DE10117242C1 - New dimeric tetraazacyclododecane derivatives and their metal complexes useful as components of diagnostic agents, especially X-ray contrast agents, and radiotherapeutics - Google Patents

Abstract

Asymmetrically bridged dimeric tetraazacyclododecane derivatives (I) and their metal complexes are new. Asymmetrically bridged dimeric tetraazacyclododecane derivatives of formula (I) and their metal complexes are new. Z<1>-Z<3>, Z'<1>-Z'<3> = H or metal ion equivalent; U = alpha -CH(R<3>)C(O)- beta or a group of formula (i); alpha = bond to N atom of cyclododecane ring; beta = bond to N atom substituted by R<1>; R<3> = H, or 1-4C alkyl optionally substituted by OH; R<1> = H, or 1-6C alkyl optionally interrupted by O and optionally substituted by OH; B = 1-14C alkylene optionally interrupted by O, optionally containing CO and/or N(R'<1>) and optionally substituted with OH; and R'<1> = R<1>; provided that compounds are excluded when B is alpha -CH(R<3>)C(O)- beta (sic). An Independent claim is included for the preparation of (I).

Description

The invention relates to asymmetrical dimeric metal complexes or ligands for them Metal complexes, processes for their preparation and pharmaceuticals or diagnostic agents, the these contain, in particular contrast media.

Precise diagnosis is a prerequisite for targeted and successful therapy. Especially in the diagnostic field, the possibilities in the past Years increased very much, whereby the X-ray diagnosis is able to be practical to display every anatomical detail selectively and with great accuracy. In many cases However, the corresponding structures can only be created by using X-ray contrast media visible. This is especially true for the blood vessels, the Development of the finest catheters and a further development of X-ray technology as well play a major role.

In contrast to normal X-ray technology, computer tomography delivers Cross-sectional images through the body that achieve a very good spatial resolution. Even though the density resolution of computed tomography is also significantly higher than that Density resolution of conventional projection radiography are becoming a sure thing Detection of many pathological changes but contrast medium is required.  

It has also been shown in the presentation of the urinary tract that rapid injection of a high contrast medium dose leads to the best results.

However, especially in the field of X-ray diagnostics in recent years Requirements for the quality of the contrast media have increased continuously.

The x-ray density of a contrast medium is dependent on the concentration of the absorbent Species in the solution used as the only parameter, as long as that Contrast medium is not diluted. This is particularly the case in angiography if the contrast agents are injected into blood vessels at high speed via catheters: The contrast medium displaces the blood. It is all the more suitable for the finest blood vessels to represent the higher the concentration of the absorbing atoms. Contrast medium with extremely high concentration are particularly useful when it comes to that determine whether a blood vessel is completely closed or still a fine channel than Connected to intact peripheral vessels and / or whether peripheral tissue through fine bypasses (collaterals) can be supplied with blood. Continues to come high concentration becomes very important when the shooting conditions are otherwise unfavorable, for example in that the beam path through the body of a heavy patient can become very long.

A number of other studies have been using highly concentrated contrast media also desirable, either because the thinning in the body would otherwise become too strong (injection in the ventricles, the aorta or in intravenous digital subtraction angiogra phie) or simply for practical reasons the injection volume to achieve a certain dose (g contrast agent / patient or g contrast agent / kg body weight) should be kept as low as possible. The x-ray contrast media are through a certain limit concentration for their use on the patient is restricted. The cause this is because they are too viscous and / or too poorly tolerated at higher concentrations become. Compatibility problems arise primarily from the high osmolality of the Solutions, especially if iodine-containing X-ray contrast agents are used. The Absorption behavior of the contrast medium is due to the X-ray capture cross section characterized contained atoms. Are atoms with a high X-ray capture cross section therefore well suited as an absorber. Heavy atoms like iodine or lanthanoids are good Absorber.  

X-ray contrast media are usually highly concentrated solutions (50 to <80 Weight percent). These solutions can become very viscous, sometimes simple This is because the water content is well below 1 g per ml of solution. On the other hand, requires the use of contrast media often the very rapid injection of large volumes (10- 200 ml) by needles that are not too thick or - even more problematic - the injection through catheters up to one meter long, some of which have several very narrow channels must contain, in addition to the contrast medium application z. B. also filling of a balloon or to measure local blood pressure. Although with some Techniques are already used in pressure injectors, should the viscosity of the Contrast media solutions should be limited to approx. 10 cP at 37 ° C.

In addition to the poor injectability, higher-viscosity contrast media also have the disadvantage poor miscibility with blood (streak formation instead of homogeneous filling of the cardiac cavities or blood vessels) and the obstruction of the passage by capillaries, for example the Lungs (M. Langer, R. Felix, R. Keysser, U. Speck, D. Banzer: Influencing the Mapping quality of the i. V. DSA due to the iodine concentration of the contrast medium. Digit. Bilddiagn. 5: 154-159 (1985)). For all of these reasons, X-ray contrast media should be used for the vasal application should be as thin as possible.

Because X-ray contrast media for most applications, the absorbing atoms in very must contain high concentration, were the originally developed preparations very hypertonic to blood and tissue. That has a number of parts causes serious side effects, e.g. B. severe pain, damage of blood vessels and cardiovascular disorders. In addition, some Investigations also the contrasting by strong osmotic dilution of the Contrast medium impaired (urography).

In the meantime, improvements have been achieved with new, nonionic contrast media (B. Hagen: Iohexol and iopromide - Two new non-ionic water-soluble radiographic contrast media: Randomized, intraindividual double-blind study versus ioxaglate in peripheral angiography. In Contrast Media, Edited by Volker Taenzer and Eberhard Zeitler (1983), Georg Thieme Verlag, pp. 104-114), but not for all applications are satisfactory.

Known water-soluble X-ray contrast media are usually derived either from triiodobenzene or from chelate structures. These compounds are only very poorly soluble and  sometimes quite toxic. Hydrophilic side chains are attached to the molecules for improvement of solubility and tolerability. Both properties are all the easier too optimize the more extensive the side chains become. Large substituents do, however at the same time a relative decrease in the atom suitable for absorption (iodine, Lanthanoid, etc.) in the molecule (in percent of the molecular weight), an undesirable Increase in viscosity and a further decrease in the already low Water content of the highly concentrated solutions, since at a given concentration each Increase in the amount of organic matter in the solution at the expense of the proportion Water goes.

So there has to be a compromise between the highest possible water solubility and good Compatibility with the smallest possible side chains can be found.

To solve these difficulties, EP-A 0 426 610 proposes nonionic X-ray contrast media with a high iodine content. These connections have advantages , but are still unsatisfactory in many respects, particularly with regard to the desired tolerance.

Another class of X-ray contrast media contains chelating ligands, which are monomeric or can also be oligomeric. These X-ray contrast media have in common that a metal cation is complexed by the chelating ligand. This metal cation is in the essentially responsible for the X-ray absorption capacity of the contrast medium. To Metal cations frequently used for this purpose are cations of the lanthanoid elements, gadolinium and dysprosium are particularly noteworthy. As a ligand in particular Nitrogen-containing, macrocyclic elements are also frequently used for the lanthanoid elements Systems used. Examples are disclosed in US-A 5,049,667. Find among other things Derivatives of 1,4,7,10-tetraazacyclododecane-N, N ', N ", N' '' - tetraacetic acid (DO4A) Use.

If a molecule has several ligand sites, this has the advantage that of this Multiple metal cations can be complexed, which has a positive effect on the molecule X-ray contrast medium affects osmolality. Therefore, were also various Proposed dimers of ligands that result from bridging two ligands.

In WO 96/05167 bridged dimeric systems are described, which differ from derive cyclic or open-chain derivatives of ethylenediamine, which on  Nitrogen atom is functionalized by further acetic acid groups. WO 95/27705 discloses ligands that have aromatic amides in the side chain. WO 95/07270, WO 95/09848 and US 5,374,416 disclose very broadly defined ligands. So far these documents specifically disclose ligands that differ from bridged 1,4,7,10- Derive tetraazacyclododecane-N, N ', N "-triacetic acid derivatives (DO3A) is the Bridge group symmetrical, so that the dimers as such are symmetrical.

Recently there has been a further increase in the requirements for X-ray contrast media register: Repeated injections even in severely damaged vascular areas, the Omission of the previously used premedication with analgesics, the waiver of the Use of anesthesia or the addition of local anesthetics to the contrast medium, the overall higher dosages and the z. T. repeated examination and / or Treatment of elderly and very sick patients have the desire for Contrast agents with even lower osmolality and thus further improved tolerability strengthened. For those that are often necessary repeatedly in the same patient Widening of individual sections of the arteries are such better tolerated contrast agents at all a requirement for the consent of the patient concerned for this Type of therapy. Since also essential practical properties of the manufacture contrast medium solution such as its injectability through the finest catheters and the flow and contrast behavior in the blood vessels depend directly on the viscosity, it is desirable to also have contrast agents, their viscosity data in comparison are lowered to the previously known means.

It is therefore an object of the invention to use contrast media, in particular X-ray contrast media, to make available that meet these increased requirements and at who do not experience the difficulties of the prior art.

This object is solved by the subject matter of the claims.

The invention thus relates to a

Compound of formula I.

in which Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and Z ^{3 '} each independently represent a hydrogen atom or a metal ion equivalent, -U- a radical

means which is bonded to the adjacent nitrogen atoms at the positions marked with and wherein the position α is bonded to the nitrogen atom of the tetraazacyclododecane ring and the position β is bonded to the nitrogen atom substituted by R ¹ , where R ^{3 is} a hydrogen atom or a straight-chain or branched C ₁ -C ₄ means alkyl radical which is optionally substituted with hydroxyl groups, R ^{1 represents} a hydrogen atom or a straight-chain or branched C ₁ -C ₆ alkyl radical which is optionally interrupted by oxygen atoms and which is optionally substituted by hydroxyl groups, and -B- a straight-chain one or branched C ₁ -C ₁₄ alkylene radical, preferably C ₁ -C ₁₀ alkylene radical, which is optionally interrupted by oxygen atoms and which optionally contains carbonyl groups and / or N (R ^{1 '} ) groups and which is optionally substituted by hydroxyl groups, where R ^{1 '} as defined for R ¹ is selected independently of R ¹ t can be provided that -B- does not have a remainder

at the positions α or β marked with the nitrogen atom of the Tetraazacyclododecanrings is bound.

The invention preferably relates to dimers which satisfy the following formula II:

wherein Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' , Z ^{3 '} , -U- and R ^{1 are} as defined above, R ^{2 is} a hydrogen atom, a C ₁ -C ₄ alkyl, C ₁ - Is C ₄ hydroxyalkyl or C ₁ -C ₄ alkoxyalkyl and -B ^' - is a straight-chain or branched C ₁ -C ₈ alkylene radical which is optionally interrupted by oxygen atoms and which optionally carbonyl groups and / or N (R ^1' ) - Contains groups and which is optionally substituted with hydroxyl groups, where R ^{1 '} is defined as R ¹ but can be selected independently of R ¹ .

