SK1552003A3 - Complexes containing perfluoroalkyl with polar radicals, method for the production and use thereof - Google Patents

Abstract

The invention relates to complexes containing perfluoroalkyl with polar radicals of general formula (I), wherein R represents the polar radical, Rf is a perfluorated carbon chain, K is a metal complex and Z is a linker group. The inventive complexes are suitable for intravenous lymphography, tumor diagnosis and infarct and necrosis imaging.

Description

Perfluoroalkylated complexes with polar residues, process for their preparation and their use

Technical field

The invention relates to the subjects as claimed in the claims, namely perfluoroalkylated metal complexes with polar residues of the general formula I, a process for their preparation and their use in NMR diagnostics, X-ray diagnostics, radiodiagnostics and radiotherapy, MRT lymphography and blood-pool reagents. . The compounds of the invention are particularly suitable for intravenous lymphography, for tumor diagnosis and for imaging of infarction and necrosis.

BACKGROUND OF THE INVENTION

In nuclear magnetic resonance, the most important element after hydrogen is fluorine:

(1) fluorine has a high sensitivity of 83% hydrogen sensitivity;

2) fluorine has only one NMR-active isotope;

3) the resonant frequency of fluorine is close to the resonant frequency of hydrogen and thus both fluorine and hydrogen can be measured on the same instrument,

4) fluorine is biologically inert,

(5) Fluorine does not occur in biological material (except teeth) and can therefore be used as a probe or contrast medium without background disturbance.

These properties have led to fluorine being given great attention in the patent literature concerning nuclear magnetic resonance diagnostics: ¹⁹ F-imaging, functional diagnosis and spectroscopy.

In U.S. Patent 4,639,364 (Mallinckrodt), three fluoromethanesulfonamides CF ₃ SO ₂ NH ₂ , CF ₃ SO ₂ NH-CH ₂ - (CHOH) ₄ -CH ₂ OH are proposed as contrast agents for ¹⁹ F-imaging.

F-Imaging is also discussed in DE 4203254 (Max Planck-Gesellschaft), in which an aniline derivative is proposed

// nhcoch ₂ i

19r

F-Imaging is also the subject of patent application WO 93/07907 (Mallinckrodt), where phenyl derivatives are claimed

Compounds with a substantially simpler structure are also proposed for ¹⁹ F-imaging. Thus, U.S. Patent 4,586,511 (Children's Hospital Medical Center) mentions perfluorooctyl bromide CF ₃ (CF ₂ ) ₇ -Br, and European Patent EP 307863 (Air Products) discloses perfluoro-15-crown-5-ether.

In U.S. Patent 4,588,279 (University of Cincinnati,

Children's Hospital Reasearch Foundation) perfluorocarbon compounds such as perfluorocyclononane or perfluorocyclooctane are disclosed, perfluorinated ethers such as perfluorotetrahydrofuran

U

F / -F or diethers such as prefluorinated propylene glycol diether ^CF 3

F - ^ - O - CF ₂ CF ₂ CF - O < * 3

Likewise, the ¹⁹ F-imaging compounds, compounds listed in WO 94/22368 (Molecular Biosystems), e.g.

which contain a perfluoro-ΙΗ, N perf-neopentyl group as the fluorinated residue.

Another structural type with extended diagnostic use is disclosed in U.S. Pat. No. 5,362,478 (Vivorx) in which a fluorinated hydrogen / polymer coating combination is claimed. Perfluoronan and human serum albumin are named. In addition, this combination can be used to utilize a fluorine atom to locally measure temperature and determine the partial pressure of oxygen.

Perfluorocarbons are also claimed in U.S. Pat. No. 4,586,511 for the determination of oxygen.

In German patent DE 4008179 (Schering) fluorinated benzenesulfonamides of the formula

Compounds containing iodine and fluorine atoms are also claimed as contrast enhancers for NMR diagnostics in WO 94/05335 and WO 94/22368 (both Molecular Biosystems):

Also, a combination of a fluorine-paramagnetic metal ion is claimed for ¹⁹ F-imaging for open chain complexes in WO 94/22368 (Molecular Biosystems), for example:

and in EP 292 306 (Terumo Kabushiki Kaisha), for example:

CF, but also for cyclic compounds, EP 628 316 (Terumo Kabushiki Kaisha) as mentioned in the file

The combination of the rare earth fluorine atom is also claimed for NMR spectroscopic temperature measurements (DE 4317588, Schering):

Ln: rare earth metal: La, Pr, Dy, Eu

While compounds containing fluorine and iodine atoms have no interactions between the two nuclei, compounds containing fluorine and paramagnetic centers (radicals, metal ions) exhibit an intense interaction resulting in a shorter fluorine core relaxation time. The magnitude of this effect depends on the number of unpaired electrons of the metal ion (Gd ^{3 +} > Mn ²⁺ > Fe ³⁺ > Cu ²⁺ ) and the distance between the paramagnetic ion and the atom F.

The more unpaired electrons have a metal ion and the closer they are to a fluorine atom, the greater the relaxation time of the fluorine nucleus.

The reduction in relaxation time as a function of distance from the paramagnetic ion is noticeable in all odd spin number nuclei (thus also in the proton) and therefore gadolinium compounds have found wide application as contrast agents in magnetic spin tomography (Magnevist®, Prohance®, Omniscan®, Dotarem®) ). However, the ¹ H-MR-imaging ( ^X H-MRI) measures and uses the proton relaxation time, T ¹ or T ² , i.e. water protons rather than the fluorine nucleus relaxation time, to display. A quantitative measure to reduce relaxation time is relaxivity (liter / mmol.s).

Paramagnetic ion complexes have been used successfully to reduce relaxation times. In the following; The table shows the relaxivity of some commercial preparations.

table

T ¹ -relaxivity in water [1 / mmol.s, 39 ° C, 0.47 T] T ¹ -relaxivity in plasma [1 / mmol.s, 39 ° C, 0.47 T] Magnevist.RTM 3.8 4.8 Dotarem.RTM 3.5 4.3 Omniscan.RTM 3.8 4.4 Prohance® 3.7 4.9

In these compounds, there are only interactions between

and Gadolinium. For these contrasting substances are therefore in the water watching relaxivity about 4 [1 / mmol]. For MR-imaging the also with success use than fluorine

compounds for ¹⁹ F-imaging using a reduced fluorine core relaxation time as well as fluorine-free compounds for which the water proton relaxation time is measured.

When a perfluorocarbon residue is introduced into a paramagnetic contrast agent, i.e., by combining properties known hitherto only as suitable for F-imaging compounds, with the compounds used for proton-imaging, the relaxation of protons in water also surprisingly increases substantially to 10 -50 [1 / mmol.s], compared to the values of 3.5 to 3.8 [1 / mmol.s] shown in the table for some commercial preparations.

Perfluoroalkylated metal complexes are already known from DE 196 03 033.1. However, these compounds cannot be used satisfactorily in all cases, so there is still a demand for contrast agents to represent malignant tumors, lymph nodes and necrotic tissue.

Malignant tumors often metastasize in regional lymph nodes, where more nodes may participate. Thus, lymph node metastases were found in 50-69% of all malignant tumor patients (Elke, Lymphographie, in: Frommhold, Stender, Thurn (eds.), Radiologic Diagnostics in Klinik und Praxis, Vol. IV, Thieme Verlag, Stuttgart) , 7 ^tn edit.,

434-496 (1984)). The diagnosis of metastatic invasion in lymph nodes is of great importance for the therapy and prognosis of malignant diseases. With modern imaging methods (CT, US and MRI), lymphogenic colonies of malignant tumors are only poorly recognized, since in most cases only lymph node size can be used as a diagnostic criterion. Thus, it is not possible to distinguish small merastases in non-enlarged lymph nodes (< 2 cm) from lymph node hyperplasia without malignant invasion (Steinkamp et al. , 158 (1992)).

It is desirable to be able to distinguish lymph nodes with metastatic invasion from hyperplastic lymph nodes using specific contrast media.

Direct X-ray lymphography (injection of a plot suspension of the contrast agent into the prepared lymphatic vessel) is known; however, it is still a rarely used invasive method that is capable of displaying only a few places in the lymphatic year.

In animal experiments, fluorescently labeled dextrans are used experimentally so that lymphatic effluent can be observed after their interstitial administration. All useful markers for the imaging of lymphatic pathways and lymph nodes following interstitial / intracutaneous application also have the common feature that they are substances of a particulate nature (for example, emulsions and suspensions of crystals) or large polymers (see WO 90/14846). ). However, the preparations described so far are not yet optimal for indirect lymphography due to their lack of local and sysrem tolerance and their lack of diagnostic ezeurivirus.

Because lymph node imaging is crucial to early recognition of metastatic invasion in cancer patients, there is still a great demand for specific contrast agents to diagnose corresponding changes in the lymphatic system.

The highest possible concentration of the contrast agent and its high stability are just as desirable as is the diagnostically relevant as uniform enrichment in lymph at multiple lymphatic sites as possible. The overall burden on the body should be low due to the rapid and complete excretion of the contrast agent. A rapid onset of action is also important for radiological practice, if possible within a few hours after application of the contrast agent. The patient should also be well tolerated.

Last but not least, it is desirable to have lymph-specific contrast agents that allow, in a single diagnostic examination, to display both the primary tumor and possible lymph node metastases.

Another important field of medicine is the detection, localization and monitoring of necroses or heart attacks. Myocardial infarction is not a stationary process but a dynamic process lasting for a long time (weeks to months). The disease takes place in roughly three phases which are not sharply separated but overlap. The first phase, the development of myocardial infarction, involves 24 hours after the heart attack; in this phase, destruction proceeds as a shock wave (the frontal wave phenomenon) from subendocard to myocardium. The second phase, an already developed heart attack, involves stabilizing the area in which fibrosis occurs as a healing process. The third phase, the healed heart attack, begins after all the destroyed tissue is replaced by fibrous scar tissue. During this period, extensive restructuring takes place.

To date, no precise method is known to be able to diagnose the actual phase of a myocardial infarction in a live patient. In assessing a heart attack, it is crucial to know the extent of the lost tissue and where the loss occurred, as this information depends on the treatment.

Heart attacks occur not only in the myocardium but also in other tissues, especially the brain.

While infarction is treatable to some extent, necrosis, which is locally limited by tissue death, can only be prevented or mitigated by the harmful effects on the rest of the body. Necrosis can occur in many ways: injuries, chemicals, oxygen deficiency or radiation. As with a heart attack, knowledge of the extent and nature of necrosis is important for further medical care.

Therefore, there have previously been attempts to improve the localization of infarction and necrosis by using contrast agents in non-invasive methods such as scintigraphy or spin tomography. There are many attempts to use porphyrins for imaging necrosis in the literature, but the results obtained are contradictory. Thus, Winkelmann and Hoyes [Nature, 200, 903 (1967)] describe that manganese-5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrin (TPPS) selectively accumulates in the necrotic portion of the tumor.

