DE10002939C1 - New aromatic-substituted tetraazacyclododecane-triacetic acid paramagnetic metal complex compounds, are useful as contrast agents for magnetic resonance imaging of necrotic or infarction tissue - Google Patents

Abstract

Polycyclic aromatic-substituted 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid metal complex derivatives (I) are new. Polycyclic aromatic-substituted 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid metal complex derivatives of formula Ar-(L-K)n (I) are new. K = cyclic metal complex residue of formula (K1) or (K2); L = linker residue selected from NHNH and NH-terminated linear or branched, saturated or unsaturated 2-20C carbon chains (optionally interrupted by 1-6 O, 1 or 2 phenylene, 1 or 2 cyclohexylidene, 1 or 2 NHCO or CONH or 1 or 2 CH2CONHNH or NHNHCOCH2; and optionally substituted by 1 or 2 OH, 1 or 2 OMe or 1 or 2 COOH); n = 1 or 2; Ar = polycyclic aromatic residue of formula (Ar1) - (Ar6); A = direct bond, CH2 or CH2OCH2; B' = H or CO (the two B' groups in (Ar1) being the same); C' = OH, O or OR' (the two C' groups in (Ar1) being the same); R1 = 1-3C alkyl; D = OH or OR1; R2 = H, 1-6C alkyl or CH2COOH; E, E', E'' = H, OR1 or N(R1)2; p = 2-10; F', F'' = H, -CO-Q-CO- or a group of formula (F1) or (F2) (both bonded to K via the right-hand terminal), provided that one of F' and F'' is H; Q = 1,4-cyclohexylene, p-phenylene or 1,4-naphthylene; R = H or Me; Z1 - Z3 = 1 equvalent of a metal of atomic number 25, 26 or 58-70; U = linear or branched, saturated or unsaturated 1-10C carbon chain (optionally interrupted by 1-6 O, one phenylene, one cyclohexylidene or 1 or 2; and optionally substituted by 1 or 2 COOH, 1-3 OH, 1-3 OMe or alkoxy); V = phenylene, phenyleneoxymethyl (bonded to K via methyl) or linear or branched, saturated or unsaturated 1-10C carbon chain (optionally interrupted and optionally substituted as for U). An Independent claim is included for the preparation of (I).

Description

The invention relates to that characterized in the claims Object, that is paramagnetic DOTA derivatives, Process for their preparation and their use for the production of pharmaceutical agents.

Detection, localization and monitoring of necrosis or infarction is one important area in medicine. So the myocardial infarction is not a stationary one Process, but a dynamic process that spans a longer period Period - weeks to months - extends. The infarction runs in phases that are not sharply separated, but are overlapping. The first phase the development of myocardial infarction, which includes the 24 hours after the infarction, in which the destruction is like a wave from subendocard to myocard spreads. The second phase, the already existing infarction, includes the Stabilization of the area in which fiber formation (fibrosis) as a healing process he follows. The third phase, the healed infarction, begins after everything destroyed tissue is replaced by fibrous scar tissue. In this period there is an extensive restructuring.

To date, no precise and reliable method is known that the current phase of a myocardial infarction can be determined on the living patient makes. It is crucial for assessing a myocardial infarction Importance of knowing how large the proportion of those who died in the infarction (lost) tissue and where the loss occurred, because of the type of therapy depends on this knowledge. Infarctions do not only take place in the Myocardium, but also in other tissues, especially in the brain.

While the infarct is curable to some extent, necrosis, localized tissue death, only the harmful consequences for the  Residual organism can be prevented or at least mitigated. Necrosis can arise in many ways: from injuries, chemicals, Oxygen deficit or radiation.

As with infarction, knowing the extent and type of necrosis is important for the further medical procedure. Attempts to detect were made early on and localization of infarcts and necrosis using contrast media improve with non-invasive procedures such as scintigraphy or MRI. In the Literature take attempts to porphyrins for necrosis imaging insert a large space. The results achieved, however, result a contradictory picture.

Thus Winkelman and Hayes in Nature, 200, 903 (1967) describe that Mn- 5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrin (TPPS) selectively in accumulates necrotic part of a tumor. Lyon et al., Magn. Res. Med. 4, 24 (1987), on the other hand, observed that Mn-TPPS is distributed in the body, namely in the kidney, liver, tumor and only to a small extent in the muscles. It is interesting that the concentration in the tumor is only on the 4th day Reached maximum and only after the authors put the dose on Had increased 0.2 mmol / kg. The authors therefore speak of one apparently non-specific uptake of the TPPS in the tumor.

Bockhorst et al. again report in Acta Neurochir. 1994 [Suppl.] 60, 347, that Mn-TPPS binds selectively to tumor cells. Foster et al., J. Nucl. Med. 26, 756 (1985) for their part found that In-111-5,10,15,20-tetrakis (4-N-methyl pyridinium) -porphyrin (TMPyP) not in the necrotic part, but in the enriched living marginal layers.

It can be concluded that a porphyrin-type tissue-dependent interaction does not exist.

In Circulation, Vol. 90, No. 4, 1994, Part 2, Page 1468, Abstr. No. 2512, Ni et al. report that they use an Mn-tetraphenyl-porphyrin (Mn-TPP) and  a Gd mesoporphyrin (in DE 42 32 925 Example 1c) (Gd-MP) infarct areas can represent well.

Both substances are the subject of the application WO 95/31219. In DE 198 24 653, radioactively labeled mesoporphyrin IX derivatives are used as Described necrosis-related compounds and for radiation therapy used.

Scintigraphic methods are used for diagnostic purposes Dose in the nanomolar range. The compatibility of the substances therefore only plays a role a subordinate role. With MR imaging, however, the dose is in the Millimole range. Compatibility plays a very important role here.

The low acute tolerances determined for MnTPP or MnTPPS (LD50) exclude their use in humans.

In addition, porphyrins - like z. B. Gd mesoporphyrin - tend to to deposit in the skin, causing photosensitization and discoloration leads. These effects can last for days, even weeks. At scintigraphic procedures would have this effect due to the low dose without Be meaningful. Against a wide application of scintigraphic processes speaks, however, that the resolution of a gamma camera is much lower than that is what can be achieved with MR imaging.

Gd complexes were also found for MR imaging of the myocardial infarction DTPA (K. Bockhorst et al., Acta Neurochir. (1997) Suppl., 60: 347-349); De Roos et al., Radiology 1989; 172: 717-720) and their bis (methylamids) (M. Saeed et al., Radiology, 1992; 182: 675-683) use. It turned out that both Contrast agents only differentiate between in a narrow time window enable healthy and infarcted tissue. Comparable results were also used with the manganese compound of DTPA (Immunomedics, WO 94/22490) and the DPDP (Radiology 1989; 172: 59-64).  

Weissleder et al., Radiology 1992; 182: 675-683, which coupled antimyosin to iron oxides (MION). Because of his specific structure, this contrast medium is not for necrosis imaging suitable.

There is therefore an urgent need to have connections for MR infarct and necrosis imaging which:
are very well tolerated,
are not phototoxic,
are chemically stable,
be completely eliminated,
accumulate in necrosis,
do not accumulate in the skin,
have a high relaxivity,
show high water solubility
provide a wide time window for the measurement,
a good differentiation between healthy
and necrotic / infarcted tissue.

The object of the invention is surprisingly achieved by the compounds of the general formula I.

Ar- (LK) n (I)

wherein
K: a cyclic metal complex,
L: a left,
Ar: an aromatic radical containing at least two aromatic rings,
n: the numbers 1 or 2 means
in which
Ar preferred for a residue

with the meaning
A: a direct bond,
a methylene group -CH ₂ -,
a dimethylene ether group -CH ₂ -O-CH ₂ -,
B: a hydrogen atom,
a carbonyl group -CO-,
C: a hydroxyl group -OH,
an oxygen function -O-,
an ether group -OR ¹ , in which R ^{1 is} an alkyl radical having 1-3 carbon atoms,
where the substituents B and C are each identical in the molecule,
for a rest

with the meaning
D: a hydrogen atom,
an ether group -OR ¹ , with R ¹ in the abovementioned meaning,
for a rest

with the meaning
B and C as described above,
for a rest

with the meaning
R ¹ : as described above,
R ² : a hydrogen atom,
a C ₁ -C ₆ alkyl group,
an acetic acid residue -CH ₂ CO ₂ H,
for a rest

with the meaning
E: a hydrogen atom,
an ether group -OR ¹ ,
a dialkylamino group N (R ¹ ) ₂ , where R ^{1 has} the meaning given above,
o: a number between 2-10,
for a rest

with the meaning
E ¹ , E ² : independently of one another in the meaning of E,
F ¹ , F ² : independently of one another for a hydrogen atom H or the radicals

with o in the meaning given above,
and the proviso that one of the substituents F ¹ or F ^{2 represents} a hydrogen atom and that α denotes the binding site in the direction of the aromatic and β denotes the binding site in the direction of the metal complex,
K: preferred for a metal complex of the general formula II

with the meaning
R: a hydrogen atom,
a methyl group,
Z ¹ , Z ² , Z ³ : a metal ion equivalent of atomic numbers 25, 26 and 58-70,
U: a C ₁ -C ₁₀ carbon chain, linear or branched, saturated or unsaturated, optionally interrupted by 1-2 oxygen atoms, by a phenylene group, by a cyclohexylidene group, by one or two groups -NH-CO- or -CONH-, optionally substituted with one to two -CO ₂ H groups, with one to three hydroxyl groups, one to three methoxy or alkoxy groups,
or for a metal complex of the general formula III

with the meaning
Z ¹ , Z ² , Z ³ : as stated above,
V: a phenylene, phenyleneoxymethyl, -δ-C ₆ H ₄ -O-CH ₂ -γ group, where γ indicates the binding site in the direction of the aromatic and δ the binding site in the direction of the metal complex, a C ₁ -C ₂₀ -Carbon chain, linear or branched, saturated or unsaturated, optionally interrupted by one or two oxygen atoms, by a phenylene group, by a cyclohexylidene group, by one or two groups -NH-CO or CONH-, optionally substituted by one or two -CO ₂ H Groups with one to three hydroxyl groups, one to three methoxy or alkoxy groups,
L for a linker meaning a hydrazine group -NHNH-, a C ₂ -C ₂₀ carbon chain with terminal -NH-, which can be linear or branched, saturated or unsaturated and optionally by 1-6 oxygen atoms, 1-2 phenylene groups, interrupted by 1-2 cyclohexylidene groups, by 1-2 groups -NH- CO- or -CONH-, by 1-2 groups -CH ₂ CONHNH- or -NHNHCOCH ₂ and optionally substituted by 1-2 hydroxyl groups by 1- 2 Methoxy groups, with 1-2 carboxy groups,
where acid groups present in the molecule are optionally present as salts of organic and / or inorganic bases or amino acids or amino acid amides.

Preferred residues for L are:
-NH-NH-
γ-CH ₂ -CONH-NH-δ
-NH-CH ₂ CH ₂ -NH-
-NHCH ₂ CH ₂ CH ₂ CH ₂ -NH-
-NH- (CH ₂ ) ₃ -NH-
-NH- (CH ₂ ) ₅ -NH-
-NH- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -NH-
γ-NH- (CH ₂ ) k-CONH- (CH ₂ ) m-NH-δ with k = 1-10; m = 0-10,
γ-NH- (CH ₂ CH ₂ O) ₂ -CH ₂ CH ₂ NH-δ

U preferably represents the group:
-CH ₂ -
-CH ₂ CH ₂ -
-C ₆ H ₄ -
-CH ₂ -O-CH ₂ CH ₂ -.

The -CH ₂ group is particularly preferred.

V preferably represents a group:
-CH ₂ -OC ₆ H ₄ -
-C ₆ H ₄ -
-CH ₂ CH ₂ -
-CH ₂ -.

The compounds according to the invention meet the requirements (see above) for Diagnostics for necrosis and infarct imaging are to be provided.

Surprisingly, the complexes according to the invention show the previously known, structurally similar connections a significantly higher Relaxivity. Since relaxivity is a measure of the contrast agent effectiveness of a Connection can be viewed using the complexes according to the invention in the field of NMR diagnostics comparable, positive signal influence even at a low dose. This significantly increases the safety distance, for which as a guideline the product can be viewed from relaxivity and tolerance.  

If desired, the carboxyl groups are not used for complexation of the metal ions are required, as esters, as amides or as salts inorganic or organic bases are present. Suitable ester residues are those with 1 to 6 carbon atoms, preferably the ethyl esters. Suitable Inorganic cations are, for example, the lithium and the potassium ion and especially the sodium ion. Suitable cations of organic bases are those of primary, secondary or tertiary amines, such as Ethanolamine, diethanolamine. Morpholine, glucamine, N, N-dimethylglucamine, especially the meglumine.

For the application of the compounds of the general formula I in NMR Diagnostics, the central ion of complex K must be paramagnetic. These are especially the divalent and trivalent ions of the elements of the Atomic numbers 25, 26 and 58-70.

Iron, manganese and gadolinium are preferred.

Gadolinium is particularly preferred.

When used in radio diagnostics and radiotherapy, complexes with the radioisotopes of the elements of atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70, 75 and 77 can be used.

The preparation of the compounds of general formula I according to the invention

Ar (LK) (I)

takes place according to the methods known to the person skilled in the art by reacting compounds of the general formula IV

Ar (LH) _n (IV)

with complexes or complexing agents of the general formula V

KX * (V)

wherein
Ar, L, K and n have the meaning already described and
X * for a hydroxyl group or a group activating the carboxylic acid such as, for. B.

stands.

The implementation takes place according to the methods known to the person skilled in the art Amide formation from active ester and amine as described, for example, in WO 98/24775 is described. As a result, metal carboxamides from acid and Amine optionally obtained without isolation of the active ester.

A mixture of metal complex carboxylic acid and at least one Solubilizing substance in dimethyl sulfoxide with a water-releasing agent Reagent, optionally with the addition of a coupling auxiliary, pretreated and then reacted with an amine.

The implementation of IV and V to I can also be done so that the Has a complexing agent in a protected form, which carries out the coupling to I. and then introduces the metal after deprotection.

The introduction of the desired metal ions takes place in the manner in which, for. B. in the patents EP 71564, EP 130934 and DE-34 01 052 has been disclosed by the metal oxide or a metal salt (for example the nitrate, acetate, carbonate, chloride or sulfate) of the element of the desired atomic numbers in water and / or a lower alcohol (such as methanol, ethanol or isopropanol) is dissolved or suspended and reacted with a solution or suspension of the equivalent amount of the complexing agent of the general formulas II or III (with Z ¹ -Z ³ in the meaning of hydrogen atoms).

The protective groups are split off according to those known to the person skilled in the art Processes, for example by hydrolysis, hydrogenolysis, alkaline Saponification of the esters with alkali in aqueous-alcoholic solution Temperatures from 0 ° to 50 ° C, acid saponification with mineral acids or in the case from Z. B. tert-butyl esters with the help of trifluoroacetic acid [Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc. New York, 1991].