In the above formulas I and II, the radicals Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and Z ^{3 'can denote} a hydrogen atom or a metal ion equivalent. Preferably at least two of the radicals mean a metal ion equivalent, most preferably all radicals Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and Z ^{3 '} mean a metal ion equivalent. The metals are, in particular, cations of elements with an atomic number of 20 to 32, 37 to 39, 42 to 44, 49 and 57 to 83. The metals are particularly preferably lanthanoids or yttrium, that is to say Metals with an atomic number of 39 or 58 to 71 and from the group of the lanthanides are most preferred gadolinium and dysprosium. As a rule, a compound of formula I or formula II binds two metal cations, where the radicals Z ¹ , Z ² and Z ³ or the radicals Z ^{1 '} , Z ^2' and Z ^{3 '} each together represent a trivalent metal cation , Z ¹ , Z ² , Z ³ or Z ^{1 '} , Z ^2' and Z ^{3 '} each preferably represent one and the same metal cation, and Z ¹ , Z ² , Z ³ and Z ^1' , Z ² are particularly preferred ^' and Z ^3' each together a Gd ³⁺ ion, a Dy ³⁺ ion or a Y ³⁺ ion. The two tetraazacyclododecane residues within the compounds of the formulas I or II can complex cations of different metals, preferably both residues complex cations of the same metal.

In the above formulas I and II, the radical R ^{3 is} preferably a hydrogen atom or a methyl or an ethyl radical. If the radical R ^{3 is} a straight-chain or branched C ₁ -C ₄ alkyl radical, it is preferably not substituted with hydroxyl groups. If the radical contains hydroxyl groups, it preferably contains one or two hydroxyl groups.

The radical R ¹ is preferably a hydrogen atom or a C ₁ -C ₄ alkyl radical. If R ^{1 represents} an alkyl radical which may be interrupted by oxygen atoms, it preferably contains one or two oxygen atoms. If R ^{1 represents} an alkyl radical which is substituted by hydroxyl groups, it is preferably substituted by one to three hydroxyl groups. R ¹ is particularly preferably a hydrogen atom, a methyl group, an ethyl group or a C ₁ -C ₄ hydroxyalkyl group, in particular a -CH ₂ CH ₂ -OH-, -CH ₂ -CH (OH) -CH ₂ -OH-, - CH ₂ -C (OH) HC (OH) H-CH ₂ -OH, or a -CH (CH ₂ OH) -C (OH) H-CH ₂ OH group is particularly preferred. R ¹ is also preferably an alkoxy or hydroxyalkoxy group, in particular a -CH ₂ -CH ₂ -OCH ₃ -, -CH ₂ -C (OH) H-CH ₂ OOH ₃ - or a -CH ₂ -C (OCH ₃ ) H-CH ₂ -OH group, R ¹ is particularly preferably a methoxy group.

The radical R ² is preferably a hydrogen atom, a methyl group, a hydroxymethyl group or a -CH ₂ -OCH ₃ group.

The radical -B- is preferably a radical -B ^' -C (OH) H-CR ² H-, so that a compound of the formula II is preferred according to the invention.

-B ^' - is preferably a linear or branched chain C ₁ -C ₆ alkylene radical, a linear alkylene radical being preferred. If the alkylene radical is interrupted by oxygen atoms, one to three oxygen atoms are preferably present. The alkylene radical can also contain carbonyl groups or N (R ^{1 '} ) radicals, which means that the alkylene chain is interrupted by such radicals. If such residues are present, one or two carbonyl groups and / or one or two residues N (R ^{1 '} ) are preferably present. If the alkylene radical is substituted by hydroxyl groups, it is preferably substituted by one or two hydroxyl groups. -B ^' - is particularly preferred -CH ₂ -, -CH ₂ O-CH ₂ CH ₂ -, -CH ₂ -CO-NH-CH ₂ -, -CH (CH ₂ OH) -CO-NH-CH ₂ -, or -CH (CH ₂ OOH ₃ ) -CO-NH-CH ₂ group. The requirement in claim 1 that the radical -B- is not bound to the nitrogen atom of the tetraazaring via a radical -CR ³ H-CO- ensures that the dimers according to the invention are asymmetrically bridged, since according to the invention it was surprisingly found that with the asymmetrically bridged dimers of the formulas I and II, in particular in X-ray contrast media, more balanced and generally better properties can be achieved than with symmetrically bridged dimers, as were already known in the prior art.

The compounds according to the invention can have one or more centers of chirality exhibit. These centers of chirality can be in enantiomerically pure form, as a racemate or exist in the unequal ratio of several configurations.

The compounds according to the invention can, in principle, according to the prior art known methods can be produced. As a rule, the 1,4,7,10- Tetraazacyclododecan-N, N ', N "-triacetic acid monomers prepared separately and then two different monomers coupled together.

In the preferred method of the present invention, coupling is via amidation. The processes according to the invention for the preparation of a compound of the formula I or II therefore preferably comprise one of the following process steps, in which

• a) a compound of formula III
  or a reactive form thereof with a compound of formula IV
  or a reactive form thereof is implemented, or
• b) a compound of formula V
  with a compound of formula IV
  or a reactive form thereof is implemented, or
• c) a compound of formula VI
  with a compound of formula VII
  is implemented, whereby a compound of formula VIII
  arises and any protective groups present in the compound of the formula VIII are removed and, if appropriate, radicals R ¹ , R ³ , B, Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and / or Z ^{3 '} into other radicals R. ¹ , R ³ , B, Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and / or Z ^{3 'are} converted, where A ¹ , A ² , A ³ , A ^1' , A ^{2 '} and A ^{3 'is} a group - (CH ₂ ) _n -Q with n = 0 or 1, where in the case that n = 0, the radical Q represents an amino protecting group which, after the formation of the dinuclear compound, forms a desired group -CH ₂ -CO ₂ -Z is converted, where Z is Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' or Z ^{3 '} , for example in that the amino protecting group is removed, followed by the deprotected amino groups of the tatraazacyclododecane ring are reacted with a compound AG-CH ₂ -L, in which AG represents a suitable leaving group (e.g. Cl, Br, I, tosyl, mesyl, etc.) and L either represents a protected carboxylic acid function, the protective group of which the Binding of the radical -CH ₂ -L to the tetraazacyclododecane ring is split off and then the metal ion equivalent Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and / or Z ^{3 'is} introduced, or L represents a free carboxylic acid function and after binding of the radical -CH ₂ -CO-OH to the tetraazacyclododecane, the metal ion equivalent Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and / or Z ^{3 'is then} introduced, or L for the carboxylic acid function bound metal ion equivalent Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and / or Z ^{3 '} , and in the event that n = 1, the radical Q either represents a protected carboxylic acid function, the protective group according to the formation of the dinuclear compound is split off and then the metal ion equivalent Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and / or Z ^{3 'is} introduced, or the rest Q stands for a free carboxylic acid function and then after formation of the binuclear compound, the metal ion equivalent Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and / or Z ^{3 'is} introduced rd, or the radical Q represents the metal ion equivalent Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and / or Z ^{3 '} bonded to a carboxylic acid function, the radical R ^{4 represents} a C ₁ -C ₄ alkyl radical, one of the radicals B ¹ and B ^{2 has} an optionally activated carboxyl group and the other the radical B ¹ and B ^{2 has} an optionally activated amino group, or the radical B ^{2 has} an optionally activated carboxyl group and the radical B ^{1 is} a hydrogen atom, where B ¹ and B ² form a radical B under an amidation reaction and the radicals R ¹ , R ³ , B, Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and Z ^{3 'are} as defined in claim 1.

The processes according to the invention for the preparation of a compound of the formula II alternatively comprise one of the following process steps in which a compound of the formula IX

is implemented with

• a) a compound of formula X
  or
• b) a compound of formula XI
  or
• c) a compound of formula XII
  or
• d) a compound of formula XIII
  where AG is a suitable leaving group (e.g. Cl, Br, I, tosyl, mesyl, etc.) and P is a hydrogen atom or a suitable alcohol protecting group (e.g. tert-butyldimethylsilyl, tetrahydropyranyl, etc.) and the other substituents as above are defined.

The compounds of the formulas III, IV, V, VI, VII, IX, X, XI, XII and XIII can per se known way to be produced, being based on the in the introduction mentioned publications and the following examples can be referenced.

In the process according to the invention, a 1,4,7,10-tetraazacyclododecane-N, N ', N "- triacetic acid derivative, which has a free carboxylic acid group, with a 1,4,7,10- Tetraazacyclododecan-N, N ', N' '' - triacetic acid derivative, which is a free Has amino group. The free carboxylic acid group or the free amino group can also be activated to facilitate the subsequent amidation reaction. What groups can be used for activation is known, and it can be used, for example, on M. and A. Bodanszky, "The Practice of Peptide Synthesis", Springer Verlag 1984 become. Examples are adducts of carboxylic acids with carbodiimides or activated ones Esters / amides, e.g. B. hydroxybenzotriazoyl esters or imidazolides. In the case of connection of formula V, an alcohol or an ester is preferably used instead of a carboxylic acid derivative the amino compound implemented.

The acetic acid residues of the 1,4,7,10-tetraazacyclododecane-N, N ', N "-triacetic acid derivatives which are not intended to take part in the reaction are advantageously protected by conventional protective groups or are introduced only after the dinuclear compound has formed, as is explained in more detail in the examples, ie all radicals A ¹ , A ² , A ³ , A ^{1 '} , A ^2' and A ^{3 '} preferably contain protected carboxyl groups or amino protecting groups Protective groups used in organic chemistry for protecting carboxyl and amino groups, such as are disclosed, for example, in TW Greene, “Protective Groups in Organic Synthesis”, J. Wiley and Sons, such as BOC groups functional groups can also be protected by conventional protective groups.

If the coupling takes place within the radical B, the radicals B ¹ and B ² are defined such that the coupled radicals B ¹ and B ² give the radical B after the amidation reaction. After coupling by amidation, existing protective groups, in particular the protective groups of the acetic acid functionalities, or also other protective groups present, can be removed in a customary manner, as a result of which the compounds of the formula VIII or the formula II, in which the radicals Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and Z ^{3 'represent} hydrogen atoms. These free acids can then be converted by reaction with a metal compound, preferably with an oxide or salt of a lanthanide, into the compounds of the formula I or II in which the radicals Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^{2 '} or Z ^3' mean a metal ion equivalent.

It is also possible to carry out changes in the radicals R ¹ , R ³ and, if appropriate, R ² and R ^{1 '} , for example introducing or deprotecting hydroxyl groups, etc.

The complex compounds according to the invention are used in particular

• 1. for X-ray and NMR diagnostics in the form of their complexes, in particular with the Ions of elements with atomic numbers 21-29, 39, 42, 44 and 57-83;
• 2. for radio diagnostics and radiotherapy in the form of their complexes, in particular with the radioisotopes of the elements with the atomic numbers 27, 29, 31, 37-39, 43, 49, 62, 64, 70, 75, 77 and 83.
• 3. for neutron capture therapy.

The agents according to the invention are particularly suitable as X-ray contrast agents, and it should be emphasized that they do not show any signs of the anaphylaxis-like reactions known from the iodine-containing contrast agents in biochemical pharmacological studies. The substances according to the invention fulfill the diverse requirements that are to be placed on contrast agents in modern diagnostics. The connections and means produced from them are characterized by

• - a high absorption coefficient for X-rays,
• - good tolerance, which is necessary to the non-invasive nature of the Maintain investigations,
• - A high level of effectiveness that is necessary to keep the body as low as possible Burden quantities of foreign substances,
• - good solubility in water (this allows highly concentrated solutions manufacture as they are particularly suitable for use as X-ray contrast media are necessary, which means that the volume load of the circuit is reasonable Limits can be kept.),
• - a low viscosity,  
• - low osmolality,
• - a favorable excretion rate.

In addition to the surprisingly high water solubility of the metal complexes, which in one for the area required for X-ray diagnostics could be increased, the effect Compounds according to the invention in X-ray diagnostics positively characterized in that the complex compounds according to the invention in particular also studies allow shorter-wave X-rays, thereby reducing the patient's radiation exposure is significantly reduced since it is known that there is a lot of soft radiation from the tissue is more strongly absorbed than hard [R. Felix, "The X-ray picture"; Thieme publishing house Stuttgart (1980)].

