59 Cl 43.84

Found: C 24.71 H 7.40 N 17.41 Cl 43.98

d) 4-hydroxymethyl-3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -undecanoic acid-di-tert-butyl-diester

The title compound is obtained analogously to the procedure for Example 1a in 78% yield (after chromatography on silica gel with ether / hexane = 1/2) as a colorless oil.

Analysis:

Calc .: C 59.71 H 9.31 N 5.97 O 25.0

Found: C 59.56 H 9.32 N 5.99 The gadolinium complex or its salts are obtained as described in Example 1e.

Gadolinium complex

Analysis:

Calc .: C 42.55 H 5.95 N 9.92 O 41.56

Found: C 43.08 H 5.88 N 9.73

Sodium salt of the Gadolinium Komolex

Analysis:

Calc .: C 30.04 H 3.53 N 7.00 O 29.35 Gd 26.22 Na 3.83

Found: C 30.51 H 3.55 N 7.04 Gd 26.22 Na 3.88

N-Hethylglucamine salt of the Gadolinium Komolex

Analysis:

Calc .: C 31.19 H 3.83 N 7.27 O 30.46 Gd 27.22

Found: C 31, 70 H 3.84 N 7.21 27.36

EXAMPLE 38

a) Bis-1,4- {4- (2,6-di- [bis- (tert-butoxycarbonylmethyl) amino] -4- (tert-butoxycarbonylmethyl) -aza-hexamethylene) phenoxy} butane

13.7 g (17.56 mmol) of 4- (4-hydroxybenzyl) -3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -undecanedioic acid-bis- (tert-butyl) - diesters (Example 9f) are dissolved in dry toluene (100 ml), 530 mg (17.6 mmol) of NAH (80% suspension in paraffin) are carefully added and the mixture is heated to 40 to 50 ° C. for 10 minutes. The mixture is then cooled to 0 ° C. and 1.9 g (8.8 mmol) of dibromobutane in 10 ml of toluene are added. The mixture is allowed to warm up to room temperature and then heated to 80-100 ° C. for a further 30 minutes. After filtering through glass wool and stripping off the solvent, the residue is chromatographed on silica gel. This gives 10.5 g (6.5 mmol, 74% of theory) of a colorless oil. Analysis:

Calc .: C 63.99 H 8.99 N 5.2 O 21.8 Found: C 64.57 H 9.11 N 5.18

b) Bis-1,4- {4- (2,6-di- [bis (carboxymethyl) amino] -4- (carboxymethyl) aza-hexamethylene) phenoxy} butane

As described for example 1e, the free complexing agent is obtained in

73% yield in the form of white crystals with a melting point of 228 ° C. (decomposition)

Analysis: Calc .: C 52.46 H 6.12 N 7.98 O 33.42

Found: C 52.1 H 6.12 N 8.05

The gadolinium complex and its salts are obtained quantitatively as described in Example 1e.

Gd complex

Analysis: Calc .: C 40.58 H 4.29 N 6.17 O 25.85 Gd 23.09 Found: C 40.21 H 4.32 N 6.18 Gd 23.32

Gd-Komolexes sodium salt

Analysis: Calc .: C 39.31 H 4.01 N 5.97 O 25.04 Na 3.27 Gd 22.37 Found: C 38.91 H 3.94 N 6.08 Na 3.31 Gd 22 , 11

Gd-Komolex's N-methylglucamine salt

Analysis: Calc .: C 41.48 H 5.92 N 6.53 O 3 1.36 Gd 14.68 Found: C 42.27 H 5.84 N 6.47 Gd 14.62

EXAMPLE 39

a) N, N'-bis- {4- [3- (tert-butoxycarbonylmethyl) -aza-5-bis- (tert-butoxycarbonylmethyl) -amino-2-bis- (tert-butoxycarbonylmethyl) aminomethyl] -pentamethylenephenoxy-acetyl-} hydrazide