In contrast, Lyon et al. [Magn. Res. Med. 4, 24 (1987)] observed that manganese-TPPS was dispersed into the kidneys, liver, tumor, and only to a minor extent in the muscles. Interestingly, the concentration in the tumor reaches a maximum of day 4 only after the authors increased the dose from 0.12 mmol / kg to 0.2 mmol / kg. The authors therefore also talk about the non-specific uptake of TPPS in the tumor. Bockhurst et al. [Acta Neurochir. 60, 347 (1994, Suppl.)] That Μη-TPPS selectively binds to tumor cells.

Foster et al. [J. Nucl. Med. 26, 756 (1985)] found that the enrichment ⁱⁿ in-5,10,15,20-tetrakis (4-N-methyl-pyridinium) porphyrin (TMPyP) does not occur in the necrotic portion, but in the living edge layers. It is easy to infer that porphyrin-tissue interaction occurs but is not proven.

Ni et al. published by [Circulation, Vol. 90, no. 4, vol. 2, p. 1468; Abstract 2512 (1994)] that were able to display infarcted areas with manganese-tetrafenylporphyrin (Mn-TPP) and gadolinium-mesoporphyrin (Gd-MP). In International Patent Application WO 95/31219, both compounds are proposed for imaging infarction and necrosis. The authors, Marchal and Ni, found (Example 3) that for Gd-MP, the metal content in the infarcted kidney was the same as in a healthy organ, while in the myocardium it was nine times higher for the infarcted tissue. Surprisingly, the ratio of signal intensities in MRI for infarcted tissue compared to healthy tissue is comparable in both cases (2.10 and 2.19, respectively). Other metalloporphyrins are described in patent application DE 19835082 (Schering AG).

Porphyrins tend to deposit in the skin, leading to photosensitization. This sensitization can take days but also weeks, and is an undesirable effect when using porphyrins for diagnostic needs. In addition, the therapeutic index for porphyrins is only very small because, for example, for Mn-TPPS, the effective dose is up to 0.2 mmol / kg, while the LD50 value is already 0.5 mmol / kg.

Contrasting agents for imaging necroses and infarcts not derived from porphyrins are described in DE 197 4 4003 (Schering AG), DE 19744004 (Schering AG) and WO 99/17809 (Epix). However, to date, there are no compounds that could be used satisfactorily as contrast agents for imaging heart attacks and necroses.

It is therefore an object of the invention to find contrast agents which could be used in particular for MRT lymphography, but also for the diagnosis of tumors and imaging of necroses and heart attacks.

SUMMARY OF THE INVENTION

The invention relates to perfluoroalkylated complexes containing polar radicals of the formula I

I (D (R) p where

R _f is a perfluorinated, straight or branched hydrocarbon chain of the formula -C _n F _2n E, where E is a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, n is equal to a number from 4 to 30,

K is a metal complex of formula II

R ² R ³

where

R ¹ is a hydrogen atom or a metal ion equivalent having atomic number 21-29, 31-33, 37-39, 42-44, 49 or 57-83, provided that at least two R ¹ are metal ion equivalents,

R ² and R ³ independently of one another are hydrogen, C 1 -C 6 -alkyl, benzyl, phenyl, -CH ₂ OH or -CH ₂ OCH ₃ , and

U is -όξΗ ₄ -Ο-0Η ₂ -ω-, - (ΟΗ R) ι -; ω, phenlene, -CH ₂ NHCO-CH ₂ -CH (CH ₂ COOH) -C 1 H 1 -ω- , -C ₆ H ₄ - (OCH ₂ CH ₂ ) o N (CH ₂ COOH) CH ₂ -g), or a C 1 -C ₁₂ -alkylene group or a C ₁ -C ₁₂ H ₅ -O- which last two groups are optionally interrupted by one or more oxygen atoms, one to three -NHCO- groups, one to three -CONH- groups, and / or are substituted by one to three - (CH ₂ ) 0-5COOH groups, wherein ω represents the point of attachment to -CO-, (III) or is a radical of formula III

where

R ¹ is as previously defined, R ⁴ is a hydrogen atom or a pre-ionized metal ion equivalent, and U ¹ is -C 8 H ¹ -O-CH 2-6) - wherein ω is the point of attachment to or is a radical of formula IV

R 'defisgroup

-C0-.

(IV) wherein R ¹ and R ² are as previously defined, or is a radical of formula VA or VB

COOR ¹ • N

ROOC / (VA)

COOR ¹

COOR ¹

COOR ¹

COOR ¹

-N

--COOR ¹

-COOR ¹ wherein R ¹ is as defined above, or is a radical of formula VI

ROOC— \ 's —CO—

N (f

ROOC- ^x COOR ¹ wherein R ¹ is as defined above, or a radical of the formula VII

ROOC— \ 9

S ^ n_, JL

ROOC-

ROOCROOCkde R ¹ is as defined above, and (VI;

(VII) is a group -Ο ₆ -4-Ο-ΟΗ ₂ -ω-, where ω stands for the point of attachment to -CO-, and optionally the free acid groups present in residue K may exist as salts of organic and / or inorganic bases or amino acids or amino acid amides,

G is at least three times a functionalized moiety selected from the following moieties a) to g) (a)

H

a. ^ ~ N (CH? C · ^CO-NH-Y-H, β

(B)

Y 2 CO-C- (CH ₂ ) ₄ -Nv 1

I ^{2 4} H NH a

(c) (d) (e)

Y

CO o

B w * -— N N —a

HH (f) and w - N-tCH 2 -CN-COCHCH 3 π 'HI ^LC NH iz (g) (h)

(i) ^ -CO- (CH _{2) 2; 3} -j: h-co ~ * t / 3

NH)

o £ β - ~ Λ * CO- (CH ₂ ) ₂ ; _3-CH-CO- ^ y | h, and a C is the point of attachment of G to complex K, β is a point of attachment of G to radical R and γ represents a point of attachment of G to radical Z,

Z is a group

Y - N - SQ ₂ -? Or γ - C (O) CH ₂ O (CH ₂ ) 2 - ε where γ represents the point of attachment of the residue Z to the residue G and ε the point of attachment of the Z to the perfluorinated residue Rf,

R is a polar radical selected from the group of K complexes of formulas II to VII, wherein R ¹ is hydrogen or the equivalent of a metal ion having atomic numbers 20-29, 31-33,

37-39, 42-44, 49 or 57-83, and the radicals R ² , R ³ , R ⁴ , U and U ¹ are as previously defined, wherein in the case G is radical (c) or (d) and R is selected from the products of formulas II and V, R must not be identical with the residue a in formula I, where z is δ-C (O) CH ₂ O (CH _{z) 2} -ε, or a folic acid radical, or unbranched or branched, saturated or unsaturated hydrocarbon chain of 2-30 carbon atoms, which binds to the remainder of G through -CO-, -SO ₂ - or by a direct bond and which is optionally interrupted by 1-10 oxygen atoms, 1-5 groups -NHCO-, 1-5 -CONH-, 1-2 sulfur atoms, 1-5 -NH- or 1-2 phenylene groups, which may optionally be substituted with 1-2 OH groups, 1-2 NH ₂ groups, 1-2 COOH groups or 1-2 SO ₃ H groups, or is optionally substituted with 1-8 OH groups, 1-5 groups

COOH, 1-2 SO 3 H groups, 1-5 NH ₂ groups, or 1-5

C 1 -C 4 -alkoxy groups, and

1, m, p independently of each other are integers 1 or 2.

If the compound of the invention is intended for use in NMR diagnostics, the metal ion in the signal giving group must be paramagnetic. Such ions are especially divalent and trivalent ions of the elements of atomic numbers 21-29, 42, 44 and 58-70. Suitable ions are, for example, the chromium (III), iron (II), cobalt (II), nickel (II), copper (II), prazodymium (III), neodymium (III), samarium (III) and yterbium (III) ions. Gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III), iron (III) and manganese (II) ions are particularly preferred for their strong magnetic moment.

For the use of the compounds of the invention in nuclear medicine (radiodiagnostics and radiotherapy), the metal ion must be radioactive. For example, radioisotopes of elements with atomic numbers 27, 29, 31-33, 37-39, 43, 49, 62, 64, 70, 75 and 77 are suitable. Technetium, gallium, indium, rhenium and yttrium are preferred.

When a compound of the invention is to be used in X-ray diagnostics, it is preferable to work with a metal ion of a higher atomic number in order to achieve sufficient X-ray absorption. Diagnostic agents containing a physiologically acceptable complex salt with element ions of atomic numbers 25, 26, 39 and 57-83 have been found to be suitable for this purpose.

Preferred are the manganese (II), iron (II), iron (III), prazodymium (III), neodymium (III), samarium (III), gadolinium (III), yterbium (III) or bismuth (III) ions, especially ions dysprosia (III) and yttria (III).

Optionally hydrogen acid atoms present in the radical R ^{@ 1} , i.e. those which are not exchanged for a central ion, can optionally be exchanged in whole or in part with cations of inorganic and / or organic bases or amino acids or amino acid amides.

Suitable inorganic cations are, for example, lithium ion, potassium ion, calcium ion, and especially sodium ion. Suitable organic base cations are derived, inter alia, from primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine and especially N-methylglucamine. Suitable amino acid cations are derived, for example, from lysine, arginine and ornithine, as well as amides of otherwise acidic or neutral amino acids.

Particularly preferred compounds of formula I are those having the macrocycle K of formula II, III, VB or VII.

The radical U in the metal complex K is preferably -CH 2 - or-alebo ₆ Ο ₄ -Ο- Η ₂ -ω, where ω is the point of attachment to -CO-.

The alkyl groups P 1 and R ³ in the macrocycle of the formula II can be unbranched or branched. They are, for example, methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl or 1,2-dimethylpropyl. Preferably, R ² and R ³ are each independently hydrogen or C 1 -C 4 -alkyl.

In a particularly preferred variation, R ^{2 is a} methyl group and R ³ is a hydrogen atom.

The benzyl or phenyl group R ² or R ³ in the macrocycle K of formula II may also be substituted in the ring.

In a preferred variant, the polar radical R in formula I means complex K, and this may preferably be other than Gd or ³¹ Mn ²⁺ -complex -complex also Ca2 ⁺ -complex. Particularly preferred as polar radicals R are the complexes K of the formula II, III, VA or VII. Especially preferred is when R ¹ therein is a metal ion equivalent of atomic numbers 20, 25 and 64th

In another preferred variant of the invention, the polar radical R has the following meanings:

-C (O) CH ₂ CH ₂ SO ₃ H,

-C (O) ch ₂ and ₂ ch ₂ and ₂ ch ₂ oh,

-C (O) CH ₂ OCH ₂ CH ₂ OH,

-C (O) CH ₂ OCH ₂ CH (OH) ₂ OH,

C (O) CH ₂ NH-C (O) CH ₂ COOH,

-C (O) CH ₂ CH (OH) CH ₂ OH,

-C (O) CH ₂ OCH ₂ COOH,

-so ₂ ch ₂ ch ₂ cooh

-C (O) -C5H3- (m-COOH) 2,

-C (O) CH ₂ O (CH ₂ ) ₂ -C ₆ H ₃ - (m-COOH) 2,

-C (O) CH ₂ OC ₆ H ₄ -m-SO ₃ H,

-C (O) CH ₂ NHC (O) CH ₂ NHC (O) ch ₂ and ₂ cooh,

-C (0) ch ₂ and ₂ ch ₂ and ₂ cooh,

-c (0) CH ₂ OCH ₂ CH (OH) ch ₂ o-ch ₂ ch ₂ oh,

-C (O) CH ₂ OCH ₂ CH (OH) CH ₂ OCH ₂ -CH (OH) -CH ₂ OH,

-C (O) CH ₂ SO ₃ H,

-C (O) CH ₂ CH ₂ COOH,

-C (O) CH (OH) CH (OH) CH ₂ OH,

-C (O) CH ₂ O [(CH ₂ ) ₂ O] 1-9-CH 3,

-C (O) CH ₂ O [(CH ₂ ) ₂ O] _x 9 -H,

-C (O) CH ₂ OCH (CH ₂ OH) ₂ ,

-C (O) CH ₂ OCH (CH ₂ OCH ₂ COOH) 2,

-C (O) -C ₅ H ₃ - (m-OCH ₂ COOH) 2,

-CO-CH ₂ O- (CH ₂ ) ₂ O (CH ₂ ) ₂ O- (CH ₂ ) ₂ O (CH ₂ ) ₂ and ₃ .