Because of the favorable absorption properties of the contrast agents according to the invention in The field of hard X-rays are also particularly useful for digital ones Subtraction techniques (which work with higher tube voltages) are suitable.

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

In general, the agents according to the invention for use as X-ray contrast media in amounts of 0.1-20 mmol / kg body weight, preferably 0.25- 5 mmol / kg body weight dosed.

If they are paramagnetic, the agents according to the invention also fulfill the many Requirements for the suitability as a contrast medium for magnetic resonance imaging. So are they are excellently suited to increase after oral or parenteral application the signal intensity of the image obtained with the aid of an MRI scanner To improve the informative value. They also show the high effectiveness that is necessary to to burden the body with the smallest possible amount of foreign substances and the good Tolerability, which is necessary to the non-invasive nature of the examinations maintain.

In general, the agents according to the invention are used for use as NMR Diagnostics 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. J. of Roentgenology 142, 619 (1984).

Particularly low doses (below 1 mg / kg body weight) of organ-specific NMR diagnostics are, for example, for the detection of tumors and heart attacks used.

Furthermore, the complex compounds according to the invention can advantageously be used as Susceptibility reagents and as shift reagents for in vivo NMR spectroscopy be used.

If the agents according to the invention are radioactive, they are cheap because of their low cost Properties and the good stability of the complex compounds contained in them suitable as radio diagnostics. Details of their application and dosage are e.g. B. in "Radiotracers for Medical Applications", CRC-Press, Boca Raton, Florida.

Another imaging method with radioisotopes is positron emission tomography, the positron emitting isotopes such as. B. ⁴³ Sc, ⁴⁴ Sc, ⁵² Fe, ⁵⁵ Co and ⁶⁶ Ga [Heiss, WD; Phelps, ME; Positron Emission Tomography of Brain, Springer-Verlag Berlin, Heidelberg, New York (1983)].

The compounds according to the invention can also be used in radioimmunotherapy or radiation therapy. This differs from the corresponding diagnostics only in the amount and type of isotope used. The goal is the destruction of tumor cells by high-energy short-wave radiation with the shortest possible range. Suitable β-emitting ions are e.g. B. ⁴⁶ Sc, ⁴⁷ Sc, ⁴⁸ Sc, ⁷² Ga, ⁷³ Ga and ⁹⁰ Y. Suitable α-emitting ions having short half-lives are e.g. B. ²¹¹ Bi, ²¹² Bi, ²¹³ Bi, ²¹⁴ Bi, with ²¹² Bi being preferred. A suitable photon and electron emitting ion is ¹⁵⁸ Gd, which can be obtained from ¹⁵⁷ Gd by neutron capture.

Is the agent according to the invention for use in the RL Mills et. al. [Nature Vol. 336, (1988), p. 787] proposed variant of the radiation therapy, the central ion must be derived from a Mössbauer isotope, such as ⁵⁷ Fe or ¹⁵¹ Eu.

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

The fluorescence properties, in particular of the Eu- and Tb- Complexes can be exploited for near infrared imaging.

The application of the aqueous X-ray and NMR contrast medium solutions can be enteral or parenterally, namely orally, rectally, intravenously, intraarterially, intravascularly, intracutaneously, subcutaneously (Lymphography), subarachnoidal (myelography), the intravenous Application is preferred.

The agents according to the invention not only have a high stability in vitro, but also also a surprisingly high stability in vivo, so that a release or an exchange of the ions which are not covalently bound in the complexes - which are toxic per se - within the Time in which the new contrast agents are completely eliminated again does not take place.

The production of the pharmaceutical or diagnostic agents according to the invention is also carried out in a manner known per se by using the inventive Complex compounds - if necessary with the addition of additives common in galenics - suspended or dissolved in an aqueous medium and then the suspension or solution sterilized if necessary. Suitable additives are, for example, physiological harmless buffers (such as tromethamine), small additions of complexing agents and / or their calcium, magnesium or zinc salts or, if desired, electrolytes (such as sodium chloride) and antioxidants (such as ascorbic acid).

Are suspensions or solutions of enteral administration or other purposes agents according to the invention in water or physiological saline are desired them with one or more auxiliary substances (e.g. methyl cellulose, Lactose, mannitol) and / or surfactant (s) (e.g. lecithins, Tween®, Myrj®) and / or Flavoring (s) for flavor correction (e.g. essential oils) mixed.

In principle, it is also possible to use the pharmaceutical compositions according to the invention without To isolate the complex salts. In any case, special care must be taken used to make the chelation so that the salts of the invention and salt solutions are practically free of non-complexed toxic metal ions.

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

example 1 10,10 '- [3-aza-5-hydroxy-2-oxo-hexan-1,6-diyl] bis [1,4,7-tris- (carboxymethyl) -1,4,7,10 tetraazacyclododecane], di-dysprosium complex 1a) [4,7,10-tris- (tert.butyloxycarbonyl) - (1,4,7,10-tetraazacyclododecan-1-yl)] - acetate

To a suspension of 20.0 g (42.3 mmol) 1,4,7-tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane (see Brandès et al., Bull soc Chim Fr ( 1996) 133, 65) and 5.84 g (42.3 mmol) potassium carbonate in 100 ml acetonitrile are added dropwise 9.69 g (42.3 mmol) benzyl bromoacetate. After stirring overnight at room temperature, the mixture is filtered, the filtrate is evaporated and the residue is purified by chromatography on silica gel (dichloromethane / methanol 95: 5).
Yield: 23.9 g (91% of theory) of colorless oil
Analysis:
calculated:
C 61.91; H 8.44; N 9.03; O 20.62;
found:
C 61.84; H 8.57; N 8.89.

1b) [4,7,10-tris (tert.butyloxycarbonyl) - (1,4,7,10-tetraazacyclododecan-1-yl)] acetic acid

A solution of 22.5 g (36.2 mmol) of [4,7,10-tris (tert-butyloxycarbonyl) - (1,4,7,10-tetraazacyclododecan-1-yl)] benzyl acetate (Example 1a) 2.0 g of palladium on activated carbon (10% Pd) is added to 220 ml of methanol and the mixture is stirred vigorously overnight under a hydrogen atmosphere. It is then filtered and the filtrate evaporated in vacuo.
Yield: 19.2 g (100% of theory) of colorless oil
Analysis:
calculated:
C 56.59; H 8.74 N; 10.56; O 24.12;
found:
C 56.45; H 8.87; N 10.36.

1c) 1- (3-benzyloxycarbonylamino-2-hydroxypropyl) -4,7,10-tris- (tert.butyloxycarbonyl) - 1,4,7,10-tetraazacyclododecane

20.0 g (42.3 mmol) 1,4,7-tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane and 8.77 g (42.3 mmol) 2-benzyloxycarbonylaminomethyl-oxirane ( C. Giordano et al., Eur.J.Med.Chem.Chim.Ther. 25; 6; 1990; 479-487) are stirred under argon at 160 ° C until the reaction is complete (approx. 5 h). The resulting dark oil is then purified chromatographically on silica gel (dichloromethane / methanol 95: 5).
Yield: 17.5 g (61% of theory) of colorless oil
Analysis:
calculated:
C 60.07; H 8.45 N; 10.30; O 21.18;
found:
C 59.91; H 8.59 N; 10.43.

1d) 1- (3-amino-2-hydroxypropyl) -4,7,10-tris- (tert.butyloxycarbonyl) -1,4,7,10- tetraazacyclododecane

A solution of 16.5 g (24.3 mmol) of 1- (3-benzyloxycarbonylamino-2-hydroxypropyl) - 4,7,10-tris (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane in 170 1.7 g of palladium on activated carbon (10% Pd) are added to ml of methanol and the mixture is stirred vigorously overnight under a hydrogen atmosphere. It is then filtered and the filtrate evaporated in vacuo.
Yield: 12.3 g (93% of theory) of colorless oil
Analysis:
calculated:
C 57.22; H 9.42 N; 12.83; O 20.52;
found:
C 57.03; H 9.56 N; 12.68.

1e) 1,1 '- (3-aza-5-hydroxy-2-oxo-hexane-1,6-diyl) -bis- [4,7,10-tris (tert.butyloxycarbonyl) - 1,4,7,10-tetraazacyclododecane]

To a solution of 9.83 g (18.5 mmol) [4,7,10-tris (tert.butyloxycarbonyl) - (1,4,7,10-tetraazacyclododecan-1-yl)] - acetic acid stirred at room temperature (Example 1b) in 50 ml dichloromethane, 2.35 g (20.4 mmol) N-hydroxysuccinimide and 3.82 g (18.5 mmol) dicyclohexylcarbodiimide are added. After one hour, 10.1 g (18.5 mmol) of 1- (3-amino-2-hydroxypropyl) -4,7,10-tris (tert-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane are added (Example 1d) and stirred overnight at room temperature. The precipitated solid is then filtered off, the filtrate is evaporated and the residue is purified by chromatography on silica gel (dichloromethane / methanol 95: 5).
Yield: 17.3 g (88% of theory) of a yellowish oil
Analysis:
calculated:
C 57.88; H 9.05 N; 11.91; O 21.16;
found:
C 57.80; H 9.23 N; 11.76.

1f) 10,10 '- [3-aza-5-hydroxy-2-oxo-hexane-1,6-diyl] -bis- [1,4,7-tris (carboxymethyl) - 1,4,7,10-tetraazacyclododecane]

15.2 g (14.4 mmol) of 1,1 '- (3-aza-5-hydroxy-2-oxo-hexane-1,6-diyl) -bis- [4,7,10-tris- (tert .butyloxycarbonyl) -1,4,7,10-tetraazacyclododecan] are stirred in 90 ml of trifluoroacetic acid overnight at room temperature. Then the solution is evaporated completely in vacuo and the residue is taken up in 100 ml of water. 8.16 g (86.4 mmol) of chloroacetic acid are added and the mixture is stirred at 50 ° C. for 5 h, the pH being adjusted to 9-10 by adding dilute sodium hydroxide solution. The pH is then adjusted to 1 using dilute hydrochloric acid, the mixture is concentrated in vacuo and the residue is applied to a column with an ion exchanger IR 120 (H ⁺ form). It is eluted first with water, then with dilute, aqueous ammonia solution. The fractions containing the product are evaporated and dried in a high vacuum.
Yield: 8.22 g (71% of theory) of a yellowish solid
Molecular weight:
calculated:
805.89
found:
MS (M ⁺ +1) 806

1g) 10,10 '- [3-aza-5-hydroxy-2-oxo-hexane-1,6-diyl] -bis- [1,4,7-tris (carboxymethyl) - 1,4,7,10-tetraazacyclododecane], di-dysprosium complex

4.05 g (5.02 mmol) 10.10 '- [3-aza-5-hydroxy-2-oxo-hexane-1,6-diyl] bis- [1,4,7-tris (carboxymethyl ) -1,4,7,10-tetraazacyclododecane] are stirred together with 1.87 g (5.02 mmol) of dysprosium oxide in 50 ml of water at 80 ° C. for 5 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile 9: 1).
Yield: 4.92 g (87% of theory) of a colorless solid
Analysis:
calculated:
C 35.24; H 4.75; Dy 28.89; N 11.21; O 19.91;
found:
C 35.11; H 4.84; Dy 28.73; N 11.04.