To a solution of 4.18 g (4.99 mmol) of 5- [4- (carboxymethoxy) benzyl] -3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -undecanedioic acid bis - (tert-Butyl) diester (Example 24a) and equimolar amounts of triethylamine and isobutyl chloroformate, which are prepared in 250 ml of tetrahydrofuran at 0 ° C with exclusion of moisture, slowly adding a solution of 74 mg (2.49 mmol ) Hydrazine in 50 ml of tetrahydrofuran. After stirring for one hour at 5 ° C, another hour at room temperature and 30 minutes at 45 ° C, the mixture is cooled, concentrated and taken up in ethyl acetate. After filtering, wash several times with water and 0.1N hydrochloric acid. Finally, it is chromatographed on silica gel with ether / hexane. 3.17 g (76% of theory) of a colorless oil are obtained.

Analysis: Calc .: C 61.77 H 8.55 N 6.7 O 22.96 Found: C 62.2, H 8.52 N 6.61

b) N, N'-bis- {4- [3- (carboxymethyl) aza-5-bis (carboxymethyl) amino-2-bis (carboxymethyl) aminomethyl] pentamethylenephenoxyacetyl} hydrazide

The free complexing agent is obtained according to the instructions given for Example 1e in 78% yield as a white powder with a melting point of 205 ° C. (decomposition).

Analysis: Calc .: C 49.72 H 5.62 N 10.08 O 34.56 Found: C 49.77 H 5.67 N 10.03 The gadolinium complex and its salts are obtained quantitatively as described in Example 1e.

DG Komolex

Analysis: Calc .: C 38.92 H 3.97 N 7.89 O 27.05 Gd 22.15 Found: C 38.71 H 3.91 N 7.87 Gd 22.34

Gd-Komolexes sodium salt

Analysis: Calc .: C 37.75 H 3.71 N 7.65 O 26.23 Na 3.14 Gd 21.49 Found: C 37.82 H 3.70 N 7.72 Na 3.09 Gd 21 , 13

N-methylglucamine salt of the Gd complex

Analysis: Calc .: C 40.39 H 5.68 N 7.63 O 31.99 Gd 14.29 Found: C 40.56 H 5.70 N 7.54 Gd 14.13

EXAMPLE 40

a) 1,12-bis- 4- [3- (tert-butoxycarbonylmethyl) -aza-5-bis- (tert-butoxycarbonylmethyl) -amino-2-bis- (tert-butoxycarbonylmethyl) aminomethyl] -pentarnethylenephenoxy -4,9-diaz.a-5,8-dioxododecamethylene

To 8.36 g (9.99 mmol) of 5- [4-3-aminopropoxy) benzyl] -3,6,9-tris (tert-butoxycarbonylmethyl) -3,6,9-triaza-undecanedioic acid bis - (tert-Butyl) diester (Example 18b) in 100 ml of toluene and an equimolar amount of triethylamine, 770 mg (4.96 mmol) of succinic acid dichloride are carefully added dropwise at 0 ° C. The mixture is then heated briefly to reflux, filtered, the organic phase is washed thoroughly with water and chromatographed on silica gel. Finally, 7.62 g (82% of theory) of a colorless oil are obtained. Analysis: Calc .: C 62.92 H 9.05 N 7.48 O 20.52 Found: C 61, 93 H 8.95 N 7.56

b) 1,12-bis- 4- [3- (carboxymethylaza) -5-bis-carboxymethyl) amino2-bis (carboxymethyl) aminomethyl-pentamethylene-phenoxy] -4,9-diaza-5,8-dioxododecamethy len

As described for Example 1e, the free complexing agent is obtained in 78% yield.

Melting point: 220 ° C (decomposition)

Analysis: Calc .: C 53.20 H 6.77 N 10.69 O 29.32 Found: C 52.82 H 6.80 N 10.76

The gadolinium complex and its salts are obtained quantitatively as described in Example 1e.