Of these, the radical -C (O) CH ₂ O [(CH ₂ ) ₂ O] ₄ -CH ₃ is preferred.

In another preferred variant, the polar residue R is a folic acid residue.

Of the compounds of formula I of the invention it is further those compounds preferred wherein R f is -C _n F _{2n +,} wherein n is preferably 4-15. Particularly preferred are -C ₄ F 9, C ₆ F ₁₃ , -C ₈ F ₇ , -C ₁₂ F ₂ , and -C ₁₄ F ₂ 9, as well as groups in the compounds described in the Examples.

At least three times the functionalized moiety G in formula I, which represents a backbone, is in one preferred variant of the invention lysine residue (a) or (b).

The radical Z represents the linker in the general formula (I), the radical y-n-sq ₂ -s being preferred.

Perfluoroalkylated metal complexes with polar residues of formula I (K) 1-G - (ZR _f ) '

IO (R) p wherein A, G, R, Z, R _f, 1, maps are defined as above, are prepared by the known method a carboxylic acid of the formula IIa

R ³ 00C

³ OU OH ^ (lial wherein R ⁵ is a metal ion equivalent of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83, or a group, a carboxy-protecting group, and R ^2, R ³ and U are as defined above, or a carboxylic acid of the formula IIIa

(IHa) wherein R ⁴ , R ⁵ and U ¹ are as defined above, or a carboxylic acid of formula IVa

OH (IVa) wherein R ⁵ and R ² are as defined above, or a carboxylic acid of formula Va or Vb \

with

R 00C /

-CO-OH

-COOR ⁵

COOR,

-COOR ⁵

N ^nec _n -COOR ^ -COOR ⁵

HOOC /

-COOR ³

-COOR (Va!

(Vb) wherein R ⁵ is as defined above, or a carboxylic acid of the formula Via

(VIa) wherein R ⁵ is as defined above, or a carboxylic acid of Formula VIIa

(VIIa) wherein R ⁵ and U ¹ are as previously defined, optionally in activated form, subjected to a condensation reaction with an amine of formula VIII

H-G- (Z-Rf) n, (VIII) (R) _P wherein G, R, Z, Rf, map have been previously defined, then optionally protecting groups present are cleaved to form a metal complex of formula I, or when R ⁵ is a protecting group, after cleavage of these protecting groups, it is reacted in known manner with at least one metal oxide or metal salt of atomic number 21-29, 31-33, 37-39, 42-44, 49 or 57 in a known manner -83, and finally, if desired, any acidic hydrogen atoms present are replaced by cations of inorganic and / or organic bases, amino acids or amino acid amides.

The carboxylic acids IIa to VIIa used are either known compounds or are prepared according to the procedures described in the Examples. The preparation of carboxylic acids of formula IIIa has been described in DE 196 52 386. Carboxylic acids of formula IIIa can be prepared analogously to Example 4 of this application.

Carboxylic acids of the formula IVa can be prepared according to DE 197 28 954.

A precursor for compounds of formula VA is the N ³ - (2,6-dioxomorpholinoethyl) -N ⁶ - (ethoxycarbonylmethyl) -3,6-diazaoctanedioic acid described in EP 263 059.

The compounds of formula (VB) are derived from isomeric diethylenetriaminepentaacetic acid, which is bound via acetic acid at a medium nitrogen atom. This DTPA is described in DE 195 07 819 and DE 195 08 058.

Compounds of formula VI are derived from N- (carboxymethyl) -N- [2- (2,6-dioxo-4-morpholinyl) ethyl] glycine, the preparation of which is described in J. Am. Oil. Chem. Soc. (1982) 59 (2)

104-107.

The compounds of formula VII are derived from 1- (4-carboxymethoxybenzyl) ethylenediaminetetraacetic acid, the preparation of which is described in U.S. Pat. No. 4,622,420.

The preparation of amines of formula VIII has been described in detail in the examples of this application and can be carried out analogously to that described.

The metal complexes according to the invention have proven to be particularly suitable for NMR and X-ray diagnostics, but also for radiodiagnostics and radiotherapy. The invention therefore also relates to the use of the perfluoroalkylated metal complexes with polar residues according to the invention for the preparation of contrast agents for use in NMR and X-ray diagnostics, in particular in lymphography, tumor diagnostics and imaging of infarcts and necroses, as well as in radiodiagnostics and radiotherapy. The compounds of the invention are well suited for use in interstitial and in particular in24 travenous lymphography. In addition, they can be used to prepare blood-pool reagents.

The invention also relates to pharmaceutical compositions comprising at least one physiologically acceptable compound according to the invention, optionally together with galenically customary additives.

The compounds of the present invention are characterized by very good systemic tolerability and high enrichment in lymph nodes at three consecutive sites (which is particularly important for i.v. lymphography). They are therefore particularly suitable for use in MRT lymphography.

The compounds of the invention are also well suited for the detection and localization of vascular diseases, since they are dispersed exclusively therein when applied to the intravascular space. The compounds according to the invention make it possible, by means of nuclear spin tomography, to define well-perfused tissue from poorly perfused tissue and thereby to diagnose ischemia. Also, using the contrast agents of the invention, infarcted tissue due to its anemia can be distinguished from surrounding healthy or ischemic tissue. This is particularly important when, for example, a heart attack is to be distinguished from ischemia.

In contrast to macromolecular compounds such as Gd-DTPA-polylysine, which have hitherto been used as blood-pooling agents, the compounds of the invention also exhibit higher T ¹ relaxivity and thus have a higher signal intensity in NMR imaging. In addition, since they have longer retention in the bloodstream, they can be administered at relatively low doses (from, for example, <50 pmol Gd / kg body weight). In particular, however, the compounds of the invention are rapidly and completely excreted from the body.

It has further been found that the compounds of the invention concentrate in areas of increased vascular permeability such as in tumors; they allow to obtain information about tissue perfusion, allow to determine the blood volume in tissues, selectively shorten relaxation times and blood density, respectively, and display the permeability of vessels. Such physiological information cannot be obtained using extracellular contrast media such as Gd-DTPA (Magnevist®). These areas also imply application areas in the field of advanced imaging techniques, nuclear spin tomography and computed tomography: specific diagnosis of malignant tumors, early therapy control for cytostatic, anti-inflammatory or vasodilative therapy, early recognition of poorly-delivered areas (e.g., myocardium), angiography diseases and the recognition and diagnosis of sterile or infectious inflammations.

The pharmaceutical compositions according to the invention are prepared in a manner known per se by suspending or dissolving the complex compounds according to the invention, optionally with the addition of galenic additives, in an aqueous medium, then optionally sterilizing the resulting suspension or solution. Suitable additives are, for example, physiologically acceptable buffers (such as tromethamine), complexing agents (such as diethylenetriaminepentaacetic acid) or weak complexes or Ca-complexes corresponding to the metal complexes of the invention, or - electrolytes such as sodium chloride as appropriate, or antioxidants such as for example ascorbic acid.

If suspensions or solutions of the compounds of the invention in water or physiological saline are desired for enteral or parenteral administration or for other purposes, they are mixed with one or more galenically customary excipients (such as methylcellulose, lactose or mannitol) and / or with surfactants (such as Lecithin, Tween® or Myrj®) and / or flavorings (such as essential oils).

In principle, the pharmaceutical compositions of the invention may also be prepared without isolation of the complexes. In any case, care must be taken to ensure that the complexes formed in the formation of chelates contain virtually no uncomplexed toxic metal ions.

This can be achieved, for example, by color indicators, such as xylene orange, in control titrations during preparation. The invention therefore also relates to a process for the preparation of complex compounds and their salts. The purification of the isolated complex remains the safest.

When administered in vivo, the compositions of the invention may be administered together with a suitable carrier, such as serum or saline, and another protein, such as human serum albumin (HSA).

The compositions of the invention are usually administered parenterally, preferably intravenously. They may also be administered intravasally or interstitially / intracutaneously, depending on whether the vessels or tissues are being examined.

The concentration of the complex in the pharmaceutical compositions of the invention is preferably 0.1 pmol - 2 mol / l and is usually applied in an amount of 0.0001 - 5 mmol / kg.

The compositions according to the invention meet the multifaceted requirements for nuclear spin tomography contrast agents. They are well suited for increasing the signal intensity after oral or parenteral administration and thereby improving the predicative value of the image obtained by nuclear spin tomography. Furthermore, these compositions exhibit high efficacy necessary to burden the organism only with small doses of foreign substances, as well as the good tolerability necessary to maintain the non-invasive nature of the examination.

Due to the good solubility of the compositions of the invention in water and low osmolality, highly concentrated solutions can be prepared to keep the volumetric load of the bloodstream within reasonable limits and to compensate for dilution with body fluid. In addition, the compositions of the invention show not only high in vitro stability but also surprisingly high in vivo stability, so that the ions bound in the complexes (and which are separately toxic) are only very releasing from the body over a period of time until these contrast agents are completely eliminated. slowly.

In general, the compositions according to the invention are applied as NMR diagnostics in an amount of 0.0001-5 mmol / kg, preferably 0.005-0.5 mmol / kg.

Furthermore, the complex compounds of the invention can be advantageously used as susceptible agents and as shifting agents in in vivo NMR spectroscopy.

Due to their favorable radioactive properties and the good stability of the complex compounds contained therein, the compositions of the invention are also suitable as radiodiagnostics. Details of such use and dosage are described, for example, in Radiotrancers for Medical Applications, CRC-Press, Boca Raton, Florida.

The compounds and compositions of the invention can be applied also in the positron emission tomography, using isotopes that emit positrons, such as ⁴³ Sc, ^4,1 Sc, ⁵² Fe, ⁵⁵ Co, Ga ^e ° and ⁸⁶ Y (Heiss, WD, Phelps, ME: Positron Emission Tomography of the Brain, Springer Verlag Berlin, Heidelberg, New York, 1983).

Surprisingly, the compounds of the invention are also useful for distinguishing malignant and benign tumors in areas without a blood-brain barrier.

They are also characterized by being completely eliminated from the body and thus well tolerated.