Example 2 10,10 '- [3-aza-5-hydroxy-2-oxo-hexan-1,6-diyl] bis [1,4,7-tris- (carboxymethyl) -1,4,7,10 tetraazacyclododecane], di-gadolinium complex

4.15 g (5.15 mmol) 10.10 '- [3-aza-5-hydroxy-2-oxo-hexane-1,6-diyl] -bis- [1,4,7-tris (carboxymethyl ) -1,4,7,10-tetraazacyclododecane] (Example 1f) are stirred together with 1.87 g (5.02 mmol) of gadolinium oxide in 50 ml of water at 80 ° C. for 2 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile 9: 1).
Yield: 5.22 g (91% of theory) of a colorless solid
Analysis:
calculated:
C 35.57; H 4.79; Gd 28.22; N 11.31; O 20.10;
found:
C 35.46; H 4.96; Gd 28.07; N 11.04.

Example 3 10,10 '- [3-aza-3- (2,3-dihydroxypropyl) -5-hydroxy-2-oxo-hexan-1,6-diyl] bis [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-dysprosium complex 3a) 1- [4-aza-2-hydroxy-5- (2,2-dimethyl-1,3-dioxolan-4-yl) pentyl] -4,7,10-tris- (T-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane

A solution of 15.3 g (28.0 mmol) of 1- (3-amino-2-hydroxypropyl) -4,7,10-tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane (example 1d) in 75 ml of N, N-dimethylformamide with 3.87 g (28.0 mmol) of potassium carbonate and 5.47 g (28.0 mmol) of 4-bromomethyl-2,2-dimethyl-1,3-dioxolane ( G. Fronza, J. Org.Chem. 52; 10; 1987; 2086-2089;). After stirring overnight at room temperature, the mixture is filtered, the filtrate is evaporated in vacuo and the residue is purified by chromatography on silica gel (dichloromethane / methanol / triethylamine 9: 1: 0.05).
Yield: 13.0 g (70% of theory) of a yellowish oil
Analysis:
calculated:
C 58.25; H 9.32; N 10.61; O 21.82;
found:
C 58.14; H 9.35; N 10.62.

3b) 1,1 '- (3-aza-5-hydroxy-3- (2,2-dimethyl-1,3-dioxolan-4-yl) -2-oxo-hexane-1,6-diyl) -bis - [4,7,10-tris (t-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane]

To a solution of 10.9 g (20.0 mmol) of [4,7,10-tris (tert-butyloxycarbonyl) - (1,4,7,10-tetraazacyclododecan-1-yl)] - acetic acid stirred at room temperature (Example 1b) in 50 ml dichloromethane, 4.95 g (20.0 mmol) of 1,2-dihydro-2-ethoxyquinoline-1-carboxylic acid ethyl ester and 13.2 g (20.0 mmol) of 1- [4-aza- 2-hydroxy-5- (2,2-dimethyl-1,3-dioxolan-4-yl) pentyl] -4,7,10-tris- (tert-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane give ge and stirred overnight at room temperature. It is then evaporated and the residue is purified by chromatography on silica gel (dichloromethane / methanol 95: 5).
Yield: 19.2 g (82% of theory) of a yellowish oil
Analysis:
calculated:
C 58.39; H 9.03; N 10.75; O 21.83;
found:
C 58.26; H 9.12; N 10.63.

3c) 10,10 '- (3-aza-5-hydroxy-3- (2,3-dihydroxypropyl) -2-oxo-hexane-1,6-diyl) -bis- [1,4,7- tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane]

17.3 g (14.8 mmol) 1,1 '- (3-aza-5-hydroxy-3- (2,2-dimethyl-1,3-dioxolan-4-yl) -2-oxo-hexane 1,6-diyl) -bis- [4,7,10-tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane] are stirred in 90 ml of trifluoroacetic acid overnight at room temperature. Then the solution is evaporated completely in vacuo and the residue is taken up in 100 ml of water. 8.37 g (88.5 mmol) of chloroacetic acid are added and the mixture is stirred at 50 ° C. for 5 h, the pH being adjusted to 9-10 by adding dilute sodium hydroxide solution. The pH is then adjusted to 1 using dilute hydrochloric acid, the mixture is concentrated in vacuo and the residue is applied to a column with an ion exchanger IR 120 (H ⁺ form). It is eluted first with water, then with dilute, aqueous ammonia solution. The fractions containing the product are evaporated and dried in a high vacuum.
Yield: 8.96 g (69% of theory) of a yellowish solid
Molecular weight:
calculated:
879.97
found:
MS (M ⁺ +1) 880

3d) 10,10 '- (3-aza-5-hydroxy-3- (2,3-dihydroxypropyl) -2-oxo-hexane-1,6-diyl) -bis- [1,4,7- tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-dysprosium complex

4.12 g (4.68 mmol) 10.10 '- (3-aza-5-hydroxy-3- (2,3-dihydroxypropyl) -2-oxo-hexane-1,6-diyl) - bis- [ 1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane] are stirred together with 1.75 g (4.68 mmol) of dysprosium oxide in 50 ml of water at 80 ° C. for 5 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile 9: 1).
Yield: 4.77 g (85% of theory) of a colorless solid
Analysis:
calculated:
C 36.07; H 4.96; Dy 27.11; N 10.51; O 21.35; found:
C 35.89; H 5.07; Dy 26.87; N 10.43.

Example 4 10,10 '- (3-Aza-5-hydroxy-3- (2,3-dihydroxypropyl) -2-oxo-hexan-1,6-diyl) bis [1,4,7-tris- (carboxymethyl) - 1,4,7,10-tetraazacyclododecane], di-gadolinium complex

4.08 g (4.64 mmol) 10.10 '- (3-aza-5-hydroxy-3- (2,3-dihydroxypropyl) -2-oxo-hexane-1,6-diyl) - bis- [ 1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane] (Example 3c) together with 1.68 g (4.64 mmol) of gadolinium oxide in 50 ml of water for 2 hours at 80 ° C. touched. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile 9: 1).
Yield: 4.57 g (83% of theory) of a colorless solid
Analysis:
calculated:
C 36.38; H 5.00; Gd 26.46; N 10.61; O 21.54;
found:
C 36.45; H 5.24; Gd 26.26; N 11.72.

Example 5 10,10 '- (3-aza-8-hydroxy-6-oxa-2-oxo-nonane-1,9-diyl) bis [1,4,7-tris- (carboxymethyl) - 1,4,7,10-tetraazacyclododecane], di-dysprosium complex 5a) (2-Oxiranylmethoxy-ethyl) -carbamic acid benzyl ester

To a stirred solution of 9.83 g (50.4 mmol) (2-hydroxy-ethyl) -carbamic acid benzyl ester (T. Wieland. Et al., Justus Liebigs Ann. Chem., 694; 1966; 38-43) in 50 ml of anhydrous N, N-dimethylformamide are 1.21 g (50.4 mmol) of sodium hydride at 0 ° C and 1 hour later 11.5 g (50.5 mmol) of p-toluenesulfonic acid oxiranyl methyl ester (Y. Gao et al., J .Amer.Chem.Soc. 109; 19; 1987; 5765-5780). After stirring overnight at room temperature, the mixture is evaporated completely in vacuo and the residue is shaken out with ethyl acetate / aqueous sodium bicarbonate solution. The organic phase is separated off, dried over magnesium sulfate and evaporated. The oily residue is purified chromatographically on silica gel (hexane / ethyl acetate gradient).
Yield: 9.11 g (72% of theory) of colorless oil
Analysis:
calculated:
C 62.14; H 6.82; N 5.57; O 25.47;
found:
C 62.23; H 6.77; N 5.60.

5b) 1- (6-benzyloxycarbonylamino-2-hydroxy-4-oxa-hexyl) -4,7,10-tris- (T-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane

20.0 g (42.3 mmol) 1,4,7-tris- (tert-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane and 10.6 g (42.3 mmol) (2-oxiranylmethoxy-ethyl ) Benzyl carbamate are stirred under argon until the reaction is complete at 160 ° C. (about 5 h). The resulting dark oil is then purified chromatographically on silica gel (dichloromethane / methanol 95: 5).
Yield: 16.5 g (54% of theory) of colorless oil
Analysis:
calculated:
C 59.73; H 8.49; N 9.67; O 22.10;
found:
C 59.82; H 8.61; N 9.48.

5c) 1- (6-amino-2-hydroxy-4-oxa-hexyl) -4,7,10-tris- (tert.butyloxycarbonyl) -1,4,7,10- tetraazacyclododecane

A solution of 15.5 g (21.4 mmol) of 1- (6-benzyloxycarbonylamino-2-hydroxy-4-oxa-hexyl) - 4,7,10-tris- (tert.butyloxycarbonyl) -1,4,7 , 10-tetraazacyclododecane in 150 ml of methanol is mixed with 1.5 g of palladium on activated carbon (10% Pd) and stirred vigorously under a hydrogen atmosphere overnight. It is then filtered and the filtrate evaporated in vacuo.
Yield: 12.0 g (95% of theory) of colorless oil
Analysis:
calculated:
C 57.02; H 9.40; N 11.87; O 21.70;
found:
C 57.23; H 9.45; N 11.65.

5d) 1,1 '- (3-aza-8-hydroxy-6-oxa-2-oxo-nonane-1,9-diyl) -bis- [4,7,10-tris- (T-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane]

To a solution of 9.98 g (18.8 mmol) [4,7,10-tris (tert.butyloxycarbonyl) - (1,4,7,10-tetraazacyclododecan-1-yl)] - acetic acid stirred at room temperature (Example 1b) in 50 ml of dichloromethane, 2.38 g (20.7 mmol) of N-hydroxysuccinimide and 3.88 g (18.8 mmol) of dicyclohexylcarbodiimide are added. After one hour, 11.1 g (18.8 mmol) of 1- (6-amino-2-hydroxy-4-oxa-hexyl) -4,7,10-tris- (tert.butyloxycarbonyl) -1.4 are added , 7,10-tetraazacyclododecane and stirred overnight at room temperature. The precipitated solid is then filtered off, the filtrate is evaporated and the residue is purified by chromatography on silica gel (dichloromethane / methanol 95: 5).
Yield: 17.4 g (84% of theory) of a yellowish oil
Analysis:
calculated:
C 57.74; H 9.05; N 11.43; O 21.77;
found:
C 57.63; H 9.22; N 11.51.

5e) 10,10 '- (3-aza-8-hydroxy-6-oxa-2-oxo-nonane-1,9-diyl) -bis- [1,4,7-tris (carboxymethyl) - 1,4,7,10-tetraazacyclododecane]

18.0 g (16.3 mmol) 1,1 '- (3-aza-8-hydroxy-6-oxa-2-oxo-nonan-1,9-diyl) -bis- [4,7,10- tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane] are stirred in 100 ml of trifluoroacetic acid overnight at room temperature. Then the solution is evaporated completely in vacuo and the residue is taken up in 100 ml of water. 9.2 g (97.8 mmol) of chloroacetic acid are added and the mixture is stirred at 50 ° C. for 5 h, the pH being adjusted to 9-10 by adding dilute sodium hydroxide solution. The pH is then adjusted to 1 using dilute hydrochloric acid, the mixture is concentrated in vacuo and the residue is applied to a column with an ion exchanger IR 120 (H ⁺ form). It is eluted first with water, then with dilute, aqueous ammonia solution. The fractions containing the product are evaporated and dried in a high vacuum.
Yield: 10.5 g (76% of theory) of a yellowish solid
Molecular weight:
calculated:
849.94
found:
MS (M ⁺ +1) 850

5f) 10,10 '- (3-aza-8-hydroxy-6-oxa-2-oxo-nonane-1,9-diyl) -bis- [1,4,7-tris (carboxymethyl) - 1,4,7,10-tetraazacyclododecane], di-dysprosium complex

5.02 g (5.88 mmol) 10.10 '- (3-aza-8-hydroxy-6-oxa-2-oxo-nonan-1,9-diyl) -bis- [1,4,7- tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane] are stirred together with 2.19 g (5.88 mmol) of dysprosium oxide in 50 ml of water at 80 ° C. for 5 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile 9: 1).
Yield: 6.12 g (89% of theory) of a colorless solid
Analysis:
calculated:
C 35.96; H 4.92; Dy 27.80; N 10.78; O 20.53;
found:
C 36.11; H 5.13; Dy 27.65; N 10.61.