The aromatic amines of the general formula IV are prepared from carboxylic acids or hydroxy compounds containing aromatics some are commercially available.  

R ^x = -OCH ₃ , -N (CH ₃ ) ₂ ,
Q = NH, O, CO, SO, SO ₂ , S.

As far as the aromatic carboxylic acids are not commercially available, they will prepared by methods known to those skilled in the art, e.g. B. by acylation of naphthalenes by appropriate acyl chlorides in the presence of Lewis Acids (e.g. Pivsa-Art et al., J. Chem. Soc. Perkin Trans. 1, 1703-1707 (1994), or by Grignard reactions of the corresponding commercially available bromine Naphthalenes (e.g. Kharasch, M. S. and Reinmuth, O. Grignard Reactions of Nonmetallic Substances Constable and Company, Ltd. Prentice-Hall Inc., 1954).

For the introduction of the radical R ^x in the meaning of dialkylamino, see, for example, Hoeve, W. et al., J. Org. Chem. 58, 5101-5106 (1993).

For the conversion of the aromatic acid containing carboxylic acid to the starting materials general formula IV is based on the methods known to the person skilled in the art [e.g. B. Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart, Volume 15/2 (1974)].

Examples include diamines

In the case of the hydroxy compounds, these are known from the literature Methods z. B. (Houben-Weyl, Volume VI / 3, Part A, Georg Thieme Verlag, Stuttgart, 1965) by alkylation with z. B. halocarboxylic acids in the corresponding ether carboxylic acids converted, then as above described in the desired starting materials of formula IV are implemented.

The synthesis of the starting compounds of the general formula V is described in WO 98/24774.

The pharmaceutical compositions containing the complex compounds according to the invention are produced also in a manner known per se, by using the inventive Complex compounds - if necessary with the addition of galenics usual additives - suspended or dissolved in aqueous medium and then if necessary, the suspension or solution is sterilized. Suitable additives are for example physiologically harmless buffers (such as tromethamine), small additions of complexing agents (such as diethylenetriaminepenta acetic acid) or, if necessary, electrolytes such. B. sodium chloride or, if necessary, antioxidants such as B. ascorbic acid.

Are suspensions or for enteral administration or other purposes Solutions of the agents containing the complex compounds according to the invention in water or in physiological Desired saline solution, they will be with one or more in galenics usual auxiliary substance (s) (e.g. methyl cellulose, lactose, mannitol) and / or Surfactant (s) (e.g. lecithins, Tween®, Myrj®) and / or flavorings Flavor correction (e.g. essential oils) mixed.  

In principle, it is also possible to use the pharmaceutical compositions containing the complex compounds according to the invention can also be produced without isolating the complex salts. In any case special care must be taken to avoid chelation make the salts and salt solutions of the invention practical are free of non-complexed toxic metal ions.

This can be done, for example, with the help of color indicators such as xylenol orange Control titrations can be guaranteed during the manufacturing process. The invention therefore also relates to processes for producing the Complex compounds and their salts. One last security remains Purification of the isolated complex salt.

The pharmaceutical compositions containing the complex compounds according to the invention preferably contain 20 μmol / L up to 200 mmol / L of the complex salt and are usually in quantities dosed from 1 µmol to 2 mmol / kg body weight, both in their application for the necrosis and infarct MR imaging as well as for therapy control by means of MRI diagnostics. They are intended for enteral and parenteral administration or are applied using the methods of interventional radiology.

The agents containing the complex compounds according to the invention meet the diverse requirements for Suitability as an agent for MRI contrast media. So they are excellent at it suitable after application by increasing the signal intensity using the Magnetic resonance imaging imaging image to improve its informative value. They also show the high effectiveness that is necessary to the body the smallest possible amount of foreign substances and the good Tolerance, which is necessary to the non-invasive nature of the Maintain investigations.

The compounds of general formula I are also used to represent the Suitable for intravascular spaces (blood pool).

The good water solubility of the agents containing the complex compounds according to the invention allows this to produce highly concentrated solutions so that the volume load of the  Circulation is to be kept within reasonable limits and thinning through Body fluid is balanced. Furthermore, the agents containing the complex compounds according to the invention not only high stability in vitro, but also surprisingly high Stability in vivo, so that a release or exchange of the in the Complex nonconvolutionally bound - inherently toxic - ions within the Time in which the contrast agents are completely excreted again is neglect.

The invention is illustrated by the following examples.  

example 1 N- [1.4.7-tris (carboxylatomethyl) -1.4.7,10-tetraazacyclododecane-Gd complex - 10- (3-aza-4-oxo-hexan-5-yl) acid] -N '- [(3-hydroxy) -2-naphthoic acid] di hydrazide

20 g (31.76 mmol) Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-aza-butyl) - 1,4,7,10-tetraaza-cyclododecane-1,4,7-triacetic acid (Gd-Gly-Me-DOTA, DE 196 52 386), 2.69 g (63.52 mmol) lithium chloride and 3.66 g (31.76 mmol) N- Hydroxysuccinimide are heated in 200 ml of dimethyl sulfoxide solved. Then 6.42 g (31.76 mmol) of 2-hydroxy-3- naphthoic acid hydrazide and stir for 20 minutes at room temperature. You cool to 10 ° C and adds 9.83 g (47.64 mmol) of N, N'-dicyclohexylcarbodiimide and stir overnight at room temperature. The reaction solution is poured into Mixture of 1000 ml acetone / 1000 ml diethyl ether and filtered precipitated solid. Further purification is done by RP-18 Chromatography (eluent: gradient from water / acetonitrile / tetrahydrofuran). Evaporation of the fractions gives 21.46 g (83% of theory) of one colorless, amorphous solid.

Water content: 7.8%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 44.27; H 4.71; Gd 19.32; N 12.05;
Found:
C 44.41; H 4.82; Gd 19.20; N 11.96.

Example 2 N- [1.4.7-tris (carboxylatomethyl) -1.4.7,10-tetraazacyclododecane-Gd complex- 10- (3-aza-4-oxo-hexan-5-yl) acid] -N '- [(3-methoxy) -2-naphthoic acid] di hydrazide

To 5 g (6.14 mmol) of the title compound from Example 1, dissolved in 30 ml of water, there are 2.12 g (20 mmol) of sodium carbonate. At 0 ° C, 1.01 g (8 mmol) is added dropwise Dimethyl sulfate and then stirred for 24 hours Room temperature. With conc. Hydrochloric acid to pH 7.4 and evaporates in Vacuum to dryness. The residue is on RP-18 (eluent: gradient from water / acetonitrile / Tetrahydrofuran).

Yield: 4.98 g (98% of theory) of an amorphous solid.

Water content: 9.1%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 44.97; H 4.87; Gd 18.99; N 11.84;
Found:
C 45.10; H 5.00; Gd 19.18; N 11.97.

Example 3 N, N-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-Gd- Complex-10- (3-aza-4-oxo-hexan-5-yl) acid] -4.4'-methylene- N, 'N'-bis [(3-hydroxy) -2-naphthoic acid] tetrahydrazide

10 g (12.29 mmol) of the title compound from Example 1 together with 50 ml Acetic acid / 50 ml water, 20 g (243.8 g mmol) sodium acetate and 0.37 g (12.3 mmol) formaldehyde (as a 30% aqueous solution) for 3 hours Reflux heated. The mixture is allowed to cool to room temperature and is made up with 10% aqu. Sodium hydroxide solution to pH 7.5 and evaporated to dryness in vacuo. The Residue is added to RP-18 (mobile solvent: gradient from water / acetonitrile / Tetrahydrofuran).

Yield: 7.65 g (76% of theory) of a colorless amorphous powder.

Water content: 7.4%.  

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 44.68; H 4.67; Gd 19.18; N 11.96;
Found:
C 44.80; H 4.78; Gd 19.03; N 12.10.

Example 4 N, N-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-Gd- Complex-10- (3-aza-4-oxo-hexan-5-yl) acid] -4.4'-methylene- N, 'N'-bis [(3-methoxy) -2-naphthoic acid] tetrahydrazide

To 5.03 g (3.07 mmol) of the title compound from Example 3, dissolved in 30 ml Water, 2.12 g (20 mmol) of sodium carbonate are added. At 0 ° C, 1.01 g is added dropwise (8 mmol) of dimethyl sulfate and then stirred in for 24 hours Room temperature. With conc. Hydrochloric acid to pH 7.4 and evaporates in Vacuum to dryness. The residue is on RP-18 (eluent: gradient from water / acetonitrile / Tetrahydrofuran).

Yield: 4.92 g (96% of theory) of an amorphous solid.

Water content: 10.1%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 45.37; H 4.83; Gd 18.86; N 11.76;
Found:
C 45.51; H 4.94; Gd 19.01; N 11.61.

Example 5 N, N-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-Gd- Complex-10- (3-aza-4-oxopentan-5-yl) acid] -N '- [(3-hydroxy) - 2-naphthoic acid] dihydrazide

19.56 g (31.76 mmol) Gd complex of 10- (4-carboxy-2-oxo-3-aza-butyl) - 1,4,7,10-tetraaza-cyclododecane-1,4,7-triacetic acid (Gd-Gly-Me-DOTA), 2.69 g (63.52 mmol) lithium chloride and 3.66 g (31.76 mmol) N-hydroxysuccinimide are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. Then 6.42 g (31.76 mmol) of 2-hydroxy-3-naphthoic acid are added hydrazide and stir for 20 minutes at room temperature. It is cooled to 10 ° C and adds 9.83 g (47.64 mmol) of N, N'-dicyclohexylcarbodiimide and stir Night at room temperature. The reaction solution is poured out into a mixture 1000 ml acetone / 1000 ml diethyl ether and the precipitated solid is filtered off. The further purification is carried out by RP-18 chromatography (eluent: Gradient from water / acetonitrile / tetrahydrofuran). After evaporating the Fractions are obtained 21.59 g (85% of theory) of a colorless, amorphous Solid.

Water content: 7.4%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 43.55; H 4.54; Gd 19.66; N 12.26;
Found:
C 43.41; H 4.61; Gd 19.50; N 12.40.

Example 6 N, N-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-Gd- Complex-10- (3-aza-4-oxopentan-5-yl) acid] -N '- [(3-methoxy) - 2-naphthoic acid] dihydrazide

To 4.91 g (6.14 mmol) of the title compound from Example 5, dissolved in 30 ml Water, 2.12 g (20 mmol) of sodium carbonate are added. At 0 ° C, 1.01 g is added dropwise (8 mmol) of dimethyl sulfate and then stirred in for 24 hours Room temperature. With conc. Hydrochloric acid to pH 7.4 and evaporates in  Vacuum to dryness. The residue is on RP-18 (eluent: gradient from water / acetonitrile / tetrahydrofuran).

Yield: 4.85 g (97% of theory) of an amorphous solid.

Water content: 6.8%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 44.27; H 4.71; Gd 19.32; N 12.05;
Found:
C 44.40; H 4.82; Gd 19.49; N 12.16.

Example 7 N, N-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane Gd complex 10- (3-aza-4-oxopentan-5-yl] acid] -4.4-methylene- N, 'N'-bis [(3-hydroxy) -2-naphthoic acid] tetrahydrazide

9.83 g (12.29 mmol) of the title compound from Example 5 are combined with 50 ml acetic acid / 50 ml water, 20 g (243.8 g mmol) sodium acetate and 0.37 g (12.3 mmol) formaldehyde (as a 30% aqueous solution) for 3 hours Reflux heated. The mixture is allowed to cool to room temperature and is made up with 10% aqu. Sodium hydroxide solution to pH 7.5 and evaporated to dryness in vacuo. The Residue is added to RP-18 (mobile solvent: gradient from water / acetonitrile / Tetrahydrofuran).

Yield: 7.23 g (73% of theory) of a colorless amorphous powder.

Water content: 8.3%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 43.97; H 4.50; Gd 19.51; N 12.17;
Found:
C 44.08; H 4.62; Gd 19.67; N 12.28.

Example 8 N ', N-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane Gd complex 10- (3-aza-4-oxopentan-5-yl] acid] -4.4-methylene- N, 'N'-bis [(3-methoxy) 2-naphthoic acid] tetrahydrazide

To 4.95 g (3.07 mmol) of the title compound from Example 7, dissolved in 30 ml Water, 2.12 g (20 mmol) of sodium carbonate are added. At 0 ° C, 1.01 g is added dropwise (8 mmol) of dimethyl sulfate and then stirred in for 24 hours Room temperature. With conc. Hydrochloric acid to pH 7.4 and evaporates in Vacuum to dryness. The residue is on RP-18 (eluent: gradient from water / acetonitrile / tetrahydrofuran).

Yield: 4.78 g (95% of theory) of an amorphous solid.

Water content: 7.8%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 44.68; H 4.67; Gd 19.18; N 11.96;
Found:
C 44.75; H 4.80; Gd 19.02; N 12.04.

Example 9 N- [1.4.7-tris (carboxylatomethyl) -1.4.7,10-tetraazacyclododecane-Gd complex - 10- (3-aza-4-oxo-hexan-5-yl) acid] -N '- [(3-ethoxy) -2-naphthoic acid] -di hydrazide

To 5 g (6.14 mmol) of the title compound from Example 1, dissolved in 30 ml of water, there are 2.12 g (20 mmol) of sodium carbonate. 1.23 g is added dropwise at 0.degree (8 mmol) of diethyl sulfate and then stirred in for 24 hours Room temperature. With conc. Hydrochloric acid to pH 7.4 and evaporates in  Vacuum to dryness. The residue is on RP-18 (eluent: gradient from water / acetonitrile / tetrahydrofuran).

Yield: 4.89 g (96% of theory) of an amorphous solid.

Water content: 11.1%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 44.86; H 5.10; Gd 18.95; N 11.81;
Found:
C 44.74; H 5.21; Gd 19.16; N 11.96.

Example 10a 2- [4- (3-Oxapropionic acid ethyl ester)] - phenyl-acetic acid methyl ester

To 200 g (1.204 mol) of methyl 4-hydroxyphenylacetate, 212 g (2 mol) Sodium carbonate in 2000 ml acetone is added 233.8 g (1.4 mol) of 2-bromoacetic acid. Ethyl ester and boiled under reflux for 5 hours. The solid is filtered off and evaporate the filtrate to dryness in vacuo. The residue is on silica gel chromatographed (eluent: n-hexane / ethyl acetate = 15: 1).

Yield 288.5 g (95% of theory) of a colorless oil.

Elemental analysis:
Calculated:
C 61.90; H 6.39;
Found:
C 62.05; H 6.51.

Example 10b 2-bromo-2- [4- (oxapropionic acid ethyl ester)] - phenyl-acetic acid methyl ester

To 285 g (1.13 mol) of the title compound from Example 10a, dissolved in 2000 ml Tetrachlorocarbon, 201 g (1.13 mol) of N-bromosuccinimide and 100 ml are added Dibenzoyl peroxide. The mixture is refluxed for 8 hours. You cool in the ice bath, the precipitated succinimide is filtered off and the filtrate is evaporated in vacuo Dry it up. The residue is purified on silica gel (mobile solvent: n- Hexane / acetone = 15: 1).