Since the compounds of the invention accumulate in malignant tumors (no diffusion into healthy tissue, but high permeability in tumor vessels), they can also promote radiation therapy for malignant tumors. This differs from the corresponding diagnosis only in the amount and nature of the isotope used. The aim here is to destroy the tumor cells by high-energy short-wave radiation with as little impact as possible. Interactions in a complex of contained metals (such as iron or gadolinium) with ionizing radiation (e.g. X-rays) or neutron flux are utilized for this purpose. As a result of this effect, the local dose of irradiation at the site where the metal complex is located (e.g. in tumors) is substantially increased. In order to achieve the desired dose of irradiation in malignant tissues, the use of such metal complexes can significantly reduce the radiation load of the healthy tissue and thus avoid the side effects of the burden on the patient. The metal complex conjugates of the invention are therefore also suitable as radiosensitizing agents in the radiation therapy of malignant tumors (for example, the use of the Mossbauer effects or in neutron absorption therapy). Suitable β-emitting ions are, for example, Sc, Sc, Sc, Ga, Ga, and Y. Suitable α-emitting ions with low half-lives are, for example, ²¹¹ Bi, ²¹² Bi, ²¹³ Bi and ²¹⁴ Bi, with ²¹² Bi being preferred. Suitable photons and electron emitting ions is ¹⁵⁸ Gd, which can be obtained from ¹⁵⁷ Gd by neutron absorption.

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

For in vivo administration, the compositions of the invention may be administered together with a suitable carrier, such as serum or saline, and another protein, such as human serum albumin. The dosage depends on the nature of the cell disorder, the metal ion used and the nature of the imaging method used.

The compositions of the invention are usually administered parenterally, preferably intravenously. However, as mentioned previously, they may be administered intravasally or interstitially / intracutaneously, depending on whether the vessels or tissues are being examined.

The compositions of the invention are particularly useful as X-ray contrast agents, with particular attention being drawn to the fact that no signs of anaphylactic reactions known from iodine-containing contrast agents have been observed in biochemical and pharmacological studies. They are particularly valuable for their favorable absorption properties in the areas of higher voltage lamps for digital subtraction techniques.

As x-ray contrast agents, the compositions according to the invention are applied, in analogy to, for example, meglumine diisrizoate in an amount of from 0.1-5 mmol / kg, preferably 0.25-1 mmol / kg.

In particular, higher blood concentrations are obtained with the compounds of the invention than with extracellular contrast media. After i.v. application is dispersed only in the intravasal space, which is a decisive advantage over extracellular contrast media.

DETAILED DESCRIPTION OF THE INVENTION

Example 1a

2-N-trifluoroacetyl-6-N-benzyloxykarbonyllyžín

100 g (356.7 mmol) of 6-N-benzyloxycarbonyl lysine are dissolved in a mixture of 1000 ml of trifluoroacetic acid ethyl ester and 500 ml of ethanol, and the resulting solution is stirred at room temperature for 24 hours. After evaporation to dryness, the residue is crystallized from diisopropyl ether to give 128.9 g (96%) of a colorless crystalline powder.

analysis:

H, 5.09; F, 15.14; N, 7.44.

Found: C, 51.25; H, 5.18; F, 15.03; N, 7.58.

Example 1b

2-N-Trifluoroacetyl-6-N-benzyloxycarbonyllysine- [1- (4-perfluoro-30-tylsulfonyl) piperazine] amide

To 125 g (332 mmol) of the title compound of Example 1a and 188.7 g (332 mmol) of 1-perfluorooctylsulfonylpiperazine (prepared according to DE 19603033) in 800 mL of tetrahydrofuran at 0 ° C was added 164.2 g (0.664 mmol) of EEDQ ( ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred overnight at room temperature. After evaporation in vacuo to dryness, the residue is chromatographed on silica gel with dichloromethane-methanol (20: 1). 286 g (93%) of a colorless solid are obtained.

analysis:

H, 2.83; F, 41.01; N, 6.05; S, 3.46; Found: C 36.18, H 2.94, F 40.87, N 5.98, S 3.40.

Example 1c

6-N-Benzyloxycarbonyllysine- [1- (4-perfluorooctylsulfonyl) -piperazine] amide

To a solution of 280 g (302.2 mmol) of the title compound of Example 1b in 200 mL of ethanol was added ammonia gas at 0 ° C for one hour. The mixture was stirred at 0 ° C for 4 hours, then evaporated to dryness and the residue was triturated with water. The solid was filtered off and dried under vacuum at 50 ° C. Yield 243.5 g (97%) of an amorphous solid.

analysis:

H, 3.28; F, 38.89; N, 6.75; S, 3.86; Found: C 37.15, H 3.33, F 38.78, N 6.68, S 3.81.

Example 1d

6-N-Benzyloxycarbonyl-2-N- (3,6,9,12,15-pentaoxahexadecanoyl) -lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 50 g (60.20 mmol) of the title compound of Example 1c and 7.10 g (70 mmol) of triethylamine in 350 mL of dichloromethane is added dropwise at 0 ° C a solution of 19.93 g (70 mmol) of acid chloride 3,6, 9,12,15-pentaoxahexadecanoic acid in 50 ml of dichloromethane and stirred at 0 ° C for 3 hours. 200 ml of 5% aqueous hydrochloric acid are then added and the mixture is stirred at room temperature for 5 minutes. The organic phase is separated, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel with dichloromethane-acetone (15: 1) to give 53.7 g (93%) of the product as a colorless viscous oil.

analysis:

Calculated: C 33.83, H 4.94, F 3.34, N 5.84, S 33.69; found: 33.75% C, 5.05% H, 3.29% F, 5.78% N, 33.75% S.

Example le

2-N- (3,6,9,12,15-pentaoxahexadecanoyl) -lysine [1- (4-perfluórokty1sulfonyl) -piperazine] amide

To a solution of 50 g (52.15 mmol) of the title compound of Example 1d in 500 mL of ethanol was added 6 g of palladium catalyst (10% Pd / C) and the mixture was subjected to hydrogenation at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield 43.0 g (100%) of a colorless solid.

analysis:

Calculated: C 27.68, H 5.01, F 39.17, N 6.79, S 3.89; found: 27.60% C, 5.13% H, 39.09% F, 6.68% N, 3.81% S.

Example 1f

6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - 2 -N- (3,6, 9, 12, 15pentaoxanexadecanoyl) lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd-complex g (24.25 mmol) of the title compound of Example 1e, 2.79 g (24 , 25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of the Gd complex 1,4,7-tris (carboxylatomethyl) -10 - [(3-aza) -4-oxo-5-methyl-5-yl) pentanoic acid] -1,4,7,10-tetracyclododecane was dissolved in 200 ml of dimethyl sulfoxide with gentle heating. 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide are then added at 10 ° C and stirred overnight at room temperature. The solution was poured into 3000 mL of acetone and stirred for 10 minutes. The precipitated solid is filtered off with suction and purified by chromatography on RP-18 silica gel with water-ethanol-acetonitrile (gradient). 28.21 g (81%) of a colorless solid are obtained which contains 11.0% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 31.78, H 4.84, F 22.49, N 8.78, S 2.23, Gd 10.95;

Found: C 31.74, H 4.98, F 22.39, N 8.69, S 2.15, Gd 10.87.

Example 2a

6-N- [3,9-Bis (tert-butyloxycarbonylmethyl) -3,6,9-triazaundecane-1,11-di (tert-butyloxycarbonyl) -6-carbonylmethyl] -2-N- (3,6,9 12,15-pentaoxahexadecanoyl) lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 20 g (24.08 mmol) of the title compound of Example 1e, 14.88 g (24.08 mmol) of 3,9-bis (tert-butyloxycarbonylmethyl) -3,6,9- bis (tert-butyl ester) bis of triazaundecane-1,11-dicarboxylic acid and 2.77 g (24.08 mmol) of N-hydroxysuccinimide in 150 ml of dimethylformamide at 0 ° C are added 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide. The mixture was stirred at 0 ° C for 3 hours and then at room temperature overnight. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo and the residue is chromatographed on silica gel with dichloromethane-ethanol (20: 1). 31.61 g (91%) of a viscous oil are obtained.

Analysis:

Calculated: C 40.80, H 6.71, F 22.39, N 6.80, S 2.22; found: 40.72% C, 6.82% H, 22.30% F, 6.75% N, 2.14% S.

Example 2b

6-N- [6-Carbonylmethyl-3,9-bis (carboxylatomethyl) -3,6,9-triazaundecane-1-carboxy-11-carboxylate] -2-N- (3,6,9,12,15- pentaoxahexadecanoyl) lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex, sodium salt g (20.8 mmol) of the title compound of Example 2a was dissolved in 300 ml of trifluoroacetic acid and the solution was stirred at room temperature for 5 hours . Then the solution is evaporated to dryness, the residue is taken up in 300 ml of water and adjusted to pH 2.5 by addition of 10% aqueous NaOH. Then, 3.77 g (10.4 mmol) of gadolinium oxide are added and the mixture is stirred at 60 ° C for 3 hours. After cooling to room temperature, the sodium hydroxide solution was adjusted to pH 7.4 and evaporated to dryness. The residue was purified on RP-18 silica gel with water-acetonitrile (gradient). Yield 19.18 g (67%) of a colorless amorphous solid containing 9.8% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 28.80, H 4.25, F 23.47, N 7.12, S 2.33, Gd 11.48, Na 1.67;

Found: C, 28.67; H, 4.34; F, 23.38; N, 7.03; S, 2.27; Gd, 11.37;

Example 3a

Lysine- [l- (4-perfluorooctylsulfonyl) -piperazine] -amide

To a solution of 20 g (24.08 mmol) of the title compound of Example 1c in 300 mL of ethanol was added 4 g of a palladium catalyst (10% Pd / C) and hydrogenated at room temperature. The catalyst is then filtered off and the filtrate is evaporated to dryness in vacuo.

16.77 g (100%) of a colorless solid are obtained.

analysis:

Calculated: 31.04% C, 3.04% H, 46.38% F, 8.04% N, 4.60% S; Found: C 30.97, H 3.15, F 46.31, N 7.98, S 4.51.

Example 3b

2,6-N, N'-Bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5) -yl)] - lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd-kompiex g (14.36 mmol) of the title compound of Example 3a, 3.34 g (29 mmol) of N-hydroxysuccinimide, 2.54 g lithium chloride and 18.26 g (29 mmol) of the 1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) -1,4,7 Gd complex 10-tetraazacyclododecane was dissolved in 200 ml of dimethylsulfoxide with gentle heating. 12.38 g (60 mmol) of N, N-dicyclohexylcarbodiimide are added at 10 ° C and the reaction mixture is stirred overnight at room temperature. The solution was then poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off with suction and purified by chromatography on RP-18 silica gel with water-ethanol-acetonitrile. (gradient). 19.02 g (69%) of a colorless solid are obtained, containing 11.3% of water.

Analysis (calculated on the anhydrous substance):

Calculated: C 35.03%, H 4.04%, F 16.82, N 10.21%, S 1.67%, Gd 16.38%;

Found: C 34.96, H 4.13, F 16.74, N 10.16, S 1.61, Gd 16.33.