DG Komolex

Analysis: Calc .: C 43.05 H 5.1 N 8.65 O 23.73 Gd 19.43 Found: C 43.28 H 5.1 N 8.74 Gd 19.51

Sodium salt of the Gd complex

Analysis: Calc .: C 41.92 H 4.85 N 8.42 O 23.10 Na 2.76 Gd 18.92 Found: C 42.63 H 4.81 N 8.28 Na 2.71 Gd 18 , 57

N-methylglucamine salt of the Gd complex

Analysis: Calc .: C 43.06 H 6.30 N 8.17 O 29.34 Gd 13.11 Found: C 43.91 H 6.19 N 8.29 Gd 13.06

EXAMPLE 41

a) 3,6-diaza-3,6-bis (tert-butoxycarbonylmethyl) -4- [4- (3- (5- <2-oxo-2,3,3a, 4,

6,6a-hexahydro-1H-thieno [3,4-d] imidazol-4-yl> -valerylamino) -propoxy) -benzyl] -succinic acid bis- (tert-butyl) diester

341.4 mg (1 mmol) of N-hydroxysuccinimidobiotin (Pierce Chem. Comp.) Are mixed with 679.9 mg (1 mmol) of 3,6-diaza-3,6-bis- (tert-butoxycarbonylmethyl) -4- [ 4- (3-aminopropoxy) benzyl] -succinic acid bis (tert-butyl) diester (Example 1c) in 6 ml of DMF and stirred overnight. The reaction solution is then evaporated and chromatographed on silica gel (toluene / glacial acetic acid / ethyl acetate / methanol = 6: 4: 4: 3). The fractions, which are pure by thin layer chromatography, are combined, the solution is evaporated in vacuo and dried over KOH. Yield: 695 mg (78% of theory)

Analysis: Calc .: C 60.97 H 8.34 N 7.73 O 19.42 S 3.54 Found: C 61.05 H 8.29 N 7.71 S 3.30

b) 3,6-Diaza-3,6-bis- (carboxylmethyl) -4- [4- (3- (5- <2-oxo-2,3,3a, 4,6,6a-hexahydro-1H- thieno- [3,4-d] imidazol-4-yl> -valerylamino) -propoxy) -benzyl] -suberic acid

453 mg (0.5 mmol) of compound 41a are mixed with 3 ml of trifluoroacetic acid and stirred for 30 minutes. Then it is precipitated with dry diethyl ether, the precipitate is washed with diethyl ether and dried. Yield: 298 mg (90% of theory)

Analysis: Calc .: C 52.85 H 6.40 N 10.27 O 25.81 S 4.70 Found: C 52.79 H 6.49 N 10.20 S 4.59

The gadolinium complex is prepared according to the procedure described in Example 1e.

Analysis: Calc .: C 43.10 H 4.82 N 8.38 O 21.05 S 3.84 Gd 18.81 Found: C 43.01 H 4.79 N 8.45 S 3.97 Gd 18 , 47 EXAMPLE 42

a) 3,6,9-Triaza-4- (4-hydroxybenzyl) -3,6,9-tris- (carboxymethyl) -undecanedioic acid

7.80 g (10 mmol) 3,6,9-triaza-4- (4-hydroxybenzyl) -3,6,9-tris- (tert-butoxy carbonylmethyl) -undecanedioic acid-bis- (tert-butyl) diester (Example 9f) who dissolved in 100 ml of trifluoroacetic acid and precipitated after one hour with diethyl ether. After chromatography on silica gel in ethanol / conc. Ammonia / water (8: 1: 1), the purified fractions are poured over Amberlite IR 120 (H ⁺ ) and the acidic eluate is freeze-dried. Yield: 4.09 g (82% of theory)

Analysis: Calc .: C 50.50 H 5.85 N 8.41 O 35.24 Found: C 50.39 H 5.85 N 8.34

b) Gadolinium complex of 3,6,9-triaza-4- (4-hydroxybenzyl) -3,6,9-tris- (carboxymethyl) -undecanedioic acid

0.50 g (1 mmol) of the complex acid described in Example 42a is dissolved in 40 ml of water and treated with 181 mg (0.5 mmol) of Gd ₂ O ₃ , stirred for 30 minutes at 80 ° C., filtered and the filtrate freeze-dried. Yield: 0.65 g (99.4% of theory)

Analysis: Calc .: C 38.58 H 4.01 N 6.43 0 26.92 Gd 24.06 Found: C 38.39 H 4.02 N 6.47 Gd 24.11

EXAMPLE OF NMR DIAGNOSTICS IN VIVO

Representation of the gallbladder and a colon carcinoma in an MRI scanner

A nude mouse (Balb / c nu / nu, female, 20 g) with subcutaneously implanted HT29 colon carcinoma was 0.1 mmol / kg of the gadolinium complex of 3, 6, 9-triaza-4- (4-hydroxybenzyl) -3.6 , 9-tris (carboxymethyl) -undecanedioic acid (Example 42) dissolved in 200 ul physiological phosphate buffer iv applied.