Example 6 10,10 '- (3-aza-8-hydroxy-6-oxa-2-oxo-nonane-1,9-diyl) bis [1,4,7-tris- (carboxymethyl) - 1,4,7,10-tetraazacyclododecane], di-gadolinium complex

2.50 g (2.94 mmol) 10.10 '- (3-aza-8-hydroxy-6-oxa-2-oxo-nonan-1,9-diyl) -bis- [1,4,7- tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane] (Example 5e) are stirred together with 1.07 g (2.94 mmol) of gadolinium oxide in 50 ml of water at 80 ° C. for 5 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile 9: 1).
Yield: 3.13 g (92% of theory) of a colorless solid
Analysis:
calculated:
C 36.29; H 4.96; Gd 27.15; N 10.88; O 20.72;
found:
C 36.42; H 5.03; Gd 27.01; N 10.96.

Example 7 10,10 '- (3-Aza-5-hydroxy-3- (2-hydroxyethyl) -2-oxo-hexan-1,6-diyl) bis [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-dysprosium complex 7a) 1- [4-aza-2,6-dihydroxyhexyl)] - 4,7,10-tris- (tert.butyloxycarbonyl) -1,4,7,10- tetraazacyclododecane

A solution of 16.4 g (30.0 mmol) of 1- (3-amino-2-hydroxypropyl) -4,7,10-tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane (example 1d) in 75 ml of N, N-dimethylformamide, 4.15 g (30.0 mmol) of potassium carbonate and 2.41 g (30.0 mmol) of 2-chloroethanol are added. After stirring overnight at room temperature, the mixture is filtered, the filtrate is evaporated in vacuo and the residue is purified by chromatography on silica gel (dichloromethane / methanol / triethylamine 9: 1: 0.05).
Yield: 13.1 g (74% of theory) of a yellowish oil
Analysis:
calculated:
C 57.02; H 9.40; N 11.87; O 21.70;
found:
C 57.19; H 9.63; N 11.65.

7b) 1,1 '- (3-aza-5-hydroxy-3- (2-hydroxyethyl) -2-oxo-hexane-1,6-diyl) -bis- [4,7,10-tris- (T-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane]

To a solution of 10.9 g (20.0 mmol) of [4,7,10-tris (tert-butyloxycarbonyl) - (1,4,7,10-tetraazacyclododecan-1-yl)] - acetic acid stirred at room temperature (Example 1b) in 50 ml dichloromethane, 4.95 g (20.0 mmol) of 1,2-dihydro-2-ethoxyquinoline-1-carboxylic acid ethyl ester and 11.8 g (20.0 mmol) of 1- [4-aza- 2,6-dihydroxy-hexyl)] - 4,7,10-tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane and stirred overnight at room temperature. It is then evaporated and the residue is purified by chromatography on silica gel (dichloromethane / methanol 95: 5).
Yield: 17.2 g (78% of theory) of a yellowish oil
Analysis:
calculated:
C 57.74; H 9.05; N 11.43; O 21.77;
found:
C 57.77; H 9.28; N 11.30.

7c) 10,10 '- (3-aza-5-hydroxy-3- (2-hydroxyethyl) -2-oxo-hexane-1,6-diyl) -bis- [1,4,7-tris (Carboxymethyl) -1,4,7,10-tetraazacyclododecane]

16.5 g (15.0 mmol) of 1,1 '- (3-aza-5-hydroxy-3- (2-hydroxyethyl) -2-oxo-hexane-1,6-diyl) -bis- [4, 7,10-tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane] are stirred in 90 ml trifluoroacetic acid overnight at room temperature. Then the solution is evaporated completely in vacuo and the residue is taken up in 100 ml of water. 8.49 g (89.8 mmol) of chloroacetic acid are added and the mixture is stirred at 50 ° C. for 5 h, the pH being adjusted to 9-10 by adding dilute sodium hydroxide solution. The pH is then adjusted to 1 using dilute hydrochloric acid, the mixture is concentrated in vacuo and the residue is applied to a column with an ion exchanger IR 120 (H ⁺ form). It is eluted first with water, then with dilute, aqueous ammonia solution. The fractions containing the product are evaporated and dried in a high vacuum.
Yield: 8.14 g (64% of theory) of a yellowish solid
Molecular weight:
calculated:
849.94
found:
MS (M ⁺ +1) 850

7d) 10,10 '- (3-aza-5-hydroxy-3- (2-hydroxyethyl) -2-oxo-hexane-1,6-diyl) -bis- [1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-dysprosium complex

6.13 g (7.21 mmol) 10.10 '- (3-aza-5-hydroxy-3- (2-hydroxyethyl) -2-oxo-hexane-1,6-diyl) -bis- [1, 4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane] are stirred together with 2.69 g (7.21 mmol) of dysprosium oxide in 50 ml of water at 80 ° C. for 5 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile 9: 1).
Yield: 7.33 g (87% of theory) of a colorless solid
Analysis:
calculated:
C 35.96; H 4.92; Dy 27.80; N 10.78; O 20.53;
found:
C 36.10; H 5.12; Dy 27.71; N 10.92.

Example 8 10,10 '- (3-Aza-5-hydroxy-3- (2-hydroxyethyl) -2-oxo-hexan-1,6-diyl) bis [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-gadolinium complex

1.23 g (1.45 mmol) 10.10 '- (3-aza-5-hydroxy-3- (2-hydroxyethyl) -2-oxo-hexane-1,6-diyl) -bis- [1, 4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane] (Example 7c) are stirred together with 0.52 g (1.45 mmol) of gadolinium oxide in 20 ml of water at 80 ° C. for 2 hours. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile 9: 1).
Yield: 1.48 g (88% of theory) of a colorless solid
Analysis:
calculated:
C 36.29; H 4.96; Gd 27.15; N 10.88; O 20.72;
found:
C 36.14; H 5.11; Gd 27.20; N 10.76.

Example 9 10,10 '- (3-Aza-5-hydroxy-3- (2-methoxyethyl) -2-oxo-hexan-1,6-diyl) bis [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-dysprosium complex 9a) 1,1 '- (3-aza-5-hydroxy-3- (2-methoxyethyl) -2-oxo-hexane-1,6-diyl) -bis- [4,7,10-tris- (T-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane]

To a solution of 20.2 g (18.3 mmol) of 1,1 '- (3-aza-5-hydroxy-3- (2-hydroxyethyl) - stirred in 100 ml of anhydrous N, N-dimethylformamide at 0 ° C 2-oxo-hexane-1,6-diyl) -bis- [4,7,10-tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane] (Example 7b) 0.48 g ( 20.2 mmol) of sodium hydride and, after 1 hour, 2.86 g (20.2 mmol) of methyl iodide. After stirring overnight at room temperature, the mixture is evaporated in vacuo and the residue is purified by chromatography on silica gel (dichloromethane / methanol 95: 5).
Yield: 12.9 g (63% of theory) of a yellowish oil
Analysis:
calculated:
C 58.08; H 9.12; N 11.29; O 21.50;
found:
C 58.24; H 8.89; N 11.13.

9b) 10,10 '- (3-aza-5-hydroxy-3- (2-methoxyethyl) -2-oxo-hexane-1,6-diyl) -bis- [1,4,7-tris (Carboxymethyl) 1,4,7,10-tetraazacyclododecane]

12.5 g (11.2 mmol) of 1,1 '- (3-aza-5-hydroxy-3- (2-methoxyethyl) -2-oxo-hexane-1,6-diyl) -bis- [4, 7,10-tris (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane] are stirred in 60 ml trifluoroacetic acid overnight at room temperature. The solution is then evaporated completely in vacuo and the residue is taken up in 80 ml of water. 6.35 g (67.2 mmol) of chloroacetic acid are added and the mixture is stirred at 50 ° C. for 5 h, the pH being adjusted to 9-10 by adding dilute sodium hydroxide solution. The pH is then adjusted to 1 using dilute hydrochloric acid, the mixture is concentrated in vacuo and the residue is applied to a column with an ion exchanger IR 120 (H ⁺ form). It is eluted first with water, then with dilute, aqueous ammonia solution. The fractions containing the product are evaporated and dried in a high vacuum.
Yield: 6.67 g (69% of theory) of a yellowish solid
Molecular weight:
calculated:
863.97
found:
MS (M ⁺ +1) 864

9c) 10,10 '- (3-aza-5-hydroxy-3- (2-methoxyethyl) -2-oxo-hexane-1,6-diyl) -bis- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-dysprosium complex

5.04 g (5.83 mmol) 10.10 '- (3-aza-5-hydroxy-3- (2-methoxyethyl) -2-oxo-hexane-1,6-diyl) -bis- [1, 4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane] are stirred together with 2.17 g (5.83 mmol) of dysprosium oxide in 50 ml of water at 80 ° C. for 5 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile 9: 1).
Yield: 6.34 g (92% of theory) of a colorless solid
Analysis:
calculated:
C 36.55; H 5.03; Dy 27.47; N 10.66; O 20.29;
found:
C 36.10; H 5.12; Dy 27.71; N 10.92.

Example 10 10,10 '- (3-Aza-5-hydroxy-3- (2-methoxyethyl) -2-oxo-hexan-1,6-diyl) bis [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-gadolinium complex

1.19 g (1.37 mmol) 10.10 '- (3-aza-5-hydroxy-3- (2-methoxyethyl) -2-oxo-hexane-1,6-diyl) -bis- [1, 4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane] (Example 9b) are stirred together with 0.50 g (1.37 mmol) of gadolinium oxide in 20 ml of water at 80 ° C. for 2 hours. It is then filtered, the filtrate is concentrated in vacuo and purified by chromatography on silica gel RP-18 (water / acetonitrile 9: 1).
Yield: 1.37 g (85% of theory) of a colorless solid
Analysis:
calculated:
C 36.88; H 5.07; Gd 26.82; N 10.75; O 20.47;
found:
C 36.76; H 5.32; Gd 26.63; N 10.54.

Example 11 10- {2- {4- [4,7,10-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecyl)] - 1-aza-3-hydroxybutyl} - 3,4-dioxo-1-cyclobutenyl} - (1,4,7,10-tetraazacyclododecan-1,4,7-triyl) -triacetic acid, di-Ga dolinium complex

6.30 g (10.1 mmol) 10- (2-ethoxy-3,4-dioxo-1-cyclobutenyl) - (1,4,7,10-tetraazacyclododecane-1,4,7-triyl) -triacetic acid, Gadolinium complex (S. Aime, Bioconjugate Chem. 1999, 10, 192) and 5.79 g (10.1 mmol) [10- (3-amino-2-hydroxypropyl) - (1,4,7,10- tetraazacyclododecane-1,4,7-triyl) -triacetic acid, gadolinium complex (WO 96/02669) are stirred in 50 ml of water overnight at room temperature. The solution is then concentrated in vacuo and purified by chromatography on silica gel RP-18 (water / acetonitrile 9: 1).
Yield: 7.10 g (61% of theory) of a colorless solid
Analysis:
calculated:
C 36.48; H 4.46; Gd 27.29; N 10.94; O 20.83;
found:
C 36.33; H 5.57; Gd 26.98; N 10.75.