Yield: 359.2 g (96% of theory) of a colorless, viscous oil.

Elemental analysis:
Calculated:
C 47.15; H 4.57; Br 24.16;
Found:
C 47.28; H 4.47; Br 24.30.

Example 10c 2- (1,4,7,10-tetraazacyclododec-1-yl) -2- [4- (3-oxapropionic acid ethyl ester)] - phenyl-acetic acid methyl ester

Add to 603 g (3.5 mol) of 1,4,7,10-tetraazacyclododecane in 6000 ml of chloroform 350 g (1.057 mol) of the title compound from Example 10b and stirred overnight at room temperature. It is extracted 3 times with 3000 ml of water, the organic phase over magnesium sulfate and evaporated to dryness in vacuo. The residue is taken into the next step = <10d without further purification puts.

Yield: 448 g (quantitative) of a viscous, yellowish oil.

Elemental analysis:
Calculated:
C 59.70; H 8.11; N 13.26;
Found:
C 59.84; H 8.25; N 13.20.

Example 10d 2- [1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododec-10-yl] - 2- [4- (3-oxapropionic acid)] phenyl acetic acid

445 g (1.053 mol) of the title compound from Example 10c and 494 g (5.27 mol) Chloroacetic acid are dissolved in 4000 ml of water. One poses with 30% Sodium hydroxide solution to pH 10. It is heated to 70 ° C and the pH by adding 30% sodium hydroxide solution kept at pH 10. The mixture is stirred at 70 ° C. for 8 hours. Then it is adjusted to pH 13 and refluxed for 30 minutes. The Solution is cooled in an ice bath and by adding conc. Hydrochloric acid to pH 1 posed. It is evaporated to dryness in vacuo. The residue is in 4000 ml Methanol taken up and stirred for one hour at room temperature. Man filtered off the precipitated table salt, the filtrate evaporated to dryness and cleans the residue on RP-18 (mobile solvent: gradient from water / ethanol / aceto nitrile).

Yield: 403 g (69% of theory) of a colorless solid.

Water content: 10.2%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 51.98; H 6.18; N 10.10;
Found:
C 52.15; H 6.29; N 10.22.

Example 10e 2- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododec-10-yl- Gd complex] -2- [4- (3-oxapropionic acid)] - phenyl acetic acid

To 400 g (721.3 mmol) of the title compound from Example 10d in 2000 ml of water there are 130.73 g (360.65 mmol) of gadolinium oxide and stirred for 5 hours at 90 ° C. The solution is filtered and the filtrate freeze-dried.

Yield: 511 g (quantitative) of an amorphous, colorless powder.  

Water content: 11.0%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 40.67; H 4.41; Gd 22.19; N 7.98;
Found:
C 40.80; H 4.52; Gd 22.03; N 7.78.

Example 10f N- (1,4,7-tris (carboxylatomethyl) -1,4,7 10-tetraazacyclododecane-Gd- Complex-10- [1-carboxylate-1- [3-oxapropionic acid) phenyl] methyl) - N '- [3- (hydroxy) -2-naphthoic acid] dihydrazide, sodium salt

22.51 g (31.76 mmol) of the title compound from Example 10e, 2.69 g (63.52 mmol) Lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide dissolved in 200 ml of dimethyl sulfoxide with gentle heating. Then there 6.42 g (31.76 mmol) of 2-hydroxy-3-naphthoic acid hydrazide are added and the mixture is stirred 20 Minutes at room temperature. The mixture is cooled to 10 ° C. and 9.83 g (47.64 mmol) are added. N, N'-dicyclohexylcarbodiimide and stirred overnight in room temperature. The reaction solution is poured into a mixture of 1000 ml Acetone / 1000 ml of diethyl ether and the precipitated solid is filtered off. The further purification is carried out by RP-18 chromatography (eluent: Gradient from water / acetonitrile / tetrahydrofuran). After evaporating the Fractions are dissolved in a little water, the pH to 7.4 with 2N sodium hydroxide solution provided and then freeze-dried. 25.0 g (86% of the Theory) of a colorless, amorphous solid.

Water content: 10.3%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 45.95; H 4.19; Gd 17.19; N 9.19; Na 2.51;
Found:
C 46.11; H 4.27; Gd 17.08; N 9.27; Na 2.60.

Example 11 N- (1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-Gd- Complex-10- [1-carboxylate-1- [3-oxapropionic acid) phenyl] methyl N'- [3- (methoxy) -2-naphthoic acid] dihydrazide, sodium salt

To 5.62 g (6.14 mmol) of the title compound from Example 10f, dissolved in 30 ml Water, 2.12 g (20 mmol) of sodium carbonate are added. At 0 ° C, 1.01 g is added dropwise (8 mmol) of dimethyl sulfate and then stirred for 24 hours in the room temperature. It is adjusted to pH 7.4 with concentrated hydrochloric acid and evaporated in Vacuum to dryness. The residue is on RP-18 (eluent: gradient from water / acetonitrile / tetrahydrofuran).

Yield: 5.48 g (96% of theory) of an amorphous solid.

Water content: 7.9%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 46.55; H 4.34; Gd 16.93; N 9.05; Na 2.47;
Found:
C 46.40; H 4.44; Gd 17.07; N 9.15; Na 2.58.

Example 12 N-bis- (1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-Gd- Complex-10- <1-carboxylate-1- [4- (3-oxapropionic acid] phenyl <- methyl) -4,4'-methylene-N, N-bis [(3-hydroxy) -2-naphthoic acid] - tetrahydrazide, disodium salt

11.24 g (12.29 mmol) of the title compound from Example 10f are combined with 50 ml acetic acid / 50 ml water, 20 g (243.8 g mmol) sodium acetate and 0.37 g (12.3 mmol) formaldehyde (as a 30% aqueous solution) for 3 hours heated under reflux, allowed to cool to room temperature, with  10% aqu. Sodium hydroxide solution to pH 7.5 and evaporates to dryness in vacuo on. The residue is on RP-18 (mobile solvent: gradient from water / acetonitrile / Tetrahydrofuran).

Yield: 8.04 g (71% of theory) of a colorless amorphous powder.

Water content: 7.3%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 46.30; H 4.16; Gd 17.07; N 9.13; Na 2.50;
Found:
C 46.46; H 4.24; Gd 17.20; N 9.21; Na 2.61.

Example 13 N, N-bis (1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane Gd complex 10- <1-carboxylate-1- [4- (3-oxapropionic acid] phenyl <- methyl) -4,4'-methylene-N, N-bis [(3-methoxy) -2-naphthoic acid] - tetrahydrazide, disodium salt

To 5.65 g (3.07 mmol) of the title compound from Example 12, dissolved in 30 ml Water, 2.12 g (20 mmol) of sodium carbonate are added. At 0 ° C, 1.01 g is added dropwise (8 mmol) of dimethyl sulfate and then stirred in for 24 hours Room temperature. With conc. Hydrochloric acid to pH 7.4 and evaporates in Vacuum to dryness. The residue is on RP-18 (eluent: gradient from water / acetonitrile / tetrahydrofuran).

Yield: 5.45 g (95% of theory) of an amorphous solid.

Water content: 9.2%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 46.89; H 4.31; Gd 16.82; N 8.99; Na 2.46;
Found:
C 47.00; H 4.45; Gd 16.99; N 9.09; Na 2.57.

Example 14a 2-Toluenesulfonylamino-benzoic acid methyl ester

To 50 g (331 mmol) of anthranilic acid methyl ester, dissolved in 200 ml of pyridine, is added at 0 ° C 66.73 g (350 mmol) p-toluenesulfonic acid chloride. Stir for 6 hours 0 ° C. The solution is poured into 1500 ml of water and the precipitated solid filtered off. The solid is recrystallized from a little methanol.

Yield: 93.0 g (92% of theory) of a crystalline solid.

Elemental analysis:
Calculated:
C 59.00; H 4.95; N 4.59; S 10.50;
Found:
C 59.15; H 5.07; N 4.71; S 10.62.

Example 14b 2-toluenesulfonylamino-benzoic acid hydrazide

20 g (65.5 mmol) of the title compound from Example 14a are dissolved in 500 ml dissolved boiling methanol and at the boiling point 10.494 g (327 mmol) hydrazine admitted. The mixture is refluxed for 6 hours. It is evaporated to dryness and crystallizes the residue from a little ethanol.

Yield: 18.26 g (91% of theory) of a colorless, crystalline solid.

Elemental analysis:
Calculated:
C 54.89; H 5.26; N 13.72; S 10.47;
Found:
C 55.01; H 5.40; N 13.88; S 10.35.

Example 14c N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane Gd complex-10- (3-aza-4-oxo-hexan-5-yl) acid] -N - [(2- toluenesulfodylamino) benzoic acid] dihydrazide

20 g (31.76 mmol) Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-aza-butyl) - 1,4,7,10-tetraaza-cyclododecane-1,4,7-triacetic acid (GD-Gly-Me-DOTA), 2.69 g (63.52 mmol) lithium chloride and 3.66 g (31.76 mmol) N-hydroxy succinimide are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. Then 9.63 g (31.76 mmol) of the title compound from Example are added 14b and stir for 20 minutes at room temperature. It is cooled to 10 ° C. and adds 9.83 g (47.64 mmol) of N, N'-dicyclohexylcarbodiimide and stirred overnight at room temperature. The reaction solution is poured out into a mixture 1000 ml acetone / 1000 ml diethyl ether and filter the precipitated solid from. The further purification is carried out by RP-18 chromatography (eluent: Gradient from water / acetonitrile / tetrahydrofuran). After evaporating the Fractions are obtained 23.62 g (81% of theory) of a colorless, amorphous Solid.

Water content: 7.8%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 43.17; H 4.83; Gd 17.13; N 12.21; S 3.49;
Found:
C 43.30; H 4.96; Gd 17.28; N 12.30; S 3.40.

Example 15a 4,4'-di (naphth-3-oxyacetic acid methyl ester)

25 g (87.31 mmol) 1,1'-Bi-2-naphthol and 37 g (349 mmol) sodium carbonate are placed in 200 ml of dimethylformamide. 29.38 g (192 mmol) are added dropwise at 60 ° C. 2-Bromoacetic acid methyl ester and stirred at 60 ° C for 8 hours. You leave Cool to room temperature, filter off the solid and evaporate the filtrate in Vacuum to dryness. The residue is chromatographed on silica gel (Mobile phase: dichloromethane / methanol = 25: 1).

Yield: 34.95 g (93% of theory) of a colorless, crystalline solid.

Elemental analysis:
Calculated:
C 72.55; H 5.15;
Found:
C 72.69; H 5.26.

Example 15b 4,4'-di (naphth-3-oxyacetic hydrazide)

20 g (46.46 mmol) of the title compound from Example 15a are dissolved in 500 ml boiling methanol dissolved and 14.9 g (465 mmol) of hydrazine at the boiling point admitted. The mixture is refluxed for 6 hours. It is evaporated to dryness and crystallizes the residue from a little ethanol.

Yield: 17.0 g (85% of theory) of a colorless, crystalline solid.

Elemental analysis:
Calculated:
C 66.97; H 5.15; N 13.02;
Found:
C 67.18; H 5.22; N 13.16.

Example 15c N, N-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane Gd complex-10- (3-aza-4-oxo-hexan-5-yl) acid] -4,4'-di (naphth-3- oxyacetic acid] tetrahydrazide

20 g (31.76 mmol) Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-aza-butyl) - 1,4,7,10-tetraaza-cyclododecane-1,4,7-triacetic acid (Gd-Gly-Me-DOTA), 2.69 g (63.52 mmol) lithium chloride and 3.66 g (31.76 mmol) N-hydroxysuccinimide are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. Then 6.80 g (15.8 mmol) of the title compound from Example are added 15b and stir for 20 minutes at room temperature. It is cooled to 10 ° C. and adds 9.83 g (47.64 mmol) of N, N'-dicyclohexylcarbodiimide and stirred overnight at room temperature. The reaction solution is poured into a mixture of 1000 ml Acetone / 1000 ml of diethyl ether and the precipitated solid is filtered off. The further purification is carried out by RP-18 chromatography (eluent: Gradient from water / acetonitrile / tetrahydrofuran). After evaporating the Fractions are obtained 22.21 g (85% of theory) of a colorless, amorphous Solid.

Water content: 9.2%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 45.03; H 4.75; Gd 19.02; N 11.86;
Found:
C 45.18; H 4.90; Gd 19.25; N 12.01.

Example 16 N, N-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane Gd complex-10-3-aza-4-oxopentan-5-yl) acid] -4,4'-di (naphth-3- oxyacetic acid] tetrahydrazide

19.56 g (31.76 mmol) Gd complex of 10- (4-carboxy-2-oxo-3-aza-butyl) - 1,4,7,10-tetraaza-cyclododecane-1,4,7-triacetic acid (Gd-Gly-Me-DOTA), 2.69 g (63.52 mmol) lithium chloride and 3.66 g (31.76 mmol) N-hydroxysuccinimide are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. Then 6.8 g (15.8 mmol) of the title compound from Example 15b are added and stir for 20 minutes at room temperature. Cool to 10 ° C and give 9.83 g (47.64 mmol) of N, N'-dicyclohexylcarbodiimide and stirred in overnight Room temperature. The reaction solution is poured into a mixture of 1000 ml Acetone / 1000 ml of diethyl ether and the precipitated solid is filtered off. The further purification is carried out by RP-18 chromatography (eluent: Gradient from water / acetonitrile / tetrahydrofuran). After evaporating the Fractions are obtained 22.35 g (87% of theory) of a colorless, amorphous Solid.

Water content: 8.7%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 44.33; H 4.59; Gd 19.34; N 12.06;
Found:
C 44.17; H 4.66; Gd 19.50; N 12.20.

Example 17 N, N-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane Gd complex 10-1 carboxylate 1- [4- (3-oxypropionic acid)] phenyl methyl] -4,4'-di [naphth-3- (oxyacetic acid)] tetrahydrazide, disodium salt

22.51 g (31.76 mmol) of the title compound from Example 10e, 2.69 g (63.52 mmol) Lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide dissolved in 200 ml of dimethyl sulfoxide with gentle heating. Then there 6.80 g (15.8 mmol) of 2-hydroxy-3-naphthoic acid hydrazide are added and the mixture is stirred 20 Minutes at room temperature. The mixture is cooled to 10 ° C. and 9.83 g (47.64 mmol) are added. N, N'-dicyclohexylcarbodiimide and stirred overnight in room temperature. The reaction solution is poured into a mixture of 1000 ml  Acetone / 1000 ml of diethyl ether and the precipitated solid is filtered off. The further purification is carried out by RP-18 chromatography (eluent: Gradient from water / acetonitrile / tetrahydrofuran). After evaporating the Fractions are dissolved in a little water, the pH to 7.4 with 2N sodium hydroxide solution provided and then freeze-dried. 24.93 g (85% of the Theory) of a colorless, amorphous solid.