Example 4a

2- [4- (Ethoxycarbonylmethyloxy)] phenylacetic acid methyl ester

To a mixture of 200 g (1.204 mol) of 4-hydroxyphenylacetic acid methyl ester and 212 g (2 mol) of sodium carbonate in 2000 ml of acetone is added 233.8 g (1.4 mol) of ethyl bromoacetate and the mixture is refluxed for 5 hours. . The solid was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was chromatographed on silica gel with n-hexane-ethyl acetate (15: 1) to give 288.5 g (95%) of a colorless oil.

analysis:

Calculated: C 61.90, H 6.39;

found: C, 61.75; H, 6.51.

Example 4b

2- (4-Ethoxycarbonyloxy) phenyl-2-bromoacetic acid methyl ester

To a solution of 285 g (1.13 mol) of the title compound of Example 4a in 2000 mL of carbon tetrachloride was added 201 g (1.13 mL) of N-bromosuccinimide and 100 mg of dibezoyl peroxide, and the mixture was refluxed for 8 hours. After cooling in an ice bath, the precipitated succinimide is filtered off, the filtrate is evaporated to dryness in vacuo and the residue is purified by chromatography on silica gel, eluting with n-hexane-acetone (15: 1). 359.2 g (96%) of a colorless viscous oil are obtained.

analysis:

Calculated: C 47.28, H 4.57, Br 24.16;

found: C, 47.19; H, 4.71; Br, 24.05.

Example 4c

2- (4-Ethoxycarbonyloxy) phenyl-2- [1- (1,4,7,10-tetraazacyclododecan-7-yl)] acetic acid methyl ester

To 603 g (3.5 mol) of 1,4,7,10-tetraazacyclododecane in 6000 ml of chloroform was added 350 g (1.057 mol) of the title compound of Example 4b and stirred overnight at room temperature. It is extracted three times with 3000 ml of water, the organic phase is dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was used in the next reaction (4d) without further purification. Yield 448 g (100%) of a viscous oil.

analysis:

H, 8.11; N, 13.26.

found: C 59.58, H 8.20, N 13.18.

Example 4d

2- [4- (carboxymethyloxy)] phenyl-2- [1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecan-10-yl] acetic acid

A solution of 445 g (1.053 mol) of the title compound of Example 4c and 496 g (5.27 mol) of chloroacetic acid in 4000 ml of water was adjusted to pH 10 with 30% aqueous NaOH, then heated to 70 ° C and maintained at pH 10 30% aqueous NaOH. The mixture was stirred at 70 ° C for 8 hours, then adjusted to pH 13 and refluxed for 30 minutes. The solution is cooled in an ice bath and adjusted to pH 1 with concentrated hydrochloric acid. After evaporation in vacuo to dryness, the residue is taken up in 4000 ml of methanol and stirred for one hour at room temperature. The precipitated sodium chloride is filtered off, the filtrate is evaporated to dryness and the residue is purified by chromatography on RP-18 silica gel with water-ethanol-acetonitrile (gradient). 403 g (69%) of a colorless solid are obtained, containing 10.2% water.

analysis:

H, 6.18; N, 10.10.

found: C 51.80, H 6.31, N 10.01%.

Example 4e

2- (4- (carboxymethyloxy)] phenyl-2- [1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecan-10-yl] acetic acid, Gd complex

To 400 g (721.3 mmol) of the title compound of Example 4d in 2000 mL of water was added 130.73 g (360.65 mmol) of gadolinium oxide and the mixture was stirred at 80 ° C for 5 hours. After filtration, the filtrate is lyophilized. Yield 511 g (100%) of an amorphous solid containing 11.0% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 40.67, H 4.41, Gd 22.19, N 7.98;

Found: C 40.51, H 4.52, Gd 22.05, N 8.03.

Example 4f

2,6-N, N'-Bis {2- [4- (3-oxapropionyl) phenyl] -2- [1,4,7-tris (methyl carboxylate) -1,4,7,10-tetraazacyclododecane-10 -yl] acetic acid (lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, digadolinium complex, disodium salt g (14.36 mmol) of the title compound of Example 3a, 3.45 g (30 mmol) of N-hydroxysuccinimide, 2.54 g (60 mmol) of lithium chloride and 21.26 g (30 mmol) of the title compound of Example 4e are dissolved in 250 ml of dimethylsulfoxide with gentle heating, and then 16.51 g (80 mmol) of N are added at 10 ° C. N-dicyclohexylcarbodiimide and stirred overnight at room temperature The solution is poured into 2000 ml of acetone and stirred for 10 minutes, and the precipitated solid is filtered off with suction and purified by chromatography on RP-18 silica gel with water-ethanol-acetonitrile (gradient) The product was dissolved in a small amount of water, adjusted to pH 7.4 by addition of sodium hydroxide, and freeze dried to give 21.02 g (69%) of a colorless solid containing 11.2% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 37.36, H 3.66, F 15.22, Gd 14.82, N 7.92, Na, 17.17, S 1.51;

found: 37.28% C, 3.74% H, 15.14% F, 14.75% Gd, 8.03% N, 2.23% Na, 1.46% S.

Example 5a

2,6-N, N'-Bis [6-carbonylmethyl-3,9-bis (tert-butyloxycarbonylmethyl) -3,6,9-triazaundecane-1,1-di (tert-butyloxycarbonyl)] - lysine- [1 - (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 10 g (14.36 mmol) of the title compound of Example 3a, 18.53 g (30 mmol) of 3,9-bis- (tert-butyloxycarbonylmethyl) -6-carboxymethyl-3,6,9- triazaundecan-1,11-dicarboxylic acid and 3.45 g (30 mmol) of N-hydroxysuccinimide in 150 ml of dimethylformamide are added at 0 ° C 10.32 g (50 mmol) of Ν, d-dicyclohexylcarbodiimide. The mixture was stirred at 0 ° C for 3 hours and then at room temperature overnight. The precipitated urea is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is chromatographed on silica gel in dichloromethane-ethanol (20: 1); yield 19.60 g (72%) of a viscous oil.

analysis:

Calculated: C 49.41, H 6.75, F 17.03, N 7.39, S 1.69; Found: C 49.35, H 6.82, F 16.92, N 7.32, S 1.62.

Example 5b

2,6-N, N'-Bis [6-carbonylmethyl-3,9-bis (carboxylatomethyl) -3,6,9-triazaundecanedioic acid-1-carboxy-11-carboxylate] lysine [1- (4-perfluorooctylsulfonyl) (piperazine) amide, Gd complex, sodium salt

To a solution of the resulting compound of Example 5a (15 g, 7.91 mmol) in chloroform (50 mL) was added trifluoroacetic acid (200 mL) and the mixture was stirred at room temperature for 10 min. After evaporation to dryness in vacuo, the residue is dissolved in 150 ml of water. 2.87 g (7.91 mmol) of gadolinium oxide are added and the mixture is stirred at 80 ° C for 5 hours. After cooling to room temperature, the pH is adjusted to 7.4 by addition of 2N sodium hydroxide, the solution is evaporated to dryness in vacuo and the residue is purified on RP-18 in a water / ethanol / n-acetonitrile (gradient) system. Yield: 8.11 g (57%) of a colorless amorphous solid containing 9.6% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 30.70, H 3.08, Gd 17.48, N 7.78, Na 2.56, S 1.78;

found: C 30.58, H 3.19, Gd 17.42, N 7.71, Na 2.68,

1,72% S.

Example 6a

6-N-Benzyloxycarbonyl-2-N- [6-carbonylmethyl-3,9-bis (tert-butyloxycarbonylmethyl) -3,6,9-triazaundecane-1,1-di (tert-butyloxycarbonyl)] lysine- [1- (4yperfluóroktylsulfonyl) piperazine]

To a solution of 20 g (24.08 mmol) of the title compound of Example 1c, 14.88 g (24.08 mmol) of 3,9-bis (tert-butyloxycarbonylmethyl) -6-carboxymethyl-3,6,9-di-tert-butyl ester -triazaundecane-1,11-dicarboxylic acid and 2.88 g (25 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide at 0 ° C are added 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide. The mixture was stirred at 0 ° C for 3 hours and at room temperature overnight. The precipitated urea is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is chromatographed on silica gel with dichloromethane-ethanol (20: 1); yield 27.21 g (79%) of a viscous oil.

analysis:

Calculated: C 47.03, H 5.64, F 22.58, N 6.85, S 2.24; found: C 46.94, H 5.58, F 22.65, N 6.84, S 2.31.

Example 6b

2-N- [6-Carbonylmethyl-3,9-bis- (tert-butyloxycarbonylmethyl) -3,6,9-triazaundecane-1,11-di- (tert-butyloxycarbonyl)] lysine [1- (4-perfluorooctylsulfonyl)] piperazine] amide g (17.48 mmol) of the title compound of Example 6a was dissolved in 350 mL of ethanol and 5 g of palladium catalyst (10% Pd / C) was added. The mixture is hydrogenated at room temperature. The catalyst is then filtered off and the filtrate is evaporated to dryness in vacuo. Yield 22.66 g (100%) of a colorless solid.

analysis:

Calculated: C 44.48, H 5.75, F 24.92, N 7.56, S 2.47; Found: C 44.59, H 5.81, F 25.03, N 7.46, S 2.52.

Example 6c

6-N- [l, 4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - 2 -N- [6-carbonylmethyl-3,9-bis (tert-butyloxycarbonylmethyl) -3,6,9-triazaundecane-1,11-di (tert-butyloxycarbonyl)] lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd-complex g (15.43 mmol) of the title compound of Example 6b, 1.78 g (15.43 mmol) of N-hydroxysuccinimide, 1.48 g (35 mmol) of lithium chloride and 9.72 g (15, 43 mmol) 1,4-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl) pentanoic acid Gd complex]

-1,4,7,10-tetraazacyclododecane was dissolved in 150 ml of dimethylsulfoxide with gentle heating. Then, 5.16 g (25 mmol) of N, N-dicyclohexylcarbodiimide was added at 10 ° C and stirred overnight at room temperature. After pouring into 2500 ml of acetone, it is stirred for 10 minutes, the precipitated solid is filtered off with suction and purified by chromatography on silica gel RP-18, water-ethanol-acetonitrile (gradient). 22.94 g (78%) of a colorless solid are obtained, containing 7.9% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 42.22, H 5.29, F 16.95, Gd 8.25, N 8.82, S 1.68%;

Found:% C, 42.15;% H, 5.41;% F, 16.87;% Gd /% 8.13;

Example 6d

6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (3-aza-4-oxo-5-methyl-5-yl-pentanoyl)] - 2-N- [6-carbonylmethyl-3,9-bis (carboxylatomethyl) -3,6,9-triazaundecanedicarboxylic acid-carboxy-11-carboxylate-z] lysine- [1- (4-perfluorooctylsulfonyl ·) piperazine] amide, digadolinium complex, sodium salt g (10.47 mmol) of the title compound of Example 6c was dissolved in 200 mL of trifluoroacetic acid and the solution was stirred at room temperature for 60 minutes. After evaporation to dryness in vacuo, the residue is dissolved in 150 ml of water. 1.90 g (5.25 mmol) of gadolinium oxide are added and the mixture is stirred at 80 ° C for 5 hours. After cooling to room temperature, the pH was adjusted to 7.4 by addition of sodium hydroxide, the solution was evaporated to dryness in vacuo and the residue was purified by chromatography on RP-18 silica gel with water-ethanol-acetonitrile (gradient). Yield: 11.89 g (61%) of a colorless amorphous solid containing 10.2% water. .