Images were taken before and after the application of the contrast medium with a spin echo sequence (T _R = 400 msec, T _E = 30 msec) in the area of the liver and tumor. The investigations were carried out in a 2 Tesla magnetic resonance scanner from General Electric.

The picture shows three pictures; one before and two after the application of the contrast agent. The gallbladder is clearly lifted from the surrounding liver tissue 30 minutes after application. Immediately after application, the tumor shows a signal enhancement in the marginal area, while after 30 minutes a clear signal increase can be seen in the entire tumor.

Claims

Claims

1. Compounds of the general formula I

where n and m are each for the digits 0, 1, 2, 3 and 4,

X represents a hydrogen atom and / or a metal ion equivalent of an element of atomic numbers 21-29,31,32,37-39,42-44, 49 or 57-83. R ¹ and R ^{2 are} different and each for a hydrogen atom or an imino, phenyleneoxy, phenylenimino, amido, hydrazido, ester group (s), oxygen, sulfur and / or nitrogen atom (s) , optionally substituted by hydroxy, mercapto, imino, epoxy, oxo, thioxo and / or amino group (s) straight-chain, branched, saturated or unsaturated C ₀ -C ₂₀ alkylene group, which in the end either a second

Molecule of the general formula I _A or I _B

a functional group or linked via this functional group

Has bio- or macromolecule, with the proviso that n and m together do not result in more than 4 and that if

X represents a metal ion equivalent, at least two of the substituents X have this meaning. and their salts with inorganic and / or organic bases or amino acids.

2. Compounds according to claim 1, characterized in that X represents hydrogen atoms.

3. Compounds according to claim 1, characterized in that at least two of the substituents X metal ion equivalents of at least one element of atomic numbers 21-29, 42, 44 or 57-83 or at least one radionuclide of an element of atomic numbers 27, 29, 31, 32, 37 -39, 43, 49, 62, 64, 70 or 77.

4. Compounds according to claim 1, characterized in that R ¹ for a hydrogen atom and R ² for an optionally imino, phenyleneoxy, phenyleneimino, amido, hydrazido, ester group (s), oxygen, sulfur and / - or C ₀ -C ₂₀ alkylene group optionally containing hydroxyl, mercapto, imino, epoxy, oxo, thioxo and / or amino group (s) containing nitrogen atom (s), which in the end is a functional group - NH ₂ ; -NHR; -NHNH ₂ ,

-NRNH ₂ , -SH, -OH, -COCH ₃

K where R and R 'are the same or different and each represents a hydrogen atom, a saturated or unsaturated C ₁ -C ₂₀ -alkyl radical optionally substituted by a phenyl group, or a phenyl group.

5. Compounds according to claim 1, characterized in that R ² for a hydrogen atom and R ¹ for an optionally imino, phenyleneoxy, phenyleneimino, amido, hydrazido, ester group (s), oxygen, sulfur and / or Containing nitrogen atom (s) optionally substituted by hydroxy, mercapto, emino, epoxy, oxo, thioxo and / or amino group (s) C ₀ -C ₂₀ alkylene group, which in the end as a functional group -NH ₂ ; -NHR; -NHNH ₂ ; -NRNH ₂ ; -SH; -OH; -COCH ₃ ;

where R and R 'are identical or different and each represents a hydrogen atom, a saturated or unsaturated, optionally substituted by a phenyl group, C ₁ -C ₂₀ alkyl radical or a phenyl group.

6. Compounds according to claim 1, characterized in that R ^{1 stands} for a What atom and R ^{2 contains} a bio or macromolecule.