Example 12 10,10 '- [3,6-diaza-8-hydroxy-2,5-dioxo-nonane-1,9-diyl] bis [1,4,7-tris- (carboxymethyl) - 1,4,7,10-tetraazacyclododecane], di-dysprosium complex a) 1- (4-Aza-6-benzyloxycarbonylamino-2-hydroxy-5-oxo-hexyl) -4,7,10-tris- (T-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane

5.6 g (10 mmol) of 1- (3-amino-2-hydroxypropyl) -4,7,10-tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane (Example 1d) are obtained in 35 ml dichloromethane dissolved and mixed with 3.06 g (10 mmol) NZ-glycine (N-hydroxy-succinimide) ester. The mixture is stirred at room temperature overnight and then filtered. The crude product is chromatographed on silica gel for purification.
Yield: 6.2 g (82% of theory) of a yellowish oil
Analysis:
calculated:
C 59.02; H 8.57; N 11.16; O 21.25;
found:
C 58.87; H 8.69; N 11.02.

b) 1- (6-amino-4-aza-2-hydroxy-5-oxo-hexyl) -4,7,10-tris- (tert.butyloxycarbonyl) - 1,4,7,10-tetraazacyclododecane

A solution of 6.1 g (8.1 mmol) of 1- (4-aza-6-benzyloxycarbonylamino-2-hydroxy-5-oxohexyl) -4,7,10-tris- (tert.butyloxycarbonyl) -1 , 4,7,10-tetraazacyclododecane (Example 12a) in 80 ml of methanol is mixed with 0.6 g of palladium on activated carbon (10% Pd) and stirred vigorously under a hydrogen atmosphere overnight. It is then filtered and the filtrate evaporated in vacuo.
Yield: 4.8 g (96% of theory) of colorless oil
Analysis:
calculated:
C 56.29; H 9.45; N 13.58; O 20.68;
found:
C 56.14; H 9.48; N 13.41.

c) 10,10 '- [3,6-diaza-8-hydroxy-2,5-dioxo-nonane-1,9-diyl] -bis- [1,4,7-tris (T-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane]

To a solution of 4.05 g (7.4 mmol) [4,7,10-tris (tert.butyloxycarbonyl) - (1,4,7,10-tetraazacyclododecan-1-yl)] - acetic acid stirred at room temperature (Example 1b) in 40 ml of dichloromethane, 0.93 g (8.1 mmol) of N-hydroxysuccinimide and 1.53 g (7.4 mmol) of dicyclohexylcarbodiimide are added. After one hour, 4.58 g (7.4 mmol) of 1- (6-amino-4-aza-2-hydroxy-5-oxo-hexyl) -4,7,10-tris- (tert.butyloxycarbonyl) are added -1,4,7,10- tetraazacyclododecane (Example 12b) and stirred overnight at room temperature. The precipitated solid is then filtered off, the filtrate is evaporated and the residue is purified by chromatography on silica gel (dichloromethane / methanol).
Yield: 7.6 g (89% of theory) of a yellowish oil
Analysis:
calculated:
C 57.57; H 9.31; N 12.21; O 20.91;
found:
C 57.41; H 9.40; N 12.13.

d) 10,10 '- [3,6-diaza-8-hydroxy-2,5-dioxo-nonane-1,9-diyl] -bis- [1,4,7-tris (Carboxymethyl) -1,4,7,10-tetraazacyclododecane]

5.5 g (4.8 mmol) 10.10 '- [3,6-diaza-8-hydroxy-2,5-dioxo-nonan-1,9-diyl] -bis- [1,4,7- tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane] (Example 12c) are stirred in 35 ml trifluoroacetic acid overnight at room temperature. The solution is then evaporated completely in vacuo and the residue is taken up in 40 ml of water. 2.72 g (28.8 mmol) of chloroacetic acid are added and the mixture is stirred at 55 ° C. for 7 h, the pH being adjusted to 9-10 by adding dilute sodium hydroxide solution. The pH is then adjusted to 1 using dilute hydrochloric acid, the mixture is concentrated in vacuo and the residue is applied to a column with an ion exchanger IR 120 (H ⁺ form). It is eluted first with water, then with dilute, aqueous ammonia solution. The fractions containing the product are evaporated and dried in a high vacuum.
Yield: 3.7 g (86% of theory) of a yellowish solid
Analysis:
calculated:
C 49.65; H 7.88; N 15.65; O 26.81;
found:
C 49.52; H 7.94; N 15.57.

e) 10,10 '- [3,6-diaza-8-hydroxy-2,5-dioxo-nonane-1,9-diyl] -bis- [1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-dysprosium complex

3.5 g (3.9 mmol) 10.10 '- [3,6-diaza-8-hydroxy-2,5-dioxo-nonane-1,9-diyl] -bis- [1,4,7- tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane] (Example 12d) are stirred together with 1.46 g (3.9 mmol) of dysprosium oxide in 30 ml of water at 85 ° C. for 6 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile).
Yield: 4.4 g (93% of theory) of a colorless solid
Analysis:
calculated:
C 36.61; H 5.31; Dy 26.77; N 11.54; O 19.77;
found:
C 36.48; H 5.24; Dy 26.61; N 11.38.

Example 13 10,10 '- [3,6-diaza-8-hydroxy-2,5-dioxo-nonane-1,9-diyl] bis [1,4,7-tris- (carboxymethyl) - 1,4,7,10-tetraazacyclododecane], di-gadolinium complex

3.5 g (3.9 mmol) 10.10 '- [3,6-diaza-8-hydroxy-2,5-dioxo-nonane-1,9-diyl] -bis- [1,4,7- tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane] (Example 12d) are stirred together with 1.41 g (3.9 mmol) of gadolinium oxide in 35 ml of water at 90 ° C. for 4 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile).
Yield: 4.2 g (89% of theory) of a colorless solid
Analysis:
calculated:
C 36.93; H 5.36; Gd 26.13; N 11.64; O 19.94;
found:
C 36.79; H 5.43; Gd 26.00; N 11.51.

Example 14 10,10 '- [3,6-diaza-8-hydroxy-4-hydroxymethyl-2,5-dioxo-nonane-1,9-diyl] bis [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-dysprosium complex a) 1- (4-Aza-6-benzyloxycarbonylamino-2-hydroxy-6-hydroxymethyl-5-oxo-hexyl) - 4,7,10-tris (t-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane

1.9 g (16.5 mmol) of N-hydroxysuccinimide and 3.09 g (15 mmol) of dicyclohexylcarbodiimide are added to a solution of 3.6 g (15 mmol) of NZ serine in 65 ml of dichloromethane which is stirred at room temperature. After one hour, 8.43 g (15 mmol) of 1- (3-amino-2-hydroxypropyl) -4,7,10-tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane (example 1d) and stirred for 15 hours at room temperature. The precipitated solid is filtered off, the filtrate is evaporated and the residue is purified by chromatography on silica gel (dichloromethane / methanol).
Yield: 9.8 g (83% of theory) of a yellowish oil
Analysis:
calculated:
C 58.29; H 8.50; N 10.73; O 22.48;
found:
C 58.12; H 8.61; N 10.57.

b) 1- (6-Amino-4-aza-2-hydroxy-6-hydroxymethyl-5-oxo-hexyl) -4,7,10-tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane 1

A solution of 9.4 g (12 mmol) of 1- (4-aza-6-benzyloxycarbonylamino-2-hydroxy-6-hydroxymethyl-5-oxo-hexyl) -4,7,10-tris- (tert.butyloxycarbonyl) -1,4,7,10- tetraazacyclododecane (Example 14a) in 100 ml of methanol is mixed with 0.9 g of palladium on activated carbon (10% Pd) and stirred vigorously under a hydrogen atmosphere overnight. It is then filtered and the filtrate evaporated in vacuo.
Yield: 7.4 g (95% of theory) of colorless oil
Analysis:
calculated:
C 55.53; H 9.32; N 12.95; O 22.19;
found:
C 55.32; H 9.27; N 12.76.

c) 10,10 '- [3,6-diaza-8-hydroxy-4-hydroxymethyl-2,5-dioxo-nonane-1,9-diyl] -bis- [1,4,7- tris- (t-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane]

To a solution of 5.47 g (10 mmol) [4,7,10-tris- (tert.butyloxycarbonyl) - (1,4,7,10-tetraazacyclododecan-1-yl)] - acetic acid (example 1b) 1.27 g (11 mmol) of N-hydroxysuccinimide and 2.06 g (10 mmol) of dicyclohexylcarbodiimide are added to 65 ml of dichloromethane. After one hour, 6.49 g (10 mmol) of 1- (6-amino-4-aza-2-hydroxy-6-hydroxymethyl-5-oxo-hexyl) -4,7,10-tris- (tert. butyloxycarbonyl) - 1,4,7,10-tetraazacyclododecane (Example 14b) and stirred overnight at room temperature. The precipitated solid is then filtered off, the filtrate is evaporated and the residue is purified by chromatography on silica gel (dichloromethane / methanol).
Yield: 9.6 g (81% of theory) of a yellowish oil
Analysis:
calculated:
C 57.12; H 9.24; N 11.89; O 21.74;
found:
C 56.99; H 9.31; N 11.96.

d) 10,10 '- [3,6-diaza-8-hydroxy-4-hydroxymethyl-2,5-dioxo-nonane-1,9-diyl] -bis- [1,4,7- tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane]

9.4 g (8 mmol) 10.10 '- [3,6-diaza-8-hydroxy-4-hydroxymethyl-2,5-dioxo-nonane-1,9-diyl] -bis- [1,4, 7-tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane] (Example 14c) are stirred in 55 ml trifluoroacetic acid overnight at room temperature. The solution is then evaporated completely in vacuo and the residue is taken up in 70 ml of water. 4.54 g (48 mmol) of chloroacetic acid are added and the mixture is stirred at 60 ° C. for 6 h, the pH being adjusted to 9-10 by adding dilute sodium hydroxide solution. The pH is then adjusted to 1 using dilute hydrochloric acid, the mixture is concentrated in vacuo and the residue is applied to a column with an ion exchanger IR 120 (H ⁺ form). It is eluted first with water, then with dilute, aqueous ammonia solution. The fractions containing the product are evaporated and dried in a high vacuum.
Yield: 6.9 g (93% of theory) of a yellowish solid
Analysis:
calculated:
C 49.34; H 7.85; N 15.14; O 27.67;
found:
C 49.19; H 7.93; N 15.02.

f) 10,10 '- [3,6-diaza-8-hydroxy-4-hydroxymethyl-2,5-dioxo-nonane-1,9-diyl] -bis- [1,4,7- tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-dysprosium complex

6.7 g (7.2 mmol) 10.10 '- (3,6-diaza-8-hydroxy-4-hydroxymethyl-2,5-dioxo-nonane-1,9-diyl] - bis- [1, 4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane] (Example 14d) are stirred together with 2.7 g (7.2 mmol) of dysprosium oxide in 50 ml of water at 85 ° C. for 5 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile).
Yield: 7.9 g (88% of theory) of a colorless solid
Analysis:
calculated:
C 36.69; H 5.35; Dy 26.13; N 11.26; O 20.58;
found:
C 36.51; H 5.44; Dy 26.02; N 11.17.