Analysis (calculated on the anhydrous substance):

Calculated: C 32.97, H 3.47, F 17.39, Gd 16.93, N 9.05, Na 1.24, S 1.73;

Found: C 32.90, H 3.53, F 17.31, Gd 16.87, N 8.92, Na 1.33, S 1.67.

Example 7a

5, β-Bis (benzyloxy) -3-oxahexanoic acid tert-butyl ester

100 g (376.2 mmol) of 1,2-di-O-benzylglycerin [prepared according to Chem. Phys. Lipids (1987), 43 (2), 113-127] and 5 g of tetrabutylammonium hydrogen sulfate are dissolved in a mixture of 400 ml of toluene and 200 ml of 50% aqueous sodium hydroxide. At 0 ° C, 78 g (400 mmol) of 2-bromoacetic acid tert -butyl ester are added dropwise over 30 minutes, and the mixture is stirred at 0 ° C for 3 hours. The organic phase is separated, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel with n-hexane-acetone (20: 1). 133.4 g (94%) of a colorless oil are obtained.

analysis:

H, 7.82; C, 71.48;

found: C, 71.61; H, 7.92.

Example 7b

5,6-Bis (benzyloxy) -3-oxahexanoic acid

To a solution of 130 g (336.4 mmol) of the title compound of Example 7a in 200 mL of dichloromethane at 0 ° C was added 100 mL of trifluoroacetic acid. The reaction mixture is stirred for 4 hours at room temperature and then evaporated to dryness. The residue was crystallized from pentane-diethyl ether. 102.2 g (92%) of a waxy solid are obtained.

analysis:

H, 6.71; C, 69.07;

found: 69.19% C, 6.82% H.

Example 7c

6-N-Benzyloxycarbonyl-2-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5) -yl)] lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex g (60.20 mmol) of the title compound of Example 1c, 6.93 g (60.20 mmol) of N-hydroxysuccinimide, 5, 09 g (120 mmol) of lithium chloride and 37.91 g (60.20 mmol) of the Gd complex of 1,4,7-tris (carboxylatomethyl) -10- (pentanoyl-3-aza-4-oxo-5-methyl- 5-yl) -1,4,7,10-tetraazacyclododecane was dissolved in 400 mL of dimethyl sulfoxide with gentle heating. 20.63 g (100 mmol) are then added at 10 ° C.

Of N, N-dicyclohexylcarbodiimide and the mixture was stirred overnight at room temperature. It is then poured into 3000 ml of acetone, stirred for 10 minutes, the precipitated solid is filtered off with suction and purified by chromatography on RP-18 silica gel with water-ethanol-acetonitrile (gradient). 75.53 g (87%) of the product were obtained as a colorless solid containing 10.1% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 37.48, H 3.84, F 22.39, Gd 10.90, N 8.74, S 2.22;

found: 37.39% C, 4.02% H, 22.29% F, 10.75% Gd, 8.70% N, 2.22% S.

Example 7d

2-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] lysine [1- (4-Perfluorooctylsulfonyl) piperazine] amide, Gd complex

To a solution of 70 g (48.53 mmol) of the title compound of Example 7c in a mixture of 500 mL of water and 100 mL of ethanol was added 5 g of palladium catalyst (10% Pd / C) and the mixture was hydrogenated at room temperature. The catalyst is then filtered off and the filtrate is evaporated to dryness in vacuo. 63.5 g (100%) of a colorless solid are obtained, containing 9.8% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 37.48, H 3.84, F 22.39, Gd 10.90, N 8.74, S 2.22;

found: 37.39% C, 4.03% H, 22.31% F, 10.78% Gd, 8.65% N, 2.20%

WITH.

Example 7e

6-N- [5,6-Bis (benzyloxy) -3-oxahexanoyl] 2-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3) -aza-444 oxo-5-methyl-5-yl)] lysine [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex g (7.64 mmol) of the title compound of Example 7d, 3.30 g ( 10 mmol) of the title compound of Example 7b, 0.85 g (20 mmol) of lithium chloride and 1.15 g (10 mmol) of N-hydroxysuccinimide were dissolved in 150 ml of dimethylsulfoxide with slight heating. 3.10 g (15 mmol) of N, N-dicyclohexylcarbodiimide are then added at 10 ° C and the mixture is stirred at room temperature for 8 hours. The reaction solution is poured into 2000 ml of acetone and the precipitate formed is collected. Purification by chromatography on RP-18 silica gel with water-ethanol-acetonitrile (gradient) afforded 11.14 g (90%) of the product as a colorless amorphous solid containing 4.3% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 41.51, H 4.29, F 19.93, N 7.78, Gd 9.70, S 1.98;

found: C 41.45, H 4.38, F 19.84, N 7.70, Gd 9.58, S 1.90.

Example 7f

6-N- (5,6-Dihydroxy-3-oxahexanoyl) -2-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3- aza-4-oxo-5-methyl-5-yl)] lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

To a solution of 10 g (6.17 mmol) of the title compound of Example 7e in 200 mL of ethanol was added 3 g of palladium catalyst (10% Pd / C) and the mixture was hydrogenated at room temperature. The catalyst is then filtered off and the filtrate is evaporated to dryness in vacuo. 8.89 g (100%) of a colorless solid are obtained, containing 3.1% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 35.03, H 3.99, F 22.42, Gd 10.92, N 8.75, S 2.23;

Found: C 34.95%, H 4.12%, F 22.30, Gd 10.78, N 8.71, S 2.18%.

Example 8a

6-N-3-benzyloxycarbonyl-2-N- [5,6-bis (benzyloxy) -3-oxahexanoyl] lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of the title compound of Example 1c (20 g, 24.08 mmol), the title compound of Example 7b (9.91 g, 30 mmol) and N-hydroxysuccinimide (3.45 g, 30 mmol) in DMF (100 mL) at 0 ° C. 9.28 g (45 mmol) of N, N-dicyclohexylcarbodiimide are added. The mixture was stirred at 0 ° C for 3 hours and at room temperature overnight. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo and the residue is purified by chromatography on silica gel (dichloromethane / ethanol 20: 1). 24.50 g (89%) of the product are obtained as a viscous oil.

analysis:

Calculated: C 47.29, H 4.14, F 28.26, N 4.90, S 2.81; Found: C, 47.14; H, 4.26; F, 28.17; N, 4.91; S, 2.69.

Example 8b

2-N- (5,6-dihydroxy) -3-oxahexanoyl] lysine- [l- (4-perfluóroktyisulfonyl) -piperazine] amide

To a solution of 20 g (17.5 mmol) of the title compound of Example 8a in 300 mL of ethanol was added 5 g of a palladium catalyst (10% Pd / C) and the mixture was hydrogenated at room temperature. The catalyst is filtered off with a pen and the filtrate is evaporated to dryness in vacuo. 17.65 g (100%) of a colorless solid are obtained.

analysis:

Calculated: C 44.05, H 4.10, F 32.02, N 5.55, S 3.18; Found: C 43.96, H 4.21, F 31.94, N 5.48, S 3.24.

Example 8c

6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] lysine- [1- (4-Perfluorooctylsulfonyl) piperazine] amide, Gd complex g (14.87 mmol) of the title compound of Example 8b, 1.73 g (15 mmol) of N-hydroxysuccinimide, 1.27 g (30 mmol) of lithium chloride and 9.48 g (15 mmol) of the Gd complex 1,4,4-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl) pentanoic acid] -1,4 The 7,10-tetraazacyclododecane was dissolved in 100 ml of dimethylsulfoxide with gentle heating. Then, 5.16 g (25 mmol) of N, N-dicyclohexylcarbodiimide was added at 10 ° C and stirred overnight at room temperature. After pouring into 1500 ml of acetone, it is stirred for 10 minutes, the precipitated solid is filtered off with suction and purified by chromatography on silica gel RP-18, water-ethanol-acetonitrile (gradient). 19.28 g (80%) of a colorless solid are obtained, containing 10.3% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 41.51, H 4.29, F 19.93, Gd 9.70, N 7.78, S 1.98;

Found: C 41.37, H 4.40, F 19.88, Gd 9.58, N 7.67, S 1.85.

Example 9a

6-N-Benzyloxycarbonyl-2-N - [2,6-N, N'-bis (benzyloxycarbonyl) ivzyl] lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 20 g (24.08 mmol) of the title compound of Example 1c and 2.53 g (25 mmol) of triethylamine in 200 mL of tetrahydrofuran was added 14.46 g (27 mmol) of di-N, N'-Z p-nitrophenol ester. lysine.

The reaction mixture was stirred at 50 ° C for 5 hours, then evaporated to dryness in vacuo and the residue was chromatographed on silica gel with dichloromethane-methanol (20: 1). Yield 28.07 g (95%) of a colorless solid.

analysis:

Calculated: C 46.99, H 4.19, F 26.32, N 6.85, S 2.61; found: 47.08% C, 4.32% H, 26.21% F, 6.75% N, 2.54% S.

Example 9b

2-N- (lysyl) lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide trihydrobromide

To 25 g (20.37 mmol) of the title compound of Example 9a was added 100 mL of a 48% solution of hydrogen bromide in acetic acid, and the mixture was stirred at 40 ° C for 2 hours. After cooling to 0 ° C, 1500 ml diethyl ether is added dropwise and the precipitated solid is filtered off and dried under vacuum at 60 ° C. 21.52 g (99%) of a slightly yellow crystalline solid are obtained.

analysis:

Calculated: C 27.01, H 3.40, Br 22.46, F 30.26, N 7.87, S 3.00;

Found: C 26.92, H 3.53, Br 22.15, F 30.14, N 7.69, S 2.87%.

Example 9c

6- N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclodoaecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -2 -N- [2,6-N, N'-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-) 5-Methyl-5-yl)] lysyl] lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, trigadolinium complex

31,49 g (50 mmol) of 1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) pentanoic acid Gd complex, 6,91 g (60 mmol) of N-hydroxysuccinimide and 4.24 g (100 mmol) of lithium chloride are dissolved in 350 ml of dimethylsulfoxide with slight heating. 16.51 g (80 mmol) of N, N-dicyclohexylcarbodiimide are then added at 10 ° C and the mixture is stirred at 10 ° C for 5 hours. To the mixture was added 10 g (9.37 mmol) of the title compound of Example 9b and 3.03 g (30 mmol) of triethylamine and stirred at 60 ° C for 12 hours. After cooling to room temperature, the mixture is poured into 3000 ml of acetone. The precipitate formed is filtered off and purified by chromatography on RP-18 silica gel with water-ethanol-acetonitrile (gradient). 16.7 g (67%) of product are obtained as a colorless solid containing 7.9% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 36.58, H 4.43, F 12.14, Gd 17.74, N 11.06, S 1.14;

Found: C 36.47, H 4.54, F 12.03, Gd 17.65, N 10.95, S 1.21.