Water content: 10.9%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 46.60; H 4.24; Gd 16.95; N 3.06; Na 2.48;
Found:
C 46.44; H 4.31; Gd 17.08; N 9.15; Na 2.55.

Example 18a 9,9-bis (4-methoxycarbonylmethoxy) phenyl] fluorene

30.6 g (87.31 mmol) 9,9-bis (4-hydroxyphenyl) fluorene and 37 g (349 mmol) Sodium carbonate are placed in 200 ml of dimethylformamide. Drips at 60 ° C 29.38 g (192 mmol) of methyl 2-bromoacetate are added and the mixture is stirred for 8 hours 60 ° C. The mixture is allowed to cool to room temperature, the solid is filtered off and the mixture is evaporated the filtrate to dryness in vacuo. The residue is on silica gel chromatographed (eluent: dichloromethane / methanol = 25: 1).

Yield: 40.59 g (94% of theory) of a colorless, crystalline solid.

Elemental analysis:
Calculated:
C 75.29; H 5.30;
Found:
C 75.40; H 5.38.

Example 18b 9,9-bis [4-hydrazinocarboxylmethoxy) phenyl] fluorene

23 g (46.46 mmol) of the title compound from Example 18a are dissolved in 500 ml boiling methanol dissolved and 14.9 g (465 mmol) of hydrazine at the boiling point admitted. The mixture is refluxed for 6 hours. It is evaporated to dryness and crystallizes the residue from a little ethanol.

Yield: 18.61 g (81% of theory) of a colorless, crystalline solid.

Elemental analysis:
Calculated:
C 70.43; H 5.30; N 11.33;
Found:
C 70.56; H 5.41; N 11.46.

Example 18c N, N- [9,9-bis (-phenoxyacetic acid) -fluorene <-N'N'-bis [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-Gd complex- 10- (3-aza-4-oxo-hexan-5-yl) acid] tetrahydrazide

20 g (31.76 mmol) Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-aza-butyl) - 1,4,7,10-tetraaza-cyclododecane-1,4,7-triacetic acid (Gd-Gly-Me-DOTA), 2.69 g (63.52 mmol) lithium chloride and 3.66 g (31.76 mmol) N-hydroxysuccinimide are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. Then 7.81 g (15.8 mmol) of the title compound from Example are added 18b and stir for 20 minutes at room temperature. It is cooled to 10 ° C. and adds 9.83 g (47.64 mmol) of N, N'-dicyclohexylcarbodiimide and stirred overnight at room temperature. The reaction solution is poured out into a mixture  1000 ml acetone / 1000 ml diethyl ether and filter the precipitated solid from. The further purification is carried out by RP-18 chromatography (eluent: Gradient from water / acetonitrile / tetrahydrofuran). After evaporating the Fractions are obtained 23.34 g (86% of theory) of a colorless, amorphous Solid.

Water content: 9.6%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 46.84; H 4.81; Gd 18.31; N 11.41;
Found:
C 46.98; H 4.90; Gd 18.17; N 11.52.

Example 19 N, N- [9,9-bis (4-phenoxyacetic acid) fluorene] -N ', N'-bis (1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-Gd complex-10- <1- carboxylate-1- [4- (3-oxapropionic acid)] - phenyl <-methyl) -tetrahydrazide, Disodium salt

22.51 g (31.76 mmol) of the title compound from Example 10e, 2.69 g (63.52 mmol) Lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide dissolved in 200 ml of dimethyl sulfoxide with gentle heating. Then there 7.81 g (15.8 mmol) of the title compound from Example 18b are added and the mixture is stirred Minutes at room temperature. The mixture is cooled to 10 ° C. and 9.83 g (47.64 mmol) are added. N, N'-dicyclohexylcarbodiimide and stirred overnight in room temperature. The reaction solution is poured into a mixture of 1000 ml Acetone / 1000 ml of diethyl ether and the precipitated solid is filtered off. The further purification is carried out by RP-18 chromatography (eluent: Gradient from water / acetonitrile / tetrahydrofuran). After evaporating the Fractions are dissolved in a little water, the pH to 7.4 with 2N sodium hydroxide solution provided and then freeze-dried. 26.4 g (87% of the Theory) of a colorless, amorphous solid.  

Water content: 7.9%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 48.17; H 4.30; Gd 16.38; N 8.75; Na 2.39;
Found:
C 48.30; H 4.39; Gd 16.50; N 8.86; Na 2.51.

Example 20a Ethylenediamine-N, N'-bis (2-naphthalenesulfonic acid amide)

20 g (333 mmol) of 1,2-diaminoethane, dissolved in 500 ml of pyridine, are added at 0 ° C 166 g (732 mmol) 2-naphthalenesulfonic acid chloride. The mixture is stirred at 0 ° C. for 6 hours. The solution is poured into 2000 ml of water and the precipitated solid filtered off. The solid is recrystallized from a little methanol.

Yield: 127.9 g (94% of theory) of a crystalline solid.

Elemental analysis:
Calculated:
C 64.69; H 4.93; N 6.86; S 7.85;
Found:
C 64.54; H 5.02; N 6.98; S 7.99.

Example 20b 3,6-diaza-3,6-bis (2-naphthalenesulfonyl) octane-1,8-dicarboxylic acid di methyl ester

30 g (73.44 mmol) of the title compound from Example 20a and 40.63 g (294 mmol) Potassium carbonate is placed in 200 ml of dimethylformamide. One drips at 60 ° C 24.78 g (162 mmol) of 2-bromoacetic acid methyl ester and stirred in for 8 hours 60 ° C. The mixture is allowed to cool to room temperature, the solid is filtered off and the mixture is evaporated  the filtrate to dryness in vacuo. The residue is on silica gel chromatographed (Mobile phase: dichloromethane / methanol = 25: 1).

Yield: 37.36 g (87% of theory) of a colorless, crystalline solid.

Elemental analysis:
Calculated:
C 57.52; H 4.83; N 4.79; S 10.97;
Found:
C 57.66; H 4.92; N 4.68; S 11.08.

Example 20c 3,6-diaza-3,6-bis (2-naphthalenesulfonyl) octane-1,8-dicarboxylic acid - bishydrazide

27.16 g (46.46 mmol) of the title compound from Example 18a are dissolved in 500 ml boiling methanol dissolved and 14.9 g (465 mmol) of hydrazine at the boiling point admitted. The mixture is refluxed for 6 hours. It is evaporated to dryness and crystallizes the residue from a little ethanol.

Yield: 23.1 g (85% of theory) of a colorless, crystalline solid.

Elemental analysis:
Calculated:
C 53.41; H 4.83; N 14.37; S 10.97;
Found:
C 53.54; H 4.94; N 14.51; S 11.13.

Example 20d N, N- [3,6-diaza-3,6-bis (2-naphthalenesulfonyl) octane-1.8-dicarbon acid] -N ', N'-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-Gd complex-10- (3-aza-4-oxo-hexane-5 -yl) -acid] - tetrahydrazide

20 g (31.76 mmol) Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-aza-butyl) - 1,4,7,10-tetraaza-cyclododecane-1,4,7-triacetic acid (Gd-Gly-Me-DOTA), 2.69 g (63.52 mmol) lithium chloride and 3.66 g (31.76 mmol) N-hydroxysuccinimide are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. Then 9.24 g (15.8 mmol) of the title compound from Example are added 20c and stir for 20 minutes at room temperature. It is cooled to 10 ° C. and adds 9.83 g (47.64 mmol) of N, N'-dicyclohexylcarbodiimide and stirred overnight at room temperature. The reaction solution is poured out into a mixture 1000 ml acetone / 1000 ml diethyl ether and filter the precipitated solid from. The further purification is carried out by RP-18 chromatography (eluent: Gradient from water / acetonitrile / tetrahydrofuran). After evaporating the Fractions are obtained 24.85 g (87% of theory) of a colorless, amorphous Solid.

Water content: 9.8%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 42.51; H 4.68; Gd 17.39; N 12.39; S 3.55;
Found:
C 42.37; H 4.75; Gd 17.53; N 12.50; S 3.44.

Example 21 N, N- [3,6-diaza-3,6-bis (2-naphthalenesulfonyl) octane-1.8-dicarbon acid] -N ', N'-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraaza cyclododecane-Gd complex-10- <1-carboxylate-1- [4- (3-oxapropion acid)] - phenyl <-methyl) -tetrahydrazide, disodium salt

22.51 g (31.76 mmol) of the title compound from Example 10e, 2.69 g (63.52 mmol) Lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide dissolved in 200 ml of dimethyl sulfoxide with gentle heating. Then there 9.24 g (15.8 mmol) of the title compound from Example 20c are added and the mixture is stirred Minutes at room temperature. The mixture is cooled to 10 ° C. and 9.83 g (47.64 mmol) are added. N, N'-dicyclohexylcarbodiimide and stirred overnight in room temperature. The reaction solution is poured into a mixture of 1000 ml Acetone / 1000 ml of diethyl ether and the precipitated solid is filtered off. The further purification is carried out by RP-18 chromatography (eluent: Gradient from water / acetonitrile / tetrahydrofuran). After evaporating the Fractions are dissolved in a little water, the pH to 7.4 with 2N sodium hydroxide solution provided and then freeze-dried. 27.31 g (86% of the Theory) of a colorless, amorphous solid.

Water content: 10.1%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 44.22; H 4.21; Gd 15.65; N 9.76; Na 2.29; S 3.19;
Found:
C 44.35; H 4.32; Gd 15.71; N 9.89; Na 2.38; S 3.31.

Example 22 a) 2-Methoxy-6 - [(4-methoxycarbonyl) cyclohexylcarbonyl] naphthalene

15.72 g (0.1 mol) of 2-methoxynaphthalene are dissolved in 130 mL of nitrogen Dissolved nitrobenzene, cooled to 12 ° C and with 17.3 g (0.13 mol) of aluminum chloride transferred. Then 26.6 g (0.13 mol) of 4-chlorocarbonyl-cyclohexane carboxylic acid methyl ester (Calaminus, W. et al., Z. Naturforsch. B, 41, 1011-1014 (1986)), dissolved in nitrobenzene, slowly added dropwise at 12 ° C, 2 h at this Temperature and stirred overnight at room temperature. You give it Mix on ice-cold conc. Hydrochloric acid and extracted several times with dichlor methane. The combined organic phase is dried over sodium sulfate  and evaporated to dryness in vacuo. The residue is on silica gel chromatographed (eluent: hexane / ethyl acetate = 3: 1).

Yield: 21.2 g (65% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 73.60; H 6.79;
Found:
C 73.42; H 6.91.

b) 2-methoxy-6 - [(4-carboxy) cyclohexylcarbonyl] naphthalene

20.4 g (62.5 mmol) of that described in Example 22a above Methyl esters are dissolved in dioxane and after addition of 250 mL 2N NaOH stirred overnight at room temperature. Then the solution becomes Evaporate to dryness and dilute the residue between ethyl acetate Hydrochloric acid distributed. The aqueous phase is extracted several times with ethyl acetate and the combined organic phase dried over sodium sulfate.

Yield: 20.3 g (quantitative).

Elemental analysis:
Calculated:
C 73.06; H 6.45;
Found:
C 72.92; H 6.61.

c) 2-methoxy-6 - [(4- [2-benzyloxycarbonylaminoethyl] - carbamoyl) cyclohexylcarbonyl] naphthalene

15.62 g (50 mmol) of those described in Example 22b above Carboxylic acid are dissolved in tetrahydrofuran (THF) and after adding 20 mL triethylamine cooled to -15 ° C in an acetone / ice bath. At this temperature 6.43 mL (50 mmol) isobutyl chloroformate are added dropwise and 15 Minutes stirred.  

In another vessel, 15.0 g (65 mmol) of N- (Benzyloxycarbonyl) ethylenediamine hydrochloride (Eisenbrand, G. et al., Synthesis 1996, 1246-1258) in dichloromethane, twice with dilute Sodium hydroxide solution shaken out, the organic phase over sodium sulfate dried and evaporated to dryness. The remaining oil is in THF dissolved and added dropwise to the reaction described above at -15 ° C. You leave 2 hours at this temperature and overnight at room temperature stir. The suspension is then evaporated to dryness Residue distributed between dichloromethane and water. The organic phase is successively with dil. hydrochloric acid and with sodium carbonate solution washed and dried over sodium sulfate. After evaporation in vacuo recrystallized from hexane.

Yield: 20.3 g (83% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 71.29; H 6.60; N 5.73;
Found:
C 71.13; H 6.88; N 5.67.

d) para-nitrophenyl active ester of the gadolinium complex of 10- [4-carboxy-1- methyl-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

10.0 g (15.9 mmol) of the gadolinium complex of 10- [4-carboxy-1-methyl-2- oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DE 196 52 386, Schering AG, (priority: 4.12.96)) are dissolved in 70 mL water, with 1.28 ml (15.9 mmol) of pyridine were added and the solution was freeze-dried. The Lyophilisate obtained is taken up in 120 mL pyridine, with 7.24 g (23.8 mmol) Bis- (4-nitrophenyl) carbonate added and the suspension at 3 days Room temperature stirred. The solid is then suctioned off with pyridine and dichloromethane and dried at 40 ° C in a vacuum.

Yield: 11.47 g (96.2% of theory)

Elemental analysis:
Calculated:
C 39.99; H 4.43; N 11.19; Gd 20.94;
Found:
C 39.71; H 4.66; N 11.01; Gd 20.32.

e) amide conjugate from the gadolinium complex of 10- [4-carboxy-1-methyl 2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid] and 2- Methoxy-6 - [(4- [2-aminoethyl] carbamoyl) cyclohexylcarbonyl] naphthalene

2.44 g (5 mmol) of the protected amine described in Example 22c dissolved in 25 mL HBr / glacial acetic acid and stirred for 30 minutes at room temperature. After adding 200 mL ether, the resulting suspension becomes overnight stirred, the precipitate filtered off, washed with ether and then in High vacuum dried. The hygroscopic hydrobromide is without further Cleaning further implemented (2.18 g, quantitative).

To 5.63 g (7.5 mmol) of the Gd- described in Example 22d above 3 mL triethylamine and then complex active ester in 75 mL DMF Added 2.18 g (5 mmol) of the amine hydrobromide. The suspension is over Stirred at room temperature overnight and then evaporated to dryness. The residue is dissolved in water and spent one hour with activated carbon stirs. It is filtered off from the coal and for the removal of low molecular weight Components via an Amicon® ultrafiltration membrane YC 05 (cut off: 500 Da) ultrafiltered. The residue is chromatographed on silica gel (mobile solvent: Methanol / water = 2: 1). The combined fractions are evaporated in Water absorbed and freeze-dried.

Yield: 3.63 g (69% of theory) of a colorless powder.

Water content (Karl Fischer): 8.3%.

Elemental analysis (based on the anhydrous substance):
Calculated:
C 49.73; H 5.63; N 10.15; Gd 16.28;
Found:
C 49.52; H 5.88; N 10.09; Gd 15.93.