Example 15 10,10 '- [3,6-diaza-8-hydroxy-4-hydroxymethyl-2,5-dioxo-nonane-1,9-diyl] bis [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-gadolinium complex

5.6 g (6.1 mmol) 10.10 '- [3,6-diaza-8-hydroxy-4-hydroxymethyl-2,5-dioxo-nonane-1,9-diyl] - bis- [1, 4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane] (Example 14d) are stirred together with 2.21 g (6.1 mmol) of gadolinium oxide in 55 ml of water at 85 ° C. for 5 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile).
Yield: 6.9 g (92% of theory) of a colorless solid
Analysis:
calculated:
C 37.00; H 5.39; Gd 25.50; N 11.36; O 20.75;
found:
C 36.84; H 5.32; Gd 25.37; N 11.22.

Example 16 10,10 '- [3,6-diaza-8-hydroxy-4-methoxymethyl-2,5-dioxo-nonane-1,9-diyl] bis [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-dysprosium complex a) 10,10 '- [3,6-diaza-8-hydroxy-4-methoxymethyl-2,5-dioxo-nonane-1,9-diyl] -bis- [1,4,7- tris- (t-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane]

9.4 g (8 mmol) 10.10 '- [3,6-diaza-8-hydroxy-4-hydroxymethyl-2,5-dioxo-nonane-1,9-diyl] -bis- [1,4, 7-tris (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane] (Example 14c) are dissolved in 25 ml of anhydrous dioxane and 0.77 g (32 mmol) of sodium hydride are added. After 15 minutes, 1.14 g (8 mmol) of methyl iodide are added and the mixture is stirred at 40 ° C. for 2 hours. The mixture is then filtered, evaporated to dryness and the residue taken up in ethyl acetate. The organic phase is washed with dilute hydrochloric acid, with saturated sodium chloride solution and the organic phase is dried over sodium sulfate. The crude product obtained after evaporation is chromatographed on silica gel.
Yield: 1.4 g (15% of theory) of yellow solid
Analysis:
calculated:
C 57.46; H 9.31; N 11.75; O 21.48;
found:
C 57.29; H 9.18; N 11.64.

b) 10,10 '- [3,6-diaza-8-hydroxy-4-methoxymethyl-2,5-dioxo-nonane-1,9-diyl] -bis- [1,4,7- tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane]

1.2 g (1 mmol) 10.10 '- [3,6-diaza-8-hydroxy-4-methoxymethyl-2,5-dioxo-nonane-1,9-diyl] -bis- [1,4, 7-tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane] (Example 16a) are stirred in 20 ml of trifluoroacetic acid overnight at room temperature. The solution is then evaporated completely in vacuo and the residue is taken up in 15 ml of water. 0.57 g (6 mmol) of chloroacetic acid are added and the mixture is stirred at 55 ° C. for 8 h, the pH being adjusted to 9-10 by adding dilute sodium hydroxide solution. The pH is then adjusted to 1 using dilute hydrochloric acid, the mixture is concentrated in vacuo and the residue is applied to a column with an ion exchanger IR 120 (H ⁺ form). It is eluted first with water, then with dilute, aqueous ammonia solution: the fractions containing the product are evaporated and dried in a high vacuum.
Yield: 0.8 g (85% of theory) of a yellowish solid
Analysis:
calculated:
C 49.88; H 7.94; N 14.92; O 27.26;
found:
C 49.64; H 7.99; N 15.06.

c) 10,10 '- [3,6-diaza-8-hydroxy-4-methoxymethyl-2,5-dioxo-nonane-1,9-diyl] -bis- [1,4,7- tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-dysprosium complex

0.7 g (0.7 mmol) 10.10 '- [3,6-diaza-8-hydroxy-4-methoxymethyl-2,5-dioxo-nonane-1,9-diyl] bis- [1.4 , 7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane] (Example 16b) are stirred together with 0.27 g (0.7 mmol) of dysprosium oxide in 15 ml of water at 85 ° C. for 5 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile).
Yield: 0.8 g (91% of theory) of a colorless solid
Analysis:
calculated:
C 37.24; H 5.45; Dy 25.83; N 11.13; O 20.35;
found:
C 37.04; H 5.53; Dy 25.70; N 11.07.

Example 17 10,10 '- [3,6-diaza-8-hydroxy-4-methoxymethyl-2,5-dioxo-nonane-1,9-diyl] bis (1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-gadolinium complex

0.6 g (0.6 mmol) 10.10 '- [3,6-diaza-8-hydroxy-4-methoxymethyl-2,5-dioxo-nonane-1,9-diyl] - bis- [1, 4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane] (Example 16b) are stirred together with 0.22 g (0.6 mmol) of gadolinium oxide in 10 ml of water at 80 ° C. for 5 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile).
Yield: 0.7 g (93.5% of theory) of a colorless solid
Analysis:
calculated:
C 37.55; H 5.49; Gd 25.21; N 11.23; O 20.52;
found:
C 37.39; H 5.55; Gd 25.11; N 11.29.

Example 18 10,10 '- [3,6-diaza-8-hydroxy-3-methyl-2,5-dioxo-nonane-1,9-diyl] bis (1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-dysprosium complex a) 1- (4-Aza-6-benzyloxycarbonyl- (N-methyl) -amino-2-hydroxy-5-oxo-hexyl) -4,7,10-tris- (T-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane

8.4 g (15 mmol) are dissolved in 55 ml of dichloromethane and mixed with 4.8 g (15 mmol) of NZ sarcosine (N-hydroxy-succinimide) ester. The mixture is stirred at room temperature overnight and then filtered. The crude product is chromatographed on silica gel for purification.
Yield: 10.6 g (92% of theory) of a yellowish oil
Analysis:
calculated:
C 59.51; H 8.67; N 10.96; O 20.86;
found:
C 59.37; H 8.74; N 10.84.

b) 1- (6-methylamino-4-aza-2-hydroxy-5-oxo-hexyl) -4,7,10-tris- (tert.butyloxycarbonyl) - 1,4,7,10-tetraazacyclododecane

A solution of 10.2 g (13.3 mmol) of 1- (4-aza-6-benzyloxycarbonyl- (N-methyl) amino-2-hydroxy-5-oxo-hexyl) -4,7,10-tris - (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane (Example 18a) in 95 ml of methanol is mixed with 1.0 g of palladium on activated carbon (10% Pd) and stirred vigorously under a hydrogen atmosphere overnight. It is then filtered and the filtrate evaporated in vacuo.
Yield: 8.0 g (95% of theory) colorless oil
Analysis:
calculated:
C 56.94; H 9.56; N 13.28; O 20.23;
found:
C 56.76; H 9.69; N 13.07.

c) 10,10 '- [3,6-diaza-8-hydroxy-3-methyl-2,5-dioxo-nonane-1,9-diyl] -bis- (1,4,7-tris (T-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane]

To a solution of 6.6 g (12 mmol) [4,7,10-tris- (tert.butyloxycarbonyl) - (1,4,7,10-tetraazacyclododecan-1-yl)] - acetic acid (example 1b) 3.05 g (12 mmol) of EEDQ are added to 70 ml of dichloromethane. After half an hour, 7.59 g (12 mmol) of 1- (6-methylamino-4-aza-2-hydroxy-5-oxo-hexyl) -4,7,10-tris- (tert.butyloxycarbonyl) - 1,4,7,10-tetraazacyclododecane (Example 18b) and stirred overnight at room temperature. The precipitated solid is then filtered off, the filtrate is evaporated and the residue is purified by chromatography on silica gel (dichloromethane / methanol).
Yield: 9.9 g (71% of theory) of a yellowish oil
Analysis:
calculated:
C 57.91; H 9.37; N 12.06; O 20.66;
found:
C 57.72; H 9.45; N 11.87.

d) 10,10 '- [3,6-diaza-8-hydroxy-3-methyl-2,5-dioxo-nonan-1,9-diyl] -bis- [1,4,7-tris- (Carboxymethyl) -1,4,7,10-tetraazacyclododecane]

9.5 g (8.2 mmol) 10.10 '- [3,6-diaza-8-hydroxy-3-methyl-2,5-dioxo-nonan-1,9-diyl] -bis- [1, 4,7-tris (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane] (Example 18c) are stirred in 35 ml of trifluoroacetic acid for 15 hours at room temperature. The solution is then evaporated completely in vacuo and the residue is taken up in 35 ml of water. 4.6 g (49.1 mmol) of chloroacetic acid are added and the mixture is stirred at 60 ° C. for 9 h, the pH being adjusted to 9-10 by adding dilute sodium hydroxide solution. The pH is then adjusted to 1 using dilute hydrochloric acid, the mixture is concentrated in vacuo and the residue is applied to a column with an ion exchanger IR 120 (H ⁺ form). It is eluted first with water, then with dilute, aqueous ammonia solution. The fractions containing the product are evaporated and dried in a high vacuum.
Yield: 7.0 g (94% of theory) of a yellowish solid
Analysis:
calculated:
C 50.21; H 7.98; N 15.41; O 26.40;
found:
C 50.03; H 8.11; N 15.27.

e) 10,10 '- [3,6-diaza-8-hydroxy-3-methyl-2,5-dioxo-nonane-1,9-diyl] -bis- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-dysprosium complex

3.4 g (3.7 mmol) 10.10 '- [3,6-diaza-8-hydroxy-3-methyl-2,5-dioxo-nonan-1,9-diyl] -bis- [1, 4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane] (Example 18d) are stirred together with 1.39 g (3.7 mmol) of dysprosium oxide in 35 ml of water at 80 ° C. for 7 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile).
Yield: 4.2 g (92% of theory) of a colorless solid
Analysis:
calculated:
C 37.17; H 5.42; Dy 26.47; N 11.41; O 19.54;
found:
C 36.98; H 5.60; Dy 26.24; N 11.19.

Example 19 10,10 '- [3,6-diaza-8-hydroxy-3-methyl-2,5-dioxo-nonane-1,9-diyl] bis [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-gadolinium complex

3.4 g (3.7 mmol) 10.10 '- (3,6-diaza-8-hydroxy-3-methyl-2,5-dioxo-nonane-1,9-diyl] -bis- [1, 4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane] (Example 18d) are stirred together with 1.34 g (3.7 mmol) of gadolinium oxide in 25 ml of water at 80 ° C. for 6 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile).
Yield: 4.1 g (91% of theory) of a colorless solid
Analysis:
calculated:
C 37.49; H 5.46; Gd 25.83; N 11.50; O 19.71;
found:
C 37.27; H 5.60; Gd 25.72; N 11.33.