Example 10a

1,7-Bis (benzyloxykarbony1) -4- (3,6,9,12,15-pentaoxahexadecanoyl) -1,4,7,10 tetraazacyclododecane

To 18.13 g (68.1 mmol) of 3,6,9,12,15-pentaoxahexadecanoic acid and 30 g (68.1 mmol) of 1,7-di-Z-cyclene (prepared according to Z. Kovacz and AD Sherry) (J. Chem. Soc., Chem. Commun. (1995), 2, 185) in 300 mL of tetrahydrofuran at 0 ° C is added 24.73 g (100 mmol) of EEDQ (ethyl 2-ethoxy-1,2-ethyl ester). dihydroquinoline-1-carboxylic acid) and stirred overnight at room temperature. It is then evaporated to dryness in vacuo and the residue is chromatographed on silica gel (dichloromethane / methanol 20: 1). 19.13 g (42%) of a colorless solid are obtained.

analysis:

H, 7.61; N, 8.13.

Found:% C, 60.92;% H, 7.75;% N, 8.04.

Example 10b

1,7-Bis (benzyloxycarbonyl) -4- (3,6,9,12,15-pentaoxahexadecanoyl) -10- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluoridecanoyl) -1, 4, 7, 10-tetraazacyclododecane

To 18 g (26.91 mmol) of the title compound of Example 10a and 14.05 g (26.91 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotidecanoic acid (prepared according to DE 19603033) in 300 mL tetrahydrofuran at 0 ° C was added 12.36 g (50 mmol) of EEDQ (ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and the mixture was stirred overnight at room temperature. It is then evaporated to dryness in vacuo and the residue is chromatographed on silica gel with dichloromethane-methanol (20: 1). Yield 21.51 g (67%) of a colorless solid.

analysis:

Calculated: C 47.32, H 4.82, F 27.07, N 4.70;

Found:% C, 47.26;% H, 5.01;% F, 26.94;% N, 4.59.

Example 10c

1- (3,6,9,12,15-Pentaoxahexadecanoyl) -7- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotidecanoyl) -1,4,7,10-tetraazacyclododecane

To a solution of the title compound of Example 10b (20 g, 16.77 mmol) in ethanol (200 mL) was added palladium catalyst (10% Pd / C) (2.5 g) and the mixture was hydrogenated at room temperature. The catalyst is then filtered off and the filtrate is evaporated to dryness in vacuo. 15.5 g (100%) of product are obtained as a colorless solid.

analysis:

Calculated: C 40.27, H 4.90, F 34.93, N 6.06;

Found: C 40.15%, H 4.99, F 34.87, N 5.94%.

Example 10d

1,7-Bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)) - 4- (3,6,9,12,15-pentaoxahexadecanoyl) -10- (2H, 2H, AH, AH, 5H, 5H-3-oxaperfluoridecanoyl) -1,4,7,10-tetraazacyclododecane, Gd complex g (16.22 mmol) of the title compound of Example 10c, 4.60 g (40 mmol) of N-hydroxysuccinimide, 3.39 g (80 mmol) of lithium chloride and 25.19 g (40 mmol) of Gd-complex 1.4 7-Tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-yl) pentanoic acid was dissolved in 300 mL of dimethyl sulfoxide with gentle heating. 24.73 g (100 mmol) of EEDQ are then added at 10 ° C and the mixture is stirred overnight at room temperature. The solution was poured into 3000 mL of acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on RP-18 silica gel with water-ethanol-acetonitrile (gradient). 19.86 g (57%) of a colorless solid are obtained, containing 11.3% of water.

Analysis (calculated on the anhydrous substance):

Calculated: C 38.58, H 4.74, F 15.04, Gd 14.64, N 9.13; Found: C 38.47, H 4.91, F 14.95, Gd 14.57, N 9.04%.

Example 11a 3,5-Dinitrobenzoic acid [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of perfluorooctylsulfonylpiperazine (20 g, 35.2 mmol) and triethylamine (8.1 g, 80 mmol) in dichloromethane (200 ml) was added dropwise a solution of 3,5-dinitrobenzoyl chloride (8.76 g, 38 mmol) in dichloromethane (55 ml) at 0 ° C. the mixture was stirred at 0 ° C for 3 hours. 200 ml of 5% aqueous hydrochloric acid are then added and the mixture is stirred at room temperature for 5 minutes. The organic phase is separated, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel with dichloromethane 51

acetone (15: 1) to give 24.96 g (93%) of a colorless solid.

analysis:

Calculated: C 29.35, H 1.45, F 42.37, N 7.35, S 4.21; Found: C 29.28, H 1.61, F 42.15, N 7.25, S 4.15.

Example 11b 3,5-Diaminobenzoic acid [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of the resulting compound of Example 11a (20 g, 26.23 mmol) in ethanol (400 mL) was added palladium catalyst (10% Pd / C, 6 g) and the mixture was hydrogenated at room temperature. The catalyst is then filtered off and the filtrate is evaporated to dryness in vacuo. 18.43 g (100%) of the product are obtained in the form of a cream-colored solid.

analysis:

Calculated: C 32.49, H 2.15, F 45.98, N 7.98, S 4.57; Found:% C, 32.29;% H, 2.35;% F, 45.69;% N, 7.81.

Example 11c 3,5-N, N'-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl) [1- (4-perfluorooctylsulfonyl) piperazine] amide -3-aza-4-oxo-5-methyl-5-yl) ibenzoic acid, Gd-kompiex g (14.24 mmol) of the title compound of Example 11b, 3.45 g (30 mmol) of N-hydroxysuccinimide, 2.54 g (60 mmol) of lithium chloride and 18.89 g (30 mmol) of the 1,4d-7-tris (carboxylatomethyl) -d-Gd complex of -10- (3-aza-4-oxo-5-methyl-5-yl) The pentane is dissolved in 200 ml of dimethyl sulfoxide with gentle heating. 10.32 g (50 mmol) of N, N-dicyclohexylcarbodiimide are then added at 10 ° C and the mixture is stirred overnight at room temperature. Pour the solution into

2000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on RP-18 silica gel with water-ethanol-acetonitrile (gradient). 19.74 g (72%) of a colorless solid are obtained, containing 11.8% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 35.55, H 3.72, F 16.77, Gd 16.33, N 10.18, S 1.67;

found: 35.48% C, 3.84% H, 16.58% F, 16.26% Gd, 10.07% N, 1.58%

WITH.

Example 12

a) 3-Oxa-2H-4H, 4H, 4H, 5H, 5H-perfluorodecanecarboxylic acid tert-butyl ester

25.04 g (53.8 mmol) of 1H, 1H, 2H, 2H-perfluoro-1-decanol (commercially available from Lancaster) are dissolved in 250 ml of absolute toluene and a catalytic amount (ca. 75 g) tetra-n-butylammonium hydrogen sulfate. A total of 7.55 g (134.6 mmol; 2.5 equivalents based on the charged alcohol component) of finely powdered potassium hydroxide is added at 0 ° C followed by 15.73 g (80.7 mmol; 1.5 equivalents based on the charged). of the alcohol component) of bromoacetic acid tert-butyl ester and the mixture was stirred at 0 ° C for a further 2 hours. The reaction solution obtained was stirred for 12 hours at room temperature and then quenched by the addition of 500 ml of ethyl acetate and 250 ml of water. The organic phase is separated and washed twice with water. After drying the organic phase over sodium sulfate, the desiccant is filtered off with suction and the solvent is evaporated off under vacuum. The oily residue was purified by chromatography on silica gel with ethyl acetate-hexane (1:10). Yield 26.3 g (84.6%) of the title compound as a colorless and strongly viscous oil.

analysis:

% H, 2.61;% F, 55.85;

found: 33.29% C, 2.61% H, 55.90% F.

b) 3-Oxa-2tf, 2H, 4H, 4H, 5H, 5H-perfluorotridecanecarboxylic acid (34.58 mmol) of the title compound of Example 12a was suspended in 200 ml of a mixture of methanol and 0.5M sodium hydroxide (2M) at room temperature. : 1) and then heated to 60 ° C. After 12 hours at 60 ° C, the clear reaction mixture is neutralized by addition of Amberlit ® IR 120 (H ⁺ -form) cation exchanger, the ion exchanger is filtered off with suction and the aqueous methanol filtrate obtained is evaporated to dryness in vacuo. The amorphous oily residue was purified by chromatography on silica gel with ethyl acetate-n-hexane (1: 3) to give 16.0 g (88.6%) of the title compound as a colorless, strongly viscous oil.

analysis:

H, 1.35; F, 61.85.

Found: C, 27.58; H, 1.36; F, 61.90.

c) 1,7-Bis ([1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-ylpentanoyl)) - 1,4,7,10 -tetraazacyclododecane) diethylenetriamine, diagadolinium complex

2.48 g (3.94 mmol; 2.05 mol equivalents based on diethylenetriamine) Gd complex of 10- (4-carboxy-1-methyl-2-oxo-3-azabutyl) -1,4,7,10 -tetraazacyclododecane-1,4,7-triacetic acid (described in patent application DE 197 28 954 Cl in Example 31h) and 167 mg (3.94 mmol) of anhydrous lithium chloride are dissolved with stirring at 40 ° C in 40 ml of absolute dimethylsulfoxide, and a total of 453 mg (3.94 mmol) of N-hydroxysuccinimide was added at this temperature. After cooling to room temperature, 814 mg (3.946 mmol) of N, N'-dicyclohexylcarbodiimide was added to the obtained reaction solution, and the mixture was stirred at room temperature for 2 hours. A solution of 198.3 mg (1.92 mmol) of diethylenetriamine in 5 ml of absolute dimethylsulfoxide was then added to the obtained active ester suspension and stirring was continued at room temperature for hours. Sufficient acetone is then added to the reaction mixture to completely precipitate the resulting compound, the precipitate is filtered off with suction, dried, taken up in water and the insoluble dicyclohexylurea is filtered off. The filtrate is freed from salts and low molecular weight components on an Amicon® YM-3 ultrafiltration membrane (cut off 3000 Da). The retentate is then lyophilized. 1.85 g (72.7%) of a colorless lyophilisate are obtained, containing 3.89% water (Karl Fischer).

Analysis (calculated on the anhydrous substance):

Calculated: C 38.03, H 5.24, N 13.73, Gd 23.71;

Found: C 37.98, H 5.20, N 13.69, Gd 23.78.

d) 1,7-Bis {[1,4,7-tris (carboxylatomethyl) -10- (3-aza-4-oxo-5-methyl-5-ylpentanoyl)] - 1,4,7,10 -tetraazacyclododecane (-4- (3-oxa-2H, 2H, 4H, 4H, 5H, 5H-perfluorotridecanoyl) diethylenetriamine, diagadolinium complex

To a solution of 3.23 g (2.44 mmol) of the title compound of Example 12c in a mixture of 30 mL of dimethylsulfoxide and 3 mL of tetrahydrofuran at 50 ° C under a nitrogen atmosphere was added dropwise a solution of 1.27 g (2.44 mmol) of the title compound. of the compound of Example 12b in a mixture of 15 mL of tetrahydrofuran and 15 mL of dimethylsulfoxide. A total of 1.80 g (3.66 mmol) of EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) was then added in portions at 0 ° C and the mixture was stirred overnight at room temperature. The reaction solution obtained is poured into sufficient acetone to completely precipitate the title compound, the precipitate is filtered off with suction, dried, taken up in water, the insoluble matter is filtered off and the filtrate is subjected to ultrafiltration on an Amicon® YM-3 ultrafiltration membrane (cut). off 3000 Da), thereby achieving not only complete desalting but also removal of low molecular weight components from the resulting compound. The retentate is then lyophilized. 3.54 g (79.4%) of a colorless lyophilisate are obtained, containing 5.87% water (Karl Fischer).