Example 23 a) N _α [4- (2-methoxynaphth-6-oyl)] cyclohexylcarbonyl) -N _ε (t-butoxycarbonyl) lysine-t-butyl ester

15.62 g (50 mmol) of the carboxylic acid described in Example 22b are in Dissolved THF and after adding 20 mL triethylamine in an acetone / ice bath to -15 ° C chilled. At this temperature, 6.43 mL (50 mmol) of chlor ants Acid isobutyl ester was added dropwise and the mixture was stirred for 15 minutes. About this suspension 16.63 g (55 mmol) of H-Lys (Boc) -OtBu (Wakimasu, M. et al., Chem. Pharm. Bull. 29, 2592-2597 (1981)) was added dropwise in as little THF as possible. The mixture is left at this temperature for 2 hours and at room temperature overnight stir. The suspension is then evaporated to dryness Residue distributed between dichloromethane and water. The organic phase is successively with dil. hydrochloric acid and with sodium carbonate solution washed and dried over sodium sulfate. After evaporation in vacuo the residue is chromatographed on silica gel (eluent: ethyl acetate / ethanol = 9: 1).

Yield: 23.9 g (81% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 69.13; H 7.17; N 4.74;
Found:
C 68.97; H 7.33; N 4.67.

b) N _α [4- (2-methoxynaphth-6-oyl)] cyclohexylcarbonyl) lysine

2.95 g (5 mmol) of the protected ones described in Example 23a above Amino acids are suspended in 30 mL trifluoroacetic acid and added for 2 hours Room temperature stirred. After adding 200 mL ether the suspension Stirred overnight, the precipitate was filtered off and washed thoroughly with ether and then in the presence of KOH under high vacuum by weight constant dried.  

Yield: 2.2 g (quantitative) of a colorless solid.

Elemental analysis:
Calculated:
C 68.16; H 7.32; N 6.36;
Found:
C 68.30; H 7.13; N 6.16.

c) N _ε- lysinamide conjugate from the gadolinium complex of 10- [4-carboxy-1-methyl-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid] and N _α [4- (2-methoxynaphth-6-oyl)] cyclohexylcarbonyl) lysine

To 5.63 g (7.5 mmol) of the Gd complex described in Example 22d 3 mL triethylamine and then 2.2 g (5 mmol) of the lysine derivative described in Example 23b above. The suspension is stirred overnight at room temperature and then evaporated to dryness. The residue is dissolved in water and one hour stirred with activated carbon. It is filtered off from the coal and removed low molecular weight components via an Amicon® ultrafiltration membrane YC 05 (cut off: 500 Da) ultrafiltered. The residue is chromato on silica gel graphed (eluent: methanol / water = 2: 1). The united fractions are evaporated, taken up in water and freeze-dried.

Yield: 4.0 g (72% of theory) of a colorless powder.

Water content (Karl Fischer): 5.3%.

Elemental analysis (based on the anhydrous substance):
Calculated:
C 50.22; H 5.75; N 9.32; Gd 14.94;
Found:
C 50.13; H 5.89; N 9.67; Gd 14.41.

Example 24 a) 2-Methoxy-6 - [(4-methoxycarbonyl) benzoyl] naphthalene

1.57 g (10 mmol) of 2-methoxynaphthalene are dissolved in 15 mL nitro under nitrogen dissolved benzene and mixed with 2.88 g (13 mmol) indium chloride. Subsequently 2.6 g (13 mmol) of 4-chlorocarbonylbenzoic acid methyl ester (Vulakh, E. et al., J. Org. Chem. USSR (Engl. Transl.), 22, 620-627 (1986)), dissolved in Nitrobenzene, slowly added dropwise, 4 h at 50 ° C and overnight in room temperature stirred. The mixture is poured onto ice-cold conc. Hydrochloric acid and extracted several times with dichloromethane. The combined organic phase is dried over sodium sulfate and evaporated to dryness in vacuo. The The residue is chromatographed on silica gel (eluent: hexane / ethyl acetate = 3: 1).

Yield: 1.95 g (61% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 74.99; H 5.03;
Found:
C 74.62; H 4.91.

b) 2-methoxy-6 - [(4-carboxy) benzoyl] naphthalene

2.0 g (6.25 mmol) of that described in Example 24a above Methyl esters are dissolved in dioxane and after addition of 25 mL 2N NaOH stirred overnight at room temperature. Then the solution becomes Evaporate to dryness and dilute the residue between ethyl acetate Hydrochloric acid distributed. The aqueous phase is extracted several times with ethyl acetate and the combined organic phase dried over sodium sulfate.

Yield: 1.9 g (quantitative).

Elemental analysis:
Calculated:
C 74.50; H 4.61;
Found:
C 74.32; H 4.60.

c) 2-methoxy-6 - [(4- [2-benzyloxycarbonylaminoethyl] carbamoyl) benzoyl] - naphthalene

1.53 g (5 mmol) of the carboxylic acid described in Example 24b above are dissolved in THF and after adding 2 mL triethylamine in acetone / ice bath cooled to -15 ° C. At this temperature, 0.64 mL (5 mmol) Isobutyl chloroformate was added dropwise and the mixture was stirred for 15 minutes. In another vessel, 1.5 g (6.5 mmol) of N- (benzyloxy carbonyl) ethylenediamine hydrochloride (Eisenbrand, G. et al., Synthesis 1996, 1246-1258) in dichloromethane, twice with diluted Sodium hydroxide solution shaken out, the organic phase over sodium sulfate dries and evaporated to dryness. The remaining oil is dissolved in THF and added dropwise to the reaction described above at -15 ° C. You leave 2 Hours at this temperature and overnight at room temperature stir. The suspension is then evaporated to dryness Residue distributed between dichloromethane and water. The organic phase is successively with dil. hydrochloric acid and with sodium carbonate solution washed and dried over sodium sulfate. After evaporation in vacuo recrystallized from hexane.

Yield: 1.94 g (80% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 71.88; H 5.82; N 5.78;
Found:
C 71.70; H 5.94; N 5.66.

d) amide conjugate from the gadolinium complex of 10- [4-carboxy-1-methyl- 2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid] and 2- Methoxy-6 - [(4- [2-aminoethyl] carbamoyl) benzoyl] naphthalene

2.42 g (5 mmol) of the protected described in Example 24c above Amines are dissolved in 3 mL HBr / glacial acetic acid and 30 minutes at room temperature touched. After adding 50 mL ether, the resulting suspension is over  Stirred overnight, the precipitate was filtered off, washed with ether and then dried in a high vacuum. The hygroscopic hydrobromide is implemented without further purification (2.16 g, quantitative). To 5.63 g (7.5 mmol) of the Gd complex described in Example 22d 3 mL triethylamine and then 2.16 g (5 mmol) are activated ester in 75 mL DMF of the amine hydrobromide. The suspension is at overnight Stirred at room temperature and then evaporated to dryness. The The residue is dissolved in water and stirred with activated carbon for one hour. It is filtered off from the coal and to remove low molecular weight components Ultrafiltered through an Amicon® ultrafiltration membrane YC 05 (cut off: 500 Da). The residue is chromatographed on silica gel (mobile solvent: Methanol / water = 2: 1). The combined fractions are evaporated in Water absorbed and freeze-dried.

Yield: 3.43 g (65% of theory) of a colorless powder.

Water content (Karl Fischer): 9.1%.

Elemental analysis (based on the anhydrous substance):
Calculated:
C 50.04; H 5.04; N 10.21; Gd 16.38;
Found:
C 49.79; H 4.88; N 10.48; DG 15.99.

Example 25 a) N _α [4- (2-methoxynaphth-6-oyl)] benzoyl) -N _ε (t-butoxycarbonyl) lysine t-butyl ester

15.31 g (50 mmol) of the carboxylic acid described in Example 24b are in Dissolved THF and after adding 20 mL triethylamine in an acetone / ice bath to -15 ° C chilled. At this temperature, 6.43 mL (50 mmol) of chlor ants Acid isobutyl ester was added dropwise and the mixture was stirred for 15 minutes. About this suspension 16.63 g (55 mmol) of H-Lys (Boc) -OtBu (Wakimasu, M. et al., Chem. Pharm. Bull. 29, 2592-2597 (1981)) was added dropwise in as little THF as possible. The mixture is left at this temperature for 2 hours and at room temperature overnight  stir. The suspension is then evaporated to dryness Residue distributed between dichloromethane and water. The organic phase is successively with dil. hydrochloric acid and with sodium carbonate solution washed and dried over sodium sulfate. After evaporation in vacuo the residue is chromatographed on silica gel (eluent: ethyl acetate / ethanol = 9: 1).

Yield: 24.64 g (84% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 69.61; H 6.53; N 4.77;
Found:
C 69.40; H 6.31; N 4.67.

b) N _α [4- (2-methoxynaphth-6-oyl) benzoyl] lysine

2.93 g (5 mmol) of the protected ones described in Example 25a above Amino acids are suspended in 30 mL trifluoroacetic acid and added for 2 hours Room temperature stirred. After adding 200 mL ether the suspension Stirred overnight, the precipitate was filtered off and washed thoroughly with ether and then in the presence of KOH under high vacuum by weight constant dried.

Yield: 2.2 g (quantitative) of a colorless solid.

Elemental analysis:
Calculated:
C 68.79; H 6.47; N 6.42;
Found:
C 68.60; H 6.77; N 6.48.

c) N _ε- lysinamide conjugate from the gadolinium complex of 10- [4-carboxy-1-methyl-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid] and N _α [4- (2-methoxynaphth-6-oyl) benzoyl] lysine

To 5.63 g (7.5 mmol) of the Gd complex described in Example 22d 3 mL triethylamine and then 2.2 g (5 mmol)  of the lysine derivative described in Example 25b above. The suspension is stirred overnight at room temperature and then evaporated to dryness. The residue is dissolved in water and one hour stirred with activated carbon. It is filtered off from the coal and removed low molecular weight components via an Amicon® ultrafiltration membrane YC 05 (cut off: 500 Da) ultrafiltered. The residue is chromato on silica gel graphed (eluent: methanol / water = 2: 1). The united fractions are evaporated, taken up in water and freeze-dried.

Yield: 3.96 g (70% of theory) of a colorless powder.

Water content (Karl Fischer): 7.3%.

Elemental analysis (based on the anhydrous substance):
Calculated:
C 50.42; H 5.38; N 9.35; Gd 15.00;
Found:
C 50.48; H 5.20; N 9.61; Gd 14.64.

Example 26 a) 2-Methoxy-6 - [(4-methoxycarbonyl) naphth-1-oyl] naphthalene

1.57 g (10 mmol) of 2-methoxynaphthalene are dissolved in 15 mL under nitrogen Dissolved nitrobenzene and mixed with 2.88 g (13 mmol) indium chloride. Then 3.23 g (13 mmol) of 1,4-naphthalenedicarboxylic acid monochloride monomethyl ester (Frischkorn, Hans et al., Ger. Offen. (1978), DE 27 15 567), dissolved in nitrobenzene, slowly added dropwise, 4 h at 50 ° C and above Stirred at room temperature overnight. The mixture is poured onto ice-cold conc. Hydrochloric acid and extracted several times with dichloromethane. The united organic Phase is dried over sodium sulfate and brought to dryness in vacuo steams. The residue is chromatographed on silica gel (mobile solvent: Hexane / ethyl acetate = 4: 1).

Yield: 2.53 g (68% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 77.40; H 5.41;
Found:
C 77.10; H 5.33.

b) 2-methoxy-6 - [(4-carboxy) naphth-1-oyl] naphthalene

2.33 g (6.25 mmol) of that described in Example 26a above Methyl esters are dissolved in dioxane and after addition of 25 mL 2N NaOH stirred overnight at room temperature. Then the solution becomes Evaporate to dryness and dilute the residue between ethyl acetate Hydrochloric acid distributed. The aqueous phase is extracted several times with ethyl acetate and the combined organic phase dried over sodium sulfate.

Yield: 2.2 g (quantitative).

Elemental analysis:
Calculated:
C 77.08; H 5.06;
Found:
C 76.90; H 5.31.

c) 2-methoxy-6 - [(4- [2-benzyloxycarbonylaminoethyl] carbamoyl) naphth-1-oyl] - naphthalene

1.79 g (5 mmol) of the carboxylic acid described in Example 26b above are dissolved in THF and after adding 2 mL triethylamine in acetone / ice bath cooled to -15 ° C. At this temperature, 0.64 mL (5 mmol) Isobutyl chloroformate was added dropwise and the mixture was stirred for 15 minutes. In another vessel, 1.5 g (6.5 mmol) of N- (benzyloxy carbonyl) ethylenediamine hydrochloride (Eisenbrand, G. et al., Synthesis 1996, 1246-1258) in dichloromethane, twice with diluted Sodium hydroxide solution shaken out, the organic phase over sodium sulfate dried and evaporated to dryness. The remaining oil is in THF dissolved and added dropwise to the reaction described above at -15 ° C. You leave 2 hours at this temperature and overnight at room temperature stir. The suspension is then evaporated to dryness  Residue distributed between dichloromethane and water. The organic phase is successively with dil. hydrochloric acid and with sodium carbonate solution washed and dried over sodium sulfate. After evaporation in vacuo recrystallized from hexane.

Yield: 2.36 g (88% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 73.86; H 6.01; N 5.22;
Found:
C 73.70; H 5.94; N 5.47.

d) amide conjugate from the gadolinium complex of 10- [4-carboxy-1-methyl- 2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid] and 2- Methoxy-6 - [(4-2-aminoethyl] carbamoyl) naphth-1-oyl] naphthalene

2.68 g (5 mmol) of the protected described in Example 26c above Amines are dissolved in 3 mL HBr / glacial acetic acid and 30 minutes at room temperature touched. After adding 50 mL ether, the resulting suspension is over Stirred overnight, the precipitate was filtered off, washed with ether and on finally dried in a high vacuum. The hygroscopic hydrobromide becomes implemented without further purification (2.42 g, quantitative). To 5.63 g (7.5 mmol) of the Gd complex described in Example 22d 3 mL triethylamine and then 2.42 g (5 mmol) are activated ester in 75 mL DMF of the amine hydrobromide. The suspension is at overnight Stirred at room temperature and then evaporated to dryness. The The residue is dissolved in water and stirred with activated carbon for one hour. It is filtered off from the coal and to remove low molecular weight components Ultrafiltered through an Amicon® ultrafiltration membrane YC 05 (cut off: 500 Da). The residue is chromatographed on silica gel (mobile solvent: Methanol / water = 3: 1). The combined fractions are evaporated in Water absorbed and freeze-dried.  

Yield: 3.81 g (69% of theory) of a colorless powder.

Water content (Karl Fischer): 8.3%.

Elemental analysis (based on the anhydrous substance):
Calculated:
C 52.21; H 5.18; N 9.69; Gd 15.54;
Found:
C 51.94; H 5.11; N 9.67; Gd 15.28.