Example 20 10,10 '- (3-Aza-5-hydroxy-3-methyl-2-oxo-hexan-1,6-diyl] bis [1,4,7-tris- (carboxymethyl) - 1,4,7,10-tetraazacyclododecane], di-dysprosium complex a) 1- (3-methylamino-2-hydroxypropyl) -4,7,10-tris- (tert.butyloxycarbonyl) -1,4,7,10- tetraazacyclododecane

To 5.6 g (10 mmol) of 1- (3-amino-2-hydroxypropyl) -4,7,10-tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane (Example 1d) in 60 ml of methanol are added 10 mmol of formaldehyde and stirred for one hour at room temperature. Then 0.63 g (10 mmol) of sodium cyanoborohydride are added and the mixture is stirred at this temperature for a further 18 hours. For working up, cold half-concentrated hydrochloric acid to pH 2 is carefully added, the mixture is largely evaporated in vacuo and the remaining aqueous solution is washed with dichloromethane. The aqueous phase is adjusted to pH 12 with potassium hydroxide, extracted with dichloromethane and the organic phase washed with saturated sodium chloride solution. It is dried over potassium carbonate, filtered and the filtrate is evaporated to dryness. The crude product is chromatographed on silica gel for purification.
Yield: 4.1 g (73.5% of theory) of a yellowish solid
Analysis:
calculated:
C 58.41; H 9.98; N 12.16; O 19.45;
found:
C 58.24; H 10.09; N 12.02.

b) 10,10 '- [3-aza-5-hydroxy-3-methyl-2-oxo-hexane-1,6-diyl] -bis- [1,4,7-tris- (T-butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane]

To a solution of 3.8 g (7 mmol) [4,7,10-tris- (tert.butyloxycarbonyl) - (1,4,7,10-tetraazacyclododecan-1-yl)] - acetic acid (example 1b) 1.73 g (7 mmol) of EEDQ are added to 30 ml of dichloromethane. After half an hour, 3.9 g (7 mmol) of 1- (3-methylamino-2-hydroxypropyl) -4,7,10-tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane ( Example 20a) and stirred overnight at room temperature. The precipitated solid is then filtered off, the filtrate is evaporated and the residue is purified by chromatography on silica gel (dichloromethane / methanol).
Yield: 6.3 g (81.5% of theory) of a yellowish oil
Analysis:
calculated:
C 58.72; H 9.58; N 11.41; O 20.28;
found:
C 58.55; H 9.67; N 11.30.

c) 10,10 '- [3-aza-5-hydroxy-3-methyl-2-oxo-hexane-1,6-diyl] -bis- [1,4,7-tris- (Carboxymethyl) -1,4,7,10-tetraazacyclododecane]

6.1 g (5.5 mmol) 10.10 '- [3-aza-5-hydroxy-3-methyl-2-oxo-hexane-1,6-diyl] -bis- [1,4,7- tris- (tert.butyloxycarbonyl) -1,4,7,10-tetraazacyclododecane] (Example 20b) are stirred in 25 ml trifluoroacetic acid for 12 hours at room temperature. The solution is then evaporated completely in vacuo and the residue is taken up in 20 ml of water. 3.1 g (33.1 mmol) of chloroacetic acid are added and the mixture is stirred at 55 ° C. for 8 h, the pH being adjusted to 9-10 by adding dilute sodium hydroxide solution. The pH is then adjusted to 1 using dilute hydrochloric acid, the mixture is concentrated in vacuo and the residue is applied to a column with an ion exchanger IR 120 (H ⁺ form). It is eluted first with water, then with dilute, aqueous ammonia solution. The fractions containing the product are evaporated and dried in a high vacuum.
Yield: 4.1 g (87.5% of theory) of a yellowish solid
Analysis:
calculated:
C 50.75; H 8.16; N 14.80; O 26.29;
found:
C 50.62; H 8.27; N 14.66.

d) 10,10 '- [3-aza-5-hydroxy-3-methyl-2-oxo-hexane-1,6-diyl] -bis- [1,4,7-tris- (carboxymethyl) -1,4,7,10-tetraazacyclododecane], di-dysprosium complex

2.0 g (2.3 mmol) 10.10 '- [3-aza-5-hydroxy-3-methyl-2-oxo-hexane-1,6-diyl] -bis- [1,4,7- tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane] (Example 20c) are stirred together with 0.88 g (2.3 mmol) of dysprosium oxide in 30 ml of water at 85 ° C. for 6 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile).
Yield: 2.5 g (93% of theory) of colorless solid
Analysis:
calculated:
C 36.93; H 5.42; Dy 27.76; N 10.77; O 19.13;
found:
C 36.79; H 5.55; Dy 27.58; N 10.86.

Example 21 10,10 '- [3-aza-5-hydroxy-3-methyl-2-oxo-hexan-1,6-diyl] bis [1,4,7-tris- (carboxymethyl) - 1,4,7,10-tetraazacyclododecane], di-gadolinium complex

2.0 g (2.3 mmol) 10.10 '- [3-aza-5-hydroxy-3-methyl-2-oxo-hexane-1,6-diyl] -bis- [1,4,7- tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane] (Example 20c) are stirred together with 0.83 g (2.3 mmol) of gadolinium oxide in 30 ml of water at 85 ° C. for 5 h. Then it is filtered, evaporated and purified by chromatography on silica gel RP-18 (water / acetonitrile).
Yield: 2.6 g (97% of theory) of a colorless solid
Analysis:
calculated:
C 37.26; H 5.47; Gd 27.10; N 10.86; O 19.30;
found:
C 37.08; H 5.61; Gd 26.96; N 10.67.

Example 22 10,10 '- (3,6-diaza-8-hydroxy-1-methyl-2,5-dioxo-nonane-1,9-diyl) -bis - ((1,4,7,10- tetraazacyclododecane-1,4,7-triyl) -triacetic acid), di-gadolinium complex

3.23 g (5 mmol) of 10- (3-aza-4-carboxy-1-methyl-2-oxo-butyl) - ((1,4,7,10-tetraazacyclodo decane-1,4,7-triyl ) -triacetic acid), gadolinium complex (WO 98/48844) are dissolved in 20 ml of dimethyl sulfoxide and mixed with 0.6 g (5.5 mmol) of N-hydroxysuccinimide and 1.03 g (5 mmol) of dicyclohexylcarbodiimide. The mixture is stirred for one hour at 80 ° C. and then 2.95 g (5 mmol) of 10- (3-amino-2-hydroxypropyl) - ((1,4,7,10-tetraazacyclododecane-1,4,7-triyl ) - triacetic acid), gadolinium complex (WO 98/48844). After stirring for six hours at 80 ° C., the batch is poured into 200 ml of dichloromethane and the precipitate is suctioned off. The solid is chromatographed for purification on a preparative HPLC. The fractions containing the product are lyophilized.
Yield: 5.1 g (84% of theory) of a colorless solid
Analysis:
calculated:
C 37.49; H 5.46; Gd 25.83; N 11.50; O 19.71;
found:
C 37.34; H 5.53; Gd 25.69; N 11.34.

Claims (12)

1. Compound of formula I.
in which Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and Z ^{3 '} each independently represent a hydrogen atom or a metal ion equivalent, -U- a radical
means which is bonded to the adjacent nitrogen atoms at the positions marked with and in which the position α is bonded to the nitrogen atom of the tetraazacyclododecane ring and the position β is bonded to the nitrogen atom substituted by R ¹ , where R ^{3 is} a hydrogen atom or a straight-chain or branched C ₁ -C ₄ means alkyl radical which is optionally substituted with hydroxyl groups, R ^{1 represents} a hydrogen atom or a straight-chain or branched C ₁ -C ₆ alkyl radical which is optionally interrupted by oxygen atoms and which is optionally substituted by hydroxyl groups, and -B- a straight-chain one or branched C ₁ -C ₁₄ alkylene radical which is optionally interrupted by oxygen atoms and which optionally contains carbonyl groups and / or N (R ^{1 '} ) groups and which is optionally substituted by hydroxyl groups, where R ^1' is defined as R ¹ but can be chosen independently of R ¹ , with the proviso that ß -B- not over a remainder
is bonded at the positions α or B to the nitrogen atom of the tetraazacyclododecane ring. 2. Compound according to claim 1 with the formula II
wherein Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' , Z ^{3 '} , -U- and R ^{1 are} as defined in claim 1, R ^{2 is} a hydrogen atom, a C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl or C ₁ -C ₄ alkoxyalkyl and -B'- is a straight-chain or branched C ₁ -C ₈ alkylene radical which is optionally interrupted by oxygen atoms and which optionally carbonyl groups and / or N (R ^{1 '} ) Contains groups and which is optionally substituted with hydroxyl groups, where R ^{1 '} is defined as R ¹ but can be selected independently of R ¹ . 3. A compound according to claim 1 or 2, wherein Z ¹ , Z ² and Z ³ or Z ^{1 '} , Z ^2' and Z ^{3 '} each together represent a metal cation, the metals being independent of the group of elements of atomic numbers 21- 29, 31, 37-39, 42-44, 49 and 57-83 are selected. 4. A compound according to claim 3, wherein Z ¹ , Z ² and Z ³ or Z ^{1 '} , Z ^2' and Z ^{3 'are} each together Dy ³⁺ , Gd ³⁺ or Y ³⁺ . 5. A compound according to any one of the preceding claims, wherein R ^{1 is} a hydrogen atom, a methyl group, a -CH ₂ C (OH) H-CH ₂ OH group, a - (CH ₂ ) ₂ -OH group, or a - ( CH ₂ ) ₂ -OCH ₃ group. 6. A compound according to any one of claims 2 to 5, wherein R ^{2 is} a hydrogen atom. 7. A compound according to any one of claims 2 to 6, wherein B ^'is a -CH ₂ -, -CH ₂ O-CH ₂ CH ₂ -, -CH ₂ -CO-NH-CH ₂ -, -CH (CH ₂ OH) -CO-NH-CH ₂ -, or -CH (CH ₂ OOH ₃ ) -CO-NH-CH ₂ group. 8. A method for producing a compound according to any one of the preceding claims, wherein

• a) a compound of formula III
  or a reactive form thereof with a compound of formula IV
  or a reactive form thereof is implemented, or
• b) a compound of formula V
  

with a compound of formula IV or a reactive form thereof is implemented, or

• a) a compound of formula VI
  

with a compound of formula VII is implemented, whereby a compound of formula VIII
arises and any protective groups present in the compound of the formula VIII are removed and, if appropriate, radicals R ¹ , R ³ , B, Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and / or Z ^{3 '} into other radicals R. ¹ , R ³ , B, Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and / or Z ^{3 'are} converted, where A ¹ , A ² , A ³ , A ^1' , A ^{2 '} and A ^{3 'is} a group - (CH ₂ ) -Q with n = 0 or 1, where, in the case where n = 0, the radical Q represents an amino protective group which, after the formation of the dinuclear compound, forms a desired group - CH ₂ -CO ₂ -Z is converted, wherein Z is Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ² or Z ^3' and in the event that n = 1, the radical Q is either one protected carboxylic acid function, the protective group of which is split off after the formation of the dinuclear compound and then, if desired, the metal ion equivalent Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' , and / or Z ^{3 'is} introduced, or the rest, Q stands for a free carboxylic acid function and then after formation of the dinuclear compound, if desired, the metal ion equivalent Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and / or Z ^{3 'is} introduced, or the radical Q for the metal ion equivalent Z ¹ , Z ² bound to a carboxylic acid function , Z ³ , Z ^{1 '} , Z ^2' , and / or Z ^{3 '} , the radical R ^{4 is} a C ₁ -C ₄ alkyl radical, one of the radicals B ¹ and B ^{2 is} an optionally activated carboxyl group and the other of the radicals B ¹ and B ^{2 has} an optionally activated amino group, or the radical B ^{2 has} an optionally activated carboxyl group and the radical B ^{1 is} a hydrogen atom, where B ¹ and B ² form a radical B under an amidation reaction and the radicals R ¹ , R ³ , B, Z ¹ , Z ² , Z ³ , Z ^{1 '} , Z ^2' and Z ^{3 '} as defined in claim 1. 9. Use of a compound according to any one of claims 1 to 7, containing at least one ion of an element selected from the elements of the atomic numbers 21-29, 39, 42, 44 and 57-83 for NMR and / or X-ray diagnostics. 10. Use of a compound according to any one of claims 1 to 7, containing at least one ion of an element selected from the elements of the atomic numbers 27, 29, 31, 37-39, 43, 49, 62, 64, 70, 75, 77 and 83 for radio diagnostics and / or Radiotherapy. 11. contrast medium containing a compound according to any one of claims 1 to 7, containing at least one ion of an element selected from the elements of the atomic numbers 21-29, 39, 42, 44 and 57-83 for NMR and / or X-ray diagnostics. 12. Contrast agent according to claim 11, characterized in that it is a X-ray contrast agent.