7. Compounds according to claim 1, characterized in that R ^{2 stands} for a What atom and R ^{1 contains} a bio or macromolecule.

8. Compounds according to claim 1, characterized in that the bio- or macromolecule contained in R ¹ or R ^{2 is} an antibody, an antibody fragment, an avidin-biotin antibody or avidin-biotin antibody fragment.

Compounds of the general formula I '

wherein n, m and X have the meaning given in claim 1, R ^{1 '} and R ^2, which have the meaning given for R ¹ and R ² , but have no bio or macromolecule, and their salts with inorganic and / or organic bases or amino acids .

10. Pharmaceutical compositions containing at least one physiologically compatible compound according to claims 1 to 9, optionally with the additives customary in galenics.

11. Use of at least one physiologically compatible compound according to claim 3 for the preparation of agents for NMR, X-ray, radio o-diagnosis or radiotherapy.

12.Use of at least one physiologically compatible compound of the general formula I 'according to claim 9 as a hapten for the production of antibodies.

13. Process for the preparation of compounds of general formula I.

where n and m are each for the digits 0, 1, 2, 3 and 4,

X for a hydrogen atom and / or a metal ion equivalent of an element of atomic numbers 21-29,31,32,37-39,42-44, 49 or 57-83, R ¹ and R ^{2 are} different and each for a hydrogen atom or an optionally Imino, phenyleneoxy, phenyleneimino, amido, hydrazido, ester group (s), oxygen, sulfur and / or nitrogen atom (s) containing, optionally by hydroxy, mercapto, imino, epoxy, Oxo, thiox o and / or amino group (s) substituted straight-chain, branched, saturated or unsaturated C ₀ -C ₂₀ alkylene group, which in the end either a second

Molecule of the general formula I _A or I _B

a functional group or linked via this functional group has a macromolecule, with the proviso that n and m together do not result in more than 4 and that if X stands for a metal ion equivalent, at least two of the substituents X have this meaning, and their Salts with inorganic and / or organic bases or amino acids, characterized in that a compound of the general formula II wherein nm have the meaning given above, R ^{1 '} and R ^{2' are} different and each represents a hydrogen atom or an optionally imino, phenyleneoxy, phenyleneimino, amido, hydrazido, ester group (s), oxygen, sulfur and / or nitrogen atom (s) containing, optionally substituted by hydroxyl, mercapto, imino, epoxy, oxo, thioxo and / or amino group (s) straight-chain, branched, saturated or unsaturated C ₀ - C ₂₀ alkylene group, which in the end either a second molecule of the general formula (I ' _A ) or (I' _B )

or has a functional group. s stand, and R ^{3 represents} a C ₁ -C ₆ alkyl group, saponified, the acids of the general formula II 'thus obtained with R ³ in the meaning of a hydrogen atom, if desired a) in a manner known per se with at least one metalloid or metal salt of an element of atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 or 57-83 and then, if desired, acidic hydrogen atoms present by cations inorganic and / or organic bases or amino acids substituted, or

b) in a manner known per se with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31, 32, 37-39, 42-44, 49, or

57-83 and then binds the metal complexes thus obtained in a manner known per se via the functional group contained in R ^{1 '} or R ^2' to a bio- or macromolecule and, if desired, azides present

Hydrogen atoms substituted by cations of inorganic and / or organic bases or amino acids, or

c) binds to a bio or macromolecule in a manner known per se via the functional group contained in R ^{1 '} or R ^2' and then in a manner known per se with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31 , 32, 37-39, 42-44, 49 or 57-83 and then, if desired, existing acidic hydrogen atoms substituted by cations of inorganic and / or organic bases or amino acids.

14. The method according to claim 13, characterized in that one carries out the coupling of the macromolecule to the functionalized complex or ligand and, in the case of coupling to the ligand, the subsequent complexation with the / the desired metal ions on a stationary phase .

15. A process for the preparation of the pharmaceutical composition according to claim 10, characterized in that the complex compound, dissolved or suspended in water or physiological saline solution, is brought into a form suitable for enteral or parenteral administration, optionally with the additives customary in galenics.