Example 27 a) 2-Dimethylamino-6 - [(4-carboxy) cyclohexylcarbonyl] naphthalene

7.81 g (25 mmol) of the carboxylic acid described in Example 22b are in THF dissolved and after adding 5.1 g (100 mmol) of lithium dimethylamide (Aldrich) refluxed for 8 hours and then at overnight Room temperature stirred. The mixture is then evaporated to dryness Residue between ethyl acetate and aqueous. Citric acid solution distributed and the organic phase finally washed with water and over sodium sulfate dried. The crude product is chromatographed on silica gel (eluent: Diisopropyl ether / glacial acetic acid = 19: 1).

Yield: 3.66 g (45% of theory).

Elemental analysis (based on the anhydrous substance):
Calculated:
C 73.82; H 7.12; N 4.30;
Found:
C 74.10; H 6.88; N 4.07.

b) N _α [4- (2-dimethylaminonaphth-6-oyl)] cyclohexylcarbonyl) - N _ε (benzloxycarbonyl) lysine methyl ester

1.63 g (5 mmol) of the carboxylic acid described in Example 27a above are dissolved in THF and after adding 2 mL triethylamine in acetone / ice bath cooled to -15 ° C. At this temperature, 0.64 mL (5 mmol) Isobutyl chloroformate was added dropwise and the mixture was stirred for 15 minutes. To this  Suspension at -15 ° C 1.62 g (5.5 mmol) H-Lys (Z) -OMe (Slotin, L.A. et al., Can. J. Chem. 55, 4257-66 (1977)) was added dropwise in as little THF as possible. Man leaves 2 hours at this temperature and overnight at room temperature stir. The suspension is then evaporated to dryness Residue distributed between dichloromethane and water. The organic phase is successively with dil. hydrochloric acid and with sodium carbonate solution washed and dried over sodium sulfate. After evaporation in vacuo the residue is chromatographed on silica gel (eluent: ethyl acetate / ethanol = 9: 1).

Yield: 2.59 g (86% of theory).

Elemental analysis:
Calculated:
C 69.86; H 7.20; N 6.98;
Found:
C 69.91; H 7.44; N 6.67.

c) N _ε- lysinamide conjugate from the gadolinium complex of 10- [4-carboxy-1-methyl-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid] and N _α [4- (2-dimethylamino-naphth-6-oyl)] cyclohexylcarbonyl) -lysine

3.01 g (5 mmol) of the protected amino acid described in Example 27b above are dissolved in 25 mL HBr / glacial acetic acid and stirred for 30 minutes at room temperature. After adding 200 mL ether, the resulting suspension is stirred overnight, the precipitate is filtered off, washed with ether and dried in vacuo. The hydrobromide is then dissolved in methanol, mixed with 25 mL 2 N sodium hydroxide solution and stirred overnight at room temperature. The organic solvent is then evaporated, the aqueous solution is adjusted to pH 8.5 with dilute hydrochloric acid and evaporated to dryness. The resulting N _α [4- (2-dimethylamino-naphth-6-oyl)] cyclohexylcarbonyl) lysine is reacted without further purification (2.3 g, quantitative).

3 ml of triethylamine and then 2.3 g (5 mmol) of the lysine derivative described are added to 5.63 g (7.5 mmol) of the Gd complex active ester described in Example 22d in 75 mL DMF. The suspension is stirred overnight at room temperature and then evaporated to dryness. The residue is dissolved in water and stirred with activated carbon for one hour. It is filtered off from the coal and ultrafiltered through an Amicon® ultra filtration membrane YC 05 (cut off: 500 Da). The residue is chromatographed on silica gel (mobile solvent: methanol / water = 2: 1). The combined fractions are evaporated and taken up in a little water. The solution is mixed with 4 mL anion exchanger IRA 410 (OH ^- - form), filtered and the filtrate freeze-dried.

Yield: 4.1 g (72% of theory).

Water content (Karl Fischer): 7.3%.

Elemental analysis (based on the anhydrous substance):
Calculated:
C 50.74; H 5.96; N 10.52; Gd 14.76;
Found:
C 50.43; H 5.96; N 10.67; Gd 14.21.

Example 28 a) N _α [4- (2-methoxynaphth-6-oyl) naphth-1-oyl] -N _ε (t-butoxycarbonyl) -lysine-t-butyl ester

17.92 g (50 mmol) of the carboxylic acid described in Example 26b are in Dissolved THF and after adding 20 mL triethylamine in an acetone / ice bath to -15 ° C chilled. At this temperature, 6.43 mL (50 mmol) of chlor ants Acid isobutyl ester was added dropwise and the mixture was stirred for 15 minutes. About this suspension 16.63 g (55 mmol) of H-Lys (Boc) -OtBu (Wakimasu, M. et al., Chem. Pharm. Bull. 29, 2592-2597 (1981)) was added dropwise in as little THF as possible. The mixture is left at this temperature for 2 hours and at room temperature overnight stir. The suspension is then evaporated to dryness Residue distributed between dichloromethane and water. The organic phase  is successively with dil. hydrochloric acid and with sodium carbonate solution washed and dried over sodium sulfate. After evaporation in vacuo the residue is chromatographed on silica gel (eluent: ethyl acetate / ethanol = 10: 1).

Yield: 31.94 g (79% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 71.45; H 6.63; N 4.39;
Found:
C 71.10; H 6.39; N 4.66.

b) N _α [4- (2-methoxynaphth-6-oyl) naphth-1-oyl] lysine

3.19 g (5 mmol) of the protected ones described in Example 28a above Amino acids are suspended in 30 mL trifluoroacetic acid and added for 2 hours Room temperature stirred. After adding 200 mL ether the suspension Stirred overnight, the precipitate was filtered off and washed thoroughly with ether and then in the presence of KOH under high vacuum by weight constant dried.

Yield: 2.5 g (quantitative) of a colorless solid.

Elemental analysis:
Calculated:
C 71.29; H 6.60; N 5.73;
Found:
C 71.21; H 6.77; N 5.48.

c) N _ε- lysinamide conjugate from the gadolinium complex of 10- [4-carboxy-1-methyl-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid] and N _α [4- (2-methoxynaphth-6-oyl) naphth-1-oyl] -lysine

To 5.63 g (7.5 mmol) of the Gd complex described in Example 22d 3 mL triethylamine and then 2.5 g (5 mmol)  of the lysine derivative described in Example 28b above. The suspension is stirred overnight at room temperature and then evaporated to dryness. The residue is dissolved in water and one Hour with activated carbon. It is filtered off from the coal and over a Amicon® ultrafiltration membrane YC 05 (cut off: 500 Da) ultrafiltered. The The residue is chromatographed on silica gel (eluent: methanol / water 3: 1). The combined fractions are evaporated and taken up in water and freeze-dried.

Yield: 5.0 g (83% of theory) of a colorless powder.

Water content (Karl Fischer): 8.9%.

Elemental analysis (based on the anhydrous substance):
Calculated:
C 52.40; H 5.50; N 8.91; Gd 14.29;
Found:
C 52.48; H 5.70; N 8.69; Gd 14.04.

Example 29 a) 2-Dimethylamino-6 - [(4-carboxy) benzoyl] naphthalene

7.66 g (25 mmol) of the carboxylic acid described in Example 24b are in THF dissolved and after adding 5.1 g (100 mmol) of lithium dimethylamide (Aldrich) refluxed for 8 hours and then at overnight Room temperature stirred. The mixture is then evaporated to dryness Residue between ethyl acetate and aqueous, citric acid solution and the organic phase finally washed with water and over sodium sulfate dried. The crude product is chromatographed on silica gel (eluent: Diisopropyl ether / glacial acetic acid = 19: 1).

Yield: 3.83 g (48% of theory).

Elemental analysis (based on the anhydrous substance):
Calculated:
C 75.22; H 5.37; N 4.39;
Found:
C 75.10; H 5.13; N 4.22.

b) N _α [4- (2-dimethylamino-naphth-6-oyl)] benzoyl) -N _ε (benzyloxycarbonyl) lysine methyl ester

1.60 g (5 mmol) of the carboxylic acid described in Example 29a above are dissolved in THF and after adding 2 mL triethylamine in acetone / ice bath cooled to -15 ° C. At this temperature, 0.64 mL (5 mmol) Isobutyl chloroformate was added dropwise and the mixture was stirred for 15 minutes. To this Suspension at -15 ° C 1.62 g (5.5 mmol) H-Lys (Z) -OMe (Slotin, L.A. et al., Can. J. Chem. 55, 4257-66 (1977)) was added dropwise in as little THF as possible. Man leaves 2 hours at this temperature and overnight at room temperature stir. The suspension is then evaporated to dryness Residue distributed between dichloromethane and water. The organic phase is successively with dil. hydrochloric acid and with sodium carbonate solution washed and dried over sodium sulfate. After evaporation in vacuo the residue is chromatographed on silica gel (eluent: ethyl acetate / ethanol = 9: 1).

Yield: 2.44 g (82% of theory).

Elemental analysis:
Calculated:
C 70.57; H 6.26; N 7.05;
Found:
C 70.80; H 6.41; N 7.27.

c) N _ε- lysinamide conjugate from the gadolinium complex of 10- [4-carboxy-1-methyl-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid] and N _α [4- (2-dimethylamino-naphth-6-oyl)] benzoyl) lysine

2.98 g (5 mmol) of the protected amino acid described in Example 29b above are dissolved in 25 mL HBr / glacial acetic acid and stirred for 30 minutes at room temperature. After adding 200 mL ether, the resulting suspension is stirred overnight, the precipitate is filtered off, washed with ether and dried in vacuo. The hydrobromide is then dissolved in methanol, mixed with 25 ml of 2N sodium hydroxide solution and stirred overnight at room temperature. The organic solvent is then evaporated off, the aqueous solution is adjusted to pH 8.5 with dilute hydrochloric acid and evaporated to dryness. The resulting N _α [4- (2-dimethylamino-naphth-6-oyl)] benzoyl) -lysine is reacted without further purification (2.2 g, quantitative). 3 ml of triethylamine and then 2.2 g (5 mmol) of the lysine derivative described are added to 5.63 g (7.5 mmol) of the Gd complex active ester described in Example 22d in 75 mL DMF. The suspension is stirred overnight at room temperature and then evaporated to dryness. The residue is dissolved in water and triturated with activated carbon for one hour. It is filtered off from the coal and ultrafiltered through an Amicon® ultra filtration membrane YC 05 (cut off: 500 Da). The residue is chromatographed on silica gel (mobile solvent: methanol / water = 2: 1). The combined fractions are evaporated and taken up in a little water. The solution is mixed with 4 mL anion exchanger IRA 410 (OH ^- - form), filtered and the filtrate freeze-dried.

Yield: 4.66 g (80% of theory).

Water content (Karl Fischer): 9.0%.

Elemental analysis (based on the anhydrous substance):
Calculated:
C 51.03; H 5.42; N 10.58; Gd 14.85;
Found:
C 50.76; H 5.21; N 10.67; Gd 14.40.

Example 30 a) 1-Methoxy-4 - [(4-methoxycarbonyl) cyclohexylcarbonyl] naphthalene

15.72 g (0.1 mol) of 1-methoxynaphthalene are dissolved in 130 mL of nitrogen Dissolved nitrobenzene, cooled to 12 ° C and with 17.3 g (0.13 mol) of aluminum chloride transferred. Then 26.6 g (0.13 mol) of 4-chlorocarbonyl-cyclohexane carboxylic acid methyl ester (Calaminus, W. et al., Z. Naturforsch. B, 41, 1011-1014  (1986)), dissolved in nitrobenzene, slowly added dropwise at 12 ° C. for 2 hours this temperature and stirred overnight at room temperature. You give it Mix on ice-cold conc. Hydrochloric acid and extracted several times with dichlor methane. The combined organic phase is dried over sodium sulfate and evaporated to dryness in vacuo. The residue is on silica gel chromatographed (eluent: hexane / ethyl acetate = 3: 1).

Yield: 22.5 g (69% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 73.60; H 6.79;
Found:
C 73.73; H 6.54.

b) 1-methoxy-4 - [(4-carboxy) cyclohexylcarbonyl] naphthalene

20.4 g (62.5 mmol) of that described in Example 30a above Methyl esters are dissolved in dioxane and after addition of 250 mL 2N NaOH stirred overnight at room temperature. Then the solution becomes Evaporate to dryness and dilute the residue between ethyl acetate Hydrochloric acid distributed. The aqueous phase is extracted several times with ethyl acetate and the combined organic phase dried over sodium sulfate.

Yield: 20.3 g (quantitative).

Elemental analysis:
Calculated:
C 73.06; H 6.45;
Found:
C 72.81; H 6.22.

c) 1-methoxy-4 - [(4- [2-benzyloxycarbonylaminoethyl] - carbamoyl) cyclohexylcarbonyl] naphthalene

15.62 g (50 mmol) of those described in Example 30b above Carboxylic acid are dissolved in THF and after adding 20 mL triethylamine in  Acetone / ice bath cooled to -15 ° C. At this temperature, 6.43 mL (50 mmol) Isobutyl chloroformate was added dropwise and the mixture was stirred for 15 minutes. In another vessel, 15.0 g (65 mmol) of N- (benzyloxy carbonyl) ethylenediamine hydrochloride (Eisenbrand, G. et al., Synthesis 1996, 1246-1258) in dichloromethane, twice with dilute sodium bicarbonate lye extracted, the organic phase dried over sodium sulfate and evaporated to dryness. The remaining 27426 00070 552 001000280000000200012000285912731500040 0002010002939 00004 27307nd oil is dissolved in THF and added to the The reaction described above was added dropwise at -15 ° C. Allow 2 hours this temperature and stir overnight at room temperature. Then The suspension is evaporated to dryness, the residue between Dichloromethane and water distributed. The organic phase is added in succession dil. hydrochloric acid and washed with sodium carbonate solution and over Dried sodium sulfate. After evaporation in vacuo, hexane becomes recrystallized.

Yield: 19.6 g (80% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 71.29; H 6.60; N 5.73;
Found:
C 71.40; H 6.42; N 5.49.

d) para-nitrophenyl active ester of the gadolinium complex of 10- [4-carboxy-2- oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

9.79 g (15.9 mmol) of the gadolinium complex of 10- [4-carboxy-2-oxo-3- azabutyl] -1,4,7,10-tetraazacyclododecan-1,4,7-triacetic acid (DE 196 52 386, Schering AG, (priority: 4.12.96)) are dissolved in 70 mL water, with 1.28 mL (15.9 mmol) of pyridine were added and the solution was freeze-dried. The received Lyophilisate is taken up in 120 mL pyridine, with 7.24 g (23.8 mmol) bis- (4- nitrophenyl) carbonate and the suspension for 3 days at room temperature touched. The solid is then suctioned off with pyridine and dichloro washed methane and dried at 40 ° C in a vacuum.

Yield: 11.0 g (93.9% of theory).  

Elemental analysis:
Calculated:
C 39.12; H 4.24; N 11.41; Gd 21.34;
Found:
C 39.61; H 4.30; N 11.77; Gd 20.87.

e) Amide conjugate from the gadolinium complex of 10- [4-carboxy-2-oxo-3- azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid] and 1-methoxy-4- [(4- [2-aminoethyl] carbamoyl) cyclohexylcarbonyl] naphthalene

2.44 g (5 mmol) of the protected amine described in Example 30c dissolved in 25 mL HBr / glacial acetic acid and stirred for 30 minutes at room temperature. After adding 200 mL ether, the resulting suspension becomes overnight stirred, the precipitate filtered off, washed with ether and then in High vacuum dried. The hygroscopic hydrobromide is without further Cleaning further implemented (2.18 g, quantitative).

To 5.53 g (7.5 mmol) of the Gd- described in Example 30d above 3 mL triethylamine and then complex active ester in 75 mL DMF Added 2.18 g (5 mmol) of the amine hydrobromide. The suspension is over Stirred at room temperature overnight and then evaporated to dryness. The residue is dissolved in water and one hour with activated carbon touched. It is filtered off from the coal and removed low molecular weight components via an Amicon® ultrafiltration membrane YC 05 (cut off: 500 Da) ultrafiltered. The residue is on silica gel chromatographed (eluent: methanol / water = 2: 1). The United Fractions are evaporated, taken up in water and freeze-dried.

Yield: 3.58 g (70% of theory) of a colorless powder.

Water content (Karl Fischer): 7.0%.

Elemental analysis (based on the anhydrous substance):
Calculated:
C 49.20; H 5.50; N 10.30; Gd 16.52;
Found:
C 49.00; H 5.41; N 10.53; Cd 16.22.

Example 31 a) 1-Dimethylamino-4 - [(4-carboxy) cyclohexylcarbonyl] naphthalene

7.81 g (25 mmol) of the carboxylic acid described in Example 30b are in THF dissolved and after adding 5.1 g (100 mmol) of lithium dimethylamide (Aldrich) refluxed for 8 hours and then at overnight Room temperature stirred. The mixture is then evaporated to dryness Residue between ethyl acetate and aqueous. Citric acid solution distributed and the organic phase finally washed with water and over sodium sulfate dried. The crude product is chromatographed on silica gel (eluent: Diisopropyl ether / glacial acetic acid = 19: 1).

Yield: 4.0 g (49% of theory).

Elemental analysis (based on the anhydrous substance):
Calculated:
C 73.82; H 7.12; N 4.30;
Found:
C 74.07; H 7.11; N 4.44.

b) N _α [4- (1-dimethylamino-naphth-4-oyl)] cyclohexylcarbonyl) - N _ε (benzloxycarbonyl) lysine methyl ester

1.63 g (5 mmol) of the carboxylic acid described in Example 31a above are dissolved in THF and after adding 2 mL triethylamine in Acetone / ice bath cooled to -15 ° C. At this temperature, 0.64 mL (5 mmol) Isobutyl chloroformate was added dropwise and the mixture was stirred for 15 minutes. To 1.62 g (5.5 mmol) of H-Lys (Z) -OMe (slotin, L.A. et al., Can. J. Chem. 55, 4257-66 (1977)) in as little THF as possible drips. The mixture is left at this temperature for 2 hours and overnight Stir in room temperature. The suspension then dries evaporated, the residue partitioned between dichloromethane and water. The  organic phase is successively with dil. hydrochloric acid and with sodium washed carbonate solution and dried over sodium sulfate. To Evaporation in vacuo, the residue is chromatographed on silica gel (Eluent: ethyl acetate / ethanol = 9: 1).

Yield: 2.71 g (90% of theory).

Elemental analysis:
Calculated:
C 69.86; H 7.20; N 6.98;
Found:
C 69.61; H 7.08; N 6.89.

c) N _ε- lysinamide conjugate from the gadolinium complex of 10- [4-carboxy-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid] and N _α [4- (1-dimethylamino-naphth-4-oyl)] cyclohexylcarbonyl) lysine

3.01 g (5 mmol) of the protected amino acid described in Example 31b above are dissolved in 25 mL HBr / glacial acetic acid and stirred for 30 minutes at room temperature. After adding 200 mL ether, the resulting suspension is stirred overnight, the precipitate is filtered off, washed with ether and dried in vacuo. The hydrobromide is then dissolved in methanol, mixed with 25 mL 2 N sodium hydroxide solution and stirred overnight at room temperature. The organic solvent is then evaporated, the aqueous solution is adjusted to pH 8.5 with dilute hydrochloric acid and evaporated to dryness. The resulting N _α [4- (1-dimethylamino-naphth-4-oyl)] cyclohexylcarbonyl) lysine is reacted without further purification (2.3 g, quantitative).

3 ml of triethylamine and then 2.3 g (5 mmol) of the lysine derivative described are added to 5.53 g (7.5 mmol) of the Gd complex active ester described in Example 30d in 75 mL DMF. The suspension is stirred overnight at room temperature and then evaporated to dryness. The residue is dissolved in water and stirred with activated carbon for one hour. It is filtered off from the coal and ultrafiltered through an Amicon® ultrafiltration membrane YC 05 (cut off: 500 Da). The residue is chromatographed on silica gel (mobile solvent: methanol / water = 2: 1). The combined fractions are evaporated and taken up in a little water. The solution is mixed with 4 mL anion exchanger IRA 410 (OH ^- - form), filtered and the filtrate freeze-dried.

Yield: 4.3 g (74% of theory).

Water content (Karl Fischer): 10.0%.

Elemental analysis (based on the anhydrous substance):
Calculated:
C 50.27; H 5.85; N 10.66; Gd 14.96;
Found:
C 50.40; H 5.62; N 10.40; Gd 14.55.

Example 32 a) 1-Methoxy-4 - [(4-methoxycarbonyl) naphth-1-oyl] naphthalene

1.57 g (10 mmol) of 1-methoxynaphthalene are dissolved in 15 mL under nitrogen Dissolved nitrobenzene and mixed with 2.88 g (13 mmol) indium chloride. Then 3.23 g (13 mmol) of 1,4-naphthalenedicarboxylic acid monochloride monomethyl ester (Frischkorn, Hans et al., Ger. Offen. (1978), DE 27 15 567), dissolved in nitrobenzene, slowly added dropwise, 4 h at 50 ° C and above Stirred at room temperature overnight. The mixture is poured onto ice-cold conc. Hydrochloric acid and extracted several times with dichloromethane. The united organic Phase is dried over sodium sulfate and dried in vacuo evaporated. The residue is chromatographed on silica gel (mobile solvent: Hexane / ethyl acetate = 4: 1).

Yield: 2.64 g (71% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 77.40; H 5.41;
Found:
C 77.42; H 5.19.

b) 1-methoxy-4 - [(4-carboxy) naphth-1-oyl] naphthalene

2.33 g (6.25 mmol) of that described in Example 32a above Methyl esters are dissolved in dioxane and after addition of 25 mL 2N NaOH stirred overnight at room temperature. Then the solution becomes Evaporated to dryness and the residue between ethyl acetate and dil. Hydrochloric acid distributed. The aqueous phase is extracted several times with ethyl acetate and the combined organic phase dried over sodium sulfate.

Yield: 2.2 g (quantitative).

Elemental analysis:
Calculated:
C 77.08; H 5.06;
Found:
C 76.81; H 5.16.

c) 1-methoxy-4 - [(4- [2-benzyloxycarbonylaminoethyl] carbamoyl) naphth-1-oyl] - naphthalene

1.79 g (5 mmol) of the carboxylic acid described in Example 32b above are dissolved in THF and after adding 2 mL triethylamine in Acetone / ice bath cooled to -15 ° C. At this temperature, 0.64 mL (5 mmol) Isobutyl chloroformate was added dropwise and the mixture was stirred for 15 minutes. In another vessel, 1.5 g (6.5 mmol) of N- (Benzyloxycarbonyl) ethylenediamine hydrochloride (Eisenbrand, G. et al., Synthesis 1996, 1246-1258) in dichloromethane, twice with dilute Sodium hydroxide solution shaken out, the organic phase over sodium sulfate dried and evaporated to dryness. The remaining oil is in THF dissolved and added dropwise to the reaction described above at -15 ° C. You leave 2 hours at this temperature and overnight at room temperature stir. The suspension is then evaporated to dryness Residue distributed between dichloromethane and water. The organic phase is successively with dil. hydrochloric acid and with sodium carbonate solution  washed and dried over sodium sulfate. After evaporation in vacuo recrystallized from hexane.

Yield: 2.25 g (84% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 73.86; H 6.01; N 5.22;
Found:
C 73.53; H 5.81; N 5.23.

d) amide conjugate from the gadolinium complex of 10- [4-carboxy-1-methyl- 2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid] and 1- Methoxy-4 - [(4- [2-aminoethyl] carbamoyl) naphth-1-oyl] naphthalene

2.68 g (5 mmol) of the protected described in Example 32c above Amines are dissolved in 3 mL HBr / glacial acetic acid and 30 minutes at room temperature touched. After adding 50 mL ether, the resulting suspension is over Stirred overnight, the precipitate was filtered off, washed with ether and then dried in a high vacuum. The hygroscopic hydrobromide is implemented without further purification (2.42 g, quantitative). To 5.63 g (7.5 mmol) of the Gd complex described in Example 22d 3 mL triethylamine and then 2.42 g (5 mmol) are activated ester in 75 mL DMF of the amine hydrobromide. The suspension is at overnight Stirred at room temperature and then evaporated to dryness. The The residue is dissolved in water and stirred with activated carbon for one hour. It is filtered off from the coal and to remove low molecular weight components Ultrafiltered through an Amicon® ultrafiltration membrane YC 05 (cut off: 500 Da). The residue is chromatographed on silica gel (mobile solvent: Methanol / water = 3: 1). The combined fractions are evaporated in Water absorbed and freeze-dried.

Yield: 4.31 g (78% of theory) of a colorless powder.

Water content (Karl Fischer): 8.3%.

Elemental analysis (based on the anhydrous substance):
Calculated:
C 52.21; H 5.18; N 9.69; Gd 15.54;
Found:
C 52.05; H 4.94; N 9.88; Gd 15.12.

Example 33 a) N _α [4- (1-methoxynaphth-4-oyl) naphth-1-oyl] -N _ε (t-butoxycarbonyl) -lysine-t-butyl ester

17.92 g (50 mmol) of the carboxylic acid described in Example 32b are in Dissolved THF and after adding 20 mL triethylamine in an acetone / ice bath to -15 ° C chilled. At this temperature, 6.43 mL (50 mmol) Isobutyl chloroformate was added dropwise and the mixture was stirred for 15 minutes. To this 16.63 g (55 mmol) of H-Lys (Boc) -OtBu (Wakimasu, M. et al., Chem. Pharm. Bull. 29, 2592-2597 (1981)) in as little THF as possible dripped. The mixture is left at this temperature for 2 hours and overnight Stir in room temperature. The suspension then dries evaporated, the residue partitioned between dichloromethane and water. The organic phase is successively with dil. hydrochloric acid and with sodium washed carbonate solution and dried over sodium sulfate. To Evaporation in vacuo, the residue is chromatographed on silica gel (Eluent: ethyl acetate / ethanol = 10: 1).

Yield: 34.4 g (85% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 71.45; H 6.63; N 4.39;
Found:
C 71.39; H 6.41; N 4.28.

b) N _α [4- (1-methoxynaphth-4-oyl) naphth-1-oyl] lysine

3.19 g (5 mmol) of the protected ones described in Example 33a above Amino acids are suspended in 30 mL trifluoroacetic acid and added for 2 hours Room temperature stirred. After adding 200 mL ether the suspension  Stirred overnight, the precipitate was filtered off and washed thoroughly with ether and then in the presence of KOH under high vacuum by weight constant dried.

Yield: 2.5 g (quantitative) of a colorless solid.

Elemental analysis:
Calculated:
C 71.29; H 6.60; N 5.73;
Found:
C 71.04; H 6.41; N 5.70.

c) N _ε- lysinamide conjugate from the gadolinium complex of 10- [4-carboxy-1-methyl-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid] and N _α [4- (1-methoxynaphth-4-oyl) naphth-1-oyl] -lysine

To 5.63 g (7.5 mmol) of the Gd complex described in Example 22d 3 mL triethylamine and then 2.5 g (5 mmol) of the lysine derivative described in Example 33b above. The suspension is stirred overnight at room temperature and then evaporated to dryness. The residue is dissolved in water and one hour stirred with activated carbon. It is filtered off from the coal and over a Amicon® ultrafiltration membrane YC 05 (cut off: 500 Da) ultrafiltered. The The residue is chromatographed on silica gel (eluent: methanol / water 3: 1). The combined fractions are evaporated and taken up in water and freeze-dried.

Yield: 4.7 g (78% of theory) of a colorless powder.

Water content (Karl Fischer): 8.5%.

Elemental analysis (based on the anhydrous substance):
Calculated:
C 52.40; H 5.50; N 8.91; Gd 14.29;
Found:
C 52.18; H 5.35; N 8.88; Gd 13.96.

Example 34 Production of manganese (II) and iron (III) complexes

The manganese and iron complexes are produced from the previous ones described gadolinium complexes. For this purpose, e.g. B. 10 mmol of a Gd Complex compound dissolved in 100 ml water and 2 equivalents per Gd ion Oxalic acid added. 1 ml of conc. Hydrochloric acid and stir for 3 hours at 70 ° C.

The mixture is cooled to 0 ° C., the precipitated gadolinium oxalate is filtered off and the mixture is evaporated Filtrate to dryness in a vacuum. The residue is purified on RP-18 (Solvent: Gradient from water / acetonitrile / tetrahydrofuran).

The complexing agents thus obtained are dissolved in water and either fresh precipitated iron (III) hydroxide or with manganese carbonate at 80 ° C (3 hours) implemented. In the case of manganese, the pH of the solution is finally raised brought to pH 7.4 (with NaOH).

The solutions are filtered and then freeze-dried.

The iron (III) complexes are obtained as dark yellow to brown amorphous solids. The manganese (II) complexes are colorless amorphous solids.

Example 35 Determination of relaxivity R1 [L. mmol ^-1 . s ^-1 ] and the R2 [L. mmol ^-1 . s ^-1 ]

Device: Minispec PC 20
Measurement at 40 ° C; 0.47 tesla
T1 sequence: 180 ° -TI-90 °, inversion recovery

MRI experiments on animals with induced myocardial infarction

Enrichment in myocardial infarction and necrosis-selective enhancement after a single intravenous application of the substance from Example 13 Animals with experimentally generated myocardial infarction were examined.

The heart attacks were induced in anesthetized (Domitor® / Dormicum®, im) rats (Shoe. Wistar, Schering SPF, approx. 300 g body weight) by occlusion of the left coronary artery. Contrast agent application (dose: 100 µmol Gd per kg body weight) took place approx. 24 h after the infarction induction. The animals were killed approximately 24 hours after substance application (in the MR tomograph) by an anesthetic overdose and immediately MR-tomographically (Siemens Allegra, 1.5 Tesla; SE sequence, T _R : 400 ms, T _E : 6 ms, NEX: 4, Ma: 128, 128, FOV: 7, 7 cm, SD ≈ 2.5 mm, 1 layer each axially) examined. To verify the infarction (size and location), the heart was prepared immediately after the MRI experiments, cut into slices and then an NBT (nitro blue tetrazolium chloride) vital staining was carried out. For the quantification of the substance enrichment, the vital (colored) myocardial areas were separated from the necrotic (unstained) based on the staining reaction and processed accordingly for the metal content determination. The metal contents were determined by means of "inductively coupled plasma atomic emission spectroscopy" (ICP-AES). The infarct accumulation was calculated from the Gd concentrations in the tissues as follows: Infarct enrichment = Gd concentration in the infarct area / Gd concentration in the "normal" myocardium.

The infarcted area in the MR tomogram is not without substance application to be distinguished from the "normal" myocardium, since both areas are isointense represent (see Figure 1; in vivo MRI of an animal without KM application). To Application of the substance was a significant enhancement in each case determine the necrotic area of the myocardium (see Figure 2) and the infarction could be differentiated very well from the intact (vital) myocardium. The Contrast of the necrotic area in the MRI experiment correlated very well  with the results of histological NBT ("vital") staining. The An Enrichment factor (infarction / "normal" myocardium) was determined to be 3.6 ± 0.4.

Fig. 1 Without contrast medium (in vivo MRI)

Fig. 2 approx. 24 h p. i. (post mortem MRI)

Example 37 a) Mono-tbutyl monoester 2-bromoterephthalic acid

50 g (184.4 mmol) of t-butyl 2-bromo-4-methyl-benzoate [shown from the acid chloride by esterification with t-butanol analogous to Org. Synth. Coll. Vol. III, 142 (1955); IV., 263 (1963)] and 63.2 g (400 mmol) of potassium permanganate are suspended in 400 ml of water and heated to 50 ° C. Stir for 8 hours at 50 ° C. The precipitated manganese dioxide is filtered off and the pH is adjusted the filtrate with 2 N sulfuric acid to a pH of 2.8. Extract 2 times with 300 ml of ethyl acetate, combines the organic phases, dries over magnesium sulfate and evaporated to dryness in vacuo.

Yield: 54.2 g (98% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 48.02; H 4.03; Br 26.62;
Found:
C 48.14; H 4.10; Br 26.81.

b) 4- (8-Quinolinyl ester) t-butyl ester of 2-bromo-terephthalate

50 g (166.6 mmol) of the title compound from Example 33a and 24.2 g (166.6 mmol) 8-hydroxyquinoline is dissolved in 500 ml dichloromethane. At 0 ° C there 34.4 g (166.6 mmol) of N, N'-dicyclohexylcarbodiimide are added and the mixture is stirred 5 Hours at 0 ° C. Allow to come to room temperature, filter the precipitated urea and evaporate the filtrate to dryness in vacuo. The residue is recrystallized from diethyl ether / n-hexane.

Yield: 60.0 g (87% of theory).

Elemental analysis:
Calculated:
C 60.88; H 4.38; Br 19.29;
Found:
C 60.99; H 4.50; Br 19.16.

c) 2-Methoxy-6 - [(3-bromo-4-tbutyloxycarbonyl) benzoyl] naphthalene

To a Grignard solution, made from 3.65 g (150 mmol) magnesium and 35.69 g (150 mmol) 2-methoxy-6-bromo-naphthalene in 200 ml tetrahydrofuran, a solution of 62.14 g (150 mmol) of the title compound is added dropwise at -50 ° C. from Example 33b, dissolved in 200 ml of tetrahydrofuran. Stir for 3 hours -50 ° C and then allowed to come to room temperature. You give 800 ml Add water and adjust to pH 3.5 by adding citric acid. It will be 2 times extracted with 500 ml of diethyl ether. The combined organic phases are dried over magnesium sulfate and evaporated to dryness in vacuo. The The residue is chromatographed on silica gel (eluent: hexane / acetic acid ethyl ester = 20: 1).

Yield: 35.8 g (81% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 62.60; H 4.80; Br 18.11;
Found:
C 62.48; H 4.91; Br 18.02.

d) 2-methoxy-6 - {[2-methoxycarbonyl) ethyl-4-tbutyloxycarbonyl] benzoyl} - naphthalene

To a mixture of 44.13 g (100 mmol) of the title compound from Example 33c 11.56 g (10 mmol) tetrakis (triphenylphosphine) palladium (Tetrahedron Lett. 1992, 33, 4859; J. Am. Chem. Soc., 1992, 114, 7292) and 30.4 g (300 mmol) Trietylamine in 400 ml dimethylformamide is added 25.8 g (300 mmol) Acrylic acid methyl ester and stirred for 5 hours at 70 ° C. 500 ml of water are added and allows to come to room temperature. It is made by adding 1N Hydrochloric acid to pH 6 and extracted 2 times with 500 ml of diethyl ether. The combined organic phases become dry in vacuo evaporated, the residue dissolved in 300 ml of methanol and 5 g of palladium Catalyst (10 Pd / C) added. The mixture is hydrogenated at room temperature  Normal pressure. The catalyst is filtered off and the filtrate is removed in vacuo Evaporated to dryness. The residue is chromatographed on silica gel (Eluent: hexane / ethyl acetate = 20: 1).

Yield: 33.64 g (75% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 72.30; H 6.29;
Found:
C 72.42; H 6.40.

e) 2-methoxy-6 - {[3- (2-hydrazinocarbonyl) ethyl-4-tbutyloxycarbonyl] benzoyl} - naphthalene

To a solution of 24.43 g (50 mmol) of the title compound from Example 33d, dissolved in 100 ml of methanol, 5.51 g (110 mmol) of hydrazine hydrate are added and boils under reflux for 8 hours. Half of the solvent is distilled in Vacuum and cool to 0 ° C. The title compound crystallizes out. It is filtered off and dried in vacuo at 40 ° C.

Yield: 40.8 g (91% of theory) of a colorless solid.

Elemental analysis:
Calculated:
C 69.63; H 6.29; N 6.25;
Found:
C 69.76; H 6.38; N 6.37.

f) hydrazide conjugate from the gadolinium complex of 10- [4-carboxy-1- methyl-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid] and 2-methoxy-6 - {[3- (2-hydrazinocarbonyl) ethyl-4- tbutyloxycarbonyl] benzoyl) naphthalene

20 g (31.76 mmol) Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-aza-butyl) - 1,4,7,10-tetraazacyclododecan-1,4,7-triacetic acid (Gd-Gly-Me-DOTA, DE 196 52 386), 2.69 g (63.52 mmol) lithium chloride and 3.66 g (31.76 mmol)  N-Hydroxysuccinimide are heated in 200 ml Dissolved dimethyl sulfoxide. Then 14.24 g (31.76 mmol) are added Title compound from Example 33e and stirred for 20 minutes at room temperature. The mixture is cooled to 10 ° C. and 9.83 g (47.64 mmol) of N, N'- Dicyclohexylcarbodiimid and stirred overnight at room temperature. Man pour the reaction solution into a mixture of 1000 ml acetone / 1000 ml Diethyl ether and the precipitated solid is filtered off. The further purification is carried out by chromatography on silica gel RP-18 (mobile solvent: gradient from Water / acetonitrile / tetrahydrofuran). After evaporating the fractions 27.95 g (83% of theory) of a colorless, amorphous solid.

Water content: 8.5%.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 50.98; H 5.32; Gd 14.83; N 9.25;
Found:
C 51.11; H 5.44; Gd 14.95; N 9.37.

g) hydrazide conjugate from the gadolinium complex of 10- [4-carboxy-1- methyl-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid] and 2-methoxy-6 - {[3- (2-hydrazinocarbonyl) ethyl-4-carboxy] - benzoyl} naphthalene, sodium salt

21.21 g (20 mmol) of the title compound from Example 33f are dissolved in 150 ml Trifluoroacetic acid dissolved and stirred for 2 hours at room temperature. Man evaporates to dryness in vacuo and cleans the residue Chromatography on silica gel RP-18 (eluent: gradient off Water / acetonitrile / tetrahydrofuran). After evaporating the fractions in Vacuum, the residue is dissolved in 400 ml of water and the pH Add 2N sodium hydroxide solution to pH 7.6. The solution is filtered and freeze-dried.

Yield: 19.46 g (95% of theory) of a colorless, amorphous powder.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 48.09; H 4.43; N 9.57; Gd 15.36; Na 2.24;
Found:
C 48.00; H 4.50; N 9.69; Gd 15.51; Na 2.31.

Example 38 a) Hydrazide conjugate from the gadolinium complex of 10- [4-carboxy-1- methyl-2-oxo-3-azabutyl] -1,4,7,10-tetraazacyclododecane-1,4,7-triessig acid] and 2-methoxy-6 - {[3- (2-hydrazinocarbonyl) ethyl-4-carboxy] - cyclohexylcarbonyl} naphthalene, sodium salt

To a solution of 21.21 g (20 mmol) of the title compound from Example 33f in 200 ml of water are given 10 g of Raney nickel and hydrogenated at 50 ° C and one Pressure of 3 bar hydrogen in the autoclave. The nickel is filtered off and evaporates the filtrate to dryness. The residue is on silica gel RP-18 chromatographed (eluent: gradient from water / acetonitrile). The factions are evaporated in vacuo.

Yield: 18.95 g (92% of theory) of a colorless, amorphous solid.

Elemental analysis (calculated on anhydrous substance):
Calculated:
C 47.80; H 4.99; N 9.52; Gd 15.27; Na 2.23;
Found:
C 47.65; H 5.10; N 9.66; Gd 15.40; Na 2.30.

Claims (7)

1. Compounds of the general formula I
Ar- (LK) _n ,
wherein
K is a cyclic metal complex,
L a linker,
Ar is an aromatic radical containing at least two aromatic rings, and
n denotes the numbers 1 or 2,
Ar for a rest
with the meaning
A: a direct bond,
a methylene group -CH ₂ -,
a dimethylene ether group -CH ₂ O-CH ₂ -,
B: a hydrogen atom,
a carbonyl group -CO-,
C: a hydroxyl group -OH,
an oxygen function -O-,
an ether group -OR ¹ , in which R ^{1 is} an alkyl radical having 1-3 carbon atoms,
where the substituents B and C are each identical in the molecule,
for a rest
with the meaning
D: a hydrogen atom,
an ether group -OR ¹ , with R ¹ in the abovementioned meaning,
for a rest
with the meaning
B and C as described above,
for a rest
with the meaning
R ¹ : as described above,
R ² : a hydrogen atom,
a C ₁ -C ₆ alkyl group,
an acetic acid residue -CH ₂ CO ₂ H,
for a rest
with the meaning
E: a hydrogen atom,
an ether group -OR ¹ ,
a dialkylamino group N (R ¹ ) ₂ , where R ^{1 has} the meaning given above,
o: a number between 2-10,
for a rest
with the meaning
E ¹ , E ² : independently of one another in the meaning of E,
F ¹ , F ² : independently of one another for a hydrogen atom H or the radicals
with o in the meaning given above
and the proviso that one of the substituents F ¹ or F ^{2 represents} a hydrogen atom and that α denotes the binding site in the direction of the aromatic and β denotes the binding site in the direction of the metal complex,
L for a linker meaning a hydrazine group -NHNH-, a C ₂ -C ₂₀ carbon chain with terminal -NH, which can be linear or branched, saturated or unsaturated and optionally by 1-6 oxygen atoms, 1-2 phenylene groups 1-2 cyclohexylidene groups, interrupted by 1-2 groups -NH- CO- or -CONH-, by 1-2 groups -CH ₂ CONHNH- or -NHNHCOCH ₂ and optionally substituted with 1-2 hydroxyl groups with 1-2 methoxy groups, with 1-2 carboxy groups, and
K for a metal complex of the general formula II
with the meaning
R: a hydrogen atom,
a methyl group,
Z ¹ , Z ² , Z ³ : a metal ion equivalent of atomic numbers 25, 26 and 58-70,
U: a C ₁ -C ₁₀ carbon chain, linear or branched, saturated or unsaturated, optionally interrupted by 1-2 oxygen atoms, by a phenylene group, by a cyclohexylidene group, by one or two groups -NH-CO- or -CONH-, optionally substituted with one to two -CO ₂ H groups, with one to three hydroxyl groups, one to three methoxy or alkoxy groups,
or for a metal complex of the general formula III
with the meaning
Z ¹ , Z ² , Z ³ : as stated above,
V: a phenylene, phenyleneoxymethyl, -δ-C ₆ H ₄ -O-CH ₂ -γ group, where γ indicates the binding site in the direction of the aromatic and δ the binding site in the direction of the metal complex, a C ₁ -C ₂₀ -Carbon chain, linear or branched, saturated or unsaturated, optionally interrupted by one or two oxygen atoms, by a phenylene group, by a cyclohexylidene group, by one or two groups -NH-CO- or CONH-, optionally substituted by one or two -CO ₂ H groups with one to three hydroxyl groups, one to three methoxy or alkoxy groups
stands. 2. Compounds according to claim 1, characterized in that
L for a rest
-NH-NH-
γ-CH ₂ -CONH-NH-δ
-NH-CH ₂ CH ₂ -NH-
-NH-CH ₂ CH ₂ CH ₂ CH ₂ -NH-
-NH- (CH ₂ ) ₃ -NH-
-NH- (CH ₂ ) ₅ -NH-
-NH- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -NH-
γ-NH- (CH ₂ ) k-CONH- (CH ₂ ) m-NH-δ with k = 1-10; m = 0-10,
γ-NH- (CH ₂ CH ₂ O) ₂ -CH ₂ CH ₂ NH-δ
stands. 3. Compounds according to claim 1, characterized in that U for a group
-CH ₂ -
-CH ₂ CH ₂ -
-C ₆ H ₄ -
-CH ₂ -O-CH ₂ CH ₂ -
stands. 4. Compounds according to claim 1, characterized in that V for a group
-CH ₂ -OC ₆ H ₄ -
-C ₆ H ₄ -
-CH ₂ CH ₂ -
-CH ₂ -
stands. 5. Compounds according to claim 1, characterized in that the Central ion of the metal complex K a gadolinium, iron or manganese ion is. 6. Use of at least one compound according to claim 1 for the Manufacture of pharmaceutical products. 7. A process for the preparation of compounds according to claim 1, characterized in that compounds of the general formula IV
Ar (LH) _n (IV)
with complexes or complexing agents of the general formula V
KX * (V)
wherein
Ar, L, K and n have the meaning given in claim 1 and X * represents a hydroxyl group or a group which activates the carboxylic acid, and if appropriate (if KX * stands for a complexing agent) subsequently in a manner known per se with a metal oxide or Metal salt of an element of atomic numbers 25, 26 or 58-70 is reacted and optionally then any or all of the acidic hydrogen atoms still present in the complexes obtained in this way are substituted by cations of inorganic and / or organic bases, amino acids or amino acid amides.