Analysis (calculated on the anhydrous substance):

Calculated: C 35.43, H 4.07, N 9.95, F 17.64, Gd 17.18%; Found: C 35.42, H 4.01, N 9.89, F 17.67, Gd 17.18%.

Example 13

a) 2-N-Trifluoroacetyl-6-N-benzyloxycarbonyl-L-lysine

100.0 g (356.7 mmol) of 6-N-benzoyloxycarbonyl-L-lysine are dissolved in a mixture of 1000 ml of trifluoroacetic acid ethyl ester and 500 ml of ethanol. The solution is stirred for 24 hours at room temperature, then evaporated to dryness and the residue is crystallized from diisopropyl ether. 128.9 g (96%) of a colorless crystalline powder are obtained, m.p. 98.5 ° C.

analysis:

Calculated: C 51.07, H 5.09, N 7.44, F 15.14;

Found: C, 51.25; H, 5.18; N, 7.58. F, 15.03.

b) 2-N-Trifluoroacetyl-6-N-benzyloxycarbonyl-T-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To 125.0 g (332.0 mmol) of the title compound of Example 1a and 188.7 g (332.0 mmol) of perfluorooctylsulfonylpiperazine (prepared according to DE 19603033) in 750 mL of tetrahydrofuran at 0 ° C was added 164.2 g ( 0.664 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred overnight at room temperature. Then the solvent was evaporated to dryness in vacuo and the residue was chromatographed on silica gel with dichloromethane-methanol (20: 1). 286.0 g (93%) of a colorless solid are obtained, m.p. 92 ° C.

analysis:

Calculated: C 36.30, H 2.83, N 6.05, F 41.01, S 3.46; Found: C 36.18, H 2.94, N 5.98, F 40.87, S 3.40.

c) 6-N-Benzyloxycarbonyl-L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of the title compound of Example ib (280.0 g, 302.2 mmol) in 2000 mL of ethanol was added ammonia gas at 0 ° C for 1 hour. Stir 4 hours at 0 ° C, evaporate to dryness and stir the residue with water. The solid is filtered off and dried under vacuum at 50 ° C. Yield 243.5 g (97.0%) of an amorphous solid.

analysis:

H, 3.28; N, 6.75; F, 38.89; S, 3.86; Found: C 37.55, H 3.33, N 6.68, F 38.78, S 3.81.

d) L-Lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

200.0 g (240.8 mmol) of the compound prepared in Example 13c are dissolved in 1000 ml of ethanol, Pearlman's catalyst (20% Pd / C) is added and hydrogenated at room temperature (1 atm) until hydrogen uptake ceases. The catalyst is filtered off with suction, washed with

gracefully with ethanol (3 x 100 ml each) and filtrate with evaporates in vacuo to dryness. It will be obtained 162.5 g (96.9%) resulting compound in f OJ RME of yellowish oil. analysis: Calculated: 31.04 % C, 3.04% H, 8.05% N, 46.38% F, 4.60% WITH; found: 31.11% C, 3.09% H, 8.08% N, 46.33% F , 4.62% S.

e) 6N-2N-Bis (4- [2,3-bis (N, N-bis (tert-butyloxycarbonylmethyl) amino) propyl] phenyl} -3-oxapropionyl-L-lysine- [1- (4-perfluorooctylsulfonyl)] piperazine] -amide

5.25 g (7.72 mmol) of 4- [2,3-bis (N, N-bis (tert-butyloxycarbonylmethyl) amino) propyl] phenyl} -3-oxapropionic acid 781.0 mg (7.72 mmol) of triethylamine is dissolved in 50 ml of methylene chloride. A solution of 1.16 g (8.5 mmol) of isobutyl chloroformate in 10 ml of methylene chloride was added dropwise over 5 minutes at -15 ° C and the mixture was stirred for a further 20 minutes at -15 ° C. The solution was then cooled to -25 ° C and a solution of 2.68 g (3.86 mmol) of the title compound of Example 13d and 2.12 g (21.0 mmol) of triethylamine in 70 mL of tetrahydrofuran was added dropwise over 30 minutes. The mixture was stirred at -15 ° C for 30 minutes and then at room temperature overnight. The solvent was evaporated in vacuo and the oily residue was taken up in 250 ml of chloroform. The chloroform phase is extracted twice with 100 ml of 10% aqueous ammonium chloride solution, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel with methylene chloride-ethanol (20: 1). 5.37 g (68.8%) of a colorless very viscous oil are obtained.

analysis:

Calculated: C 52.27, H 6.43, N 5.54, F 15.97, S 1.59; Found: C 52.22, H 6.51, N 5.49, F 15.99, S 1.63%.

f) 6N-2N-Bis {4- [2,3-bis (N, N-bis (carboxylatomethyl) amino) propyl] phenyl} -3-oxapropionyl-L-lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, octasodium salt

To a solution of 5.0 g (2.47 mmol) of the title compound of Example 13e in 60 mL of absolute dichloromethane was added dropwise a total of 75 mL of trifluoroacetic acid at 0 ° C. After 12 hours at room temperature, the reaction mixture is evaporated to dryness in vacuo. Water (100 ml) was added to the residue and evaporated to dryness again in vacuo. The residue thus obtained is dissolved in 200 ml of distilled water and the resulting product solution is extracted twice with 60 ml of diethyl ether each time. The aqueous product solution was adjusted to a total volume of 300 mL, insoluble matter was filtered off and the filtrate was subjected to ultrafiltration on an Amicon® YM-3 ultrafiltration membrane (cut off 3000 Da). This completely desalinates the solution and removes the low molecular weight fractions. The retentate is made up to 200 ml with water and adjusted to pH 10.0 by addition of 15% sodium hydroxide. The alkaline aqueous solution of the product is then subjected to lyophilization. 4.0 g (92.8%) of the resultant octanetriate salt are obtained in the form of an amorphous lyophilisate containing 5.37% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 38.46, H 3.28, N 6.41, F 18.47, S 1.83, Na 10.52;

Found: C 38.42, H 3.31, N 6.39, F 18.51, S 1.87, Na 10.38.

g) 6N-2N-Bis (4- [2,3-bis (N, N-bis (carboxymethyl) amino) propyl] phenyl) -3-oxapropionyl-1-lysine- [1- (4-perfluorooctylsulfonyl) piperazine amide, dimangan complex, tetranatrium salt

1.94 g (1.11 mmol) of the title compound of Example 13f are dissolved in 100 ml of distilled water and the solution is adjusted to pH 4.0 by addition of 1 M aqueous hydrochloric acid. 0.25 g (2.22 mmol) of manganese carbonate is then added portionwise at 80 ° C. The resulting reaction solution was refluxed for 5 hours. After cooling to room temperature, the aqueous solution of the product is adjusted to pH 7.2 with vigorous stirring by the addition of 1 N sodium hydroxide and freed from salts and low-molecular fractions by filtration through an Amicon® YM-3 ultrafiltration membrane (cut off 3000 Da). The retentate is then lyophilized. 1.80 g (92.0%) of the title compound are obtained in the form of a colorless lyophilisate containing 7.28% water (Karl Fischer).

Analysis (calculated on the anhydrous substance):

H, 3.25; F, 18.28; M, 6.22; N, 6.34; Na, 5.20; S, 1.81;

found: 38.01% C, 3.29% H, 18.29% F, 6.21% Mn, 6.36% N, 5.28% Na, 1.78% S.

Example 14

a) 6-N- (Benzyloxycarbonyl) -2-N - [(N-pteroyl) -1-glutaminyl] -lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide g (45.31 mmol) of folic acid is dissolved in 300 ml of dimethylsulfoxide and to this solution is added 9.49 g (46 mmol ·) of N, N-dicyclohexylcarbodiimide at 10 ° C. The mixture was stirred overnight at room temperature. Subsequently, 29.1 g (35 mmol) of the title compound of Example 1c and 20 ml of pyridine were added to the mixture, and the mixture was stirred at 50 ° C for 3 hours. After cooling, a mixture of 1500 ml of diethyl ether and 1500 ml of acetone is added and the precipitate formed is filtered off and purified by chromatography on an RP-18 phase in a water-ethanol-tetrahydrofuran system (gradient). 21.59 g (38%) of product are obtained as a yellow solid containing 2.1% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 43.10, H 3.54, F 25.76, N 11.29, S 2.56; found: C 43.02, H 3.62, F 25.68, N 11.21, S 2.48.

b) 2-N - [(N-Pteroyl) -L-glutaminyl] lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To 20 g (15.95 mmol) of the title compound of Example 14a was added 200 mL of a 48% solution of hydrogen bromide in acetic acid and

is stirred for 2 hours at 40 ° C. After cooling to 0 ° C dropped 2000 ml diethyl ether and in ylúčená solid is filtered and dried. it sews in vacuum at 60 C. 18.96 g are obtained (99%) yellow colored crystalline substance. analysis: Calculated: 37.01% c. 3.27% 1 4.66% Br, 26.90% F, N, 12.83 2.67% S; found: 36.91% C, 3 42% H, 6.31% Br, 29.75% F, N, 12.72

2.56% S.

c) 6- N - [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -2-N - [(N-pteroyl) -Lglutaminyl] lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

0.92 g (8 mmol) of N-hydroxysuccinimide, 0.68 g (16 mmol) of lithium chloride and 5.04 g (8 mmol) of the Gd-complex of 1,4,7-tris (carboxy-60-methylmethyl) -10- (3) -aza-4-oxo-5-methyl-5-yl) -1,4,7,10-tetraazacyclodecane was dissolved in 80 mL of dimethylsulfoxide with gentle heating. 2.06 g (10 mmol) of N, N-dicyclohexylcarbodiimide are then added at 10 ° C and the mixture is stirred for 3 hours at room temperature. To this reaction solution was added 5 g (4.16 mmol) of the title compound of Example 14b and 10 mL of pyridine and stirred overnight at room temperature. The solution is then poured into 1000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on RP-18 silica gel with water-ethanol-acetonitrile (gradient). The product was dissolved in a small amount of water, adjusted to pH 7.4 by addition of sodium hydroxide and lyophilized. 3.87 g (53%) of product are obtained as a yellow solid containing 5.8% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 38.36, H 3.74, F 18.42, Gd 8.97, N 12.78, Na 1.31, S 1.83;

found: 38.28% C, 3.85% H, 18.33% F, 8.85% Gd, 12.69% N, 1.42% Na, 1.75% S.

Example 15

a) 6-N-Benzyloxycarbonyl-2-N- (3,6,9,12-tetraoxanedecanoyl) lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 50 g (60.20 mmol) of the title compound of Example 1c and 7.10 g (70 mmol) of triethylamine in 350 mL of dichloromethane is added dropwise at 0 ° C a solution of 16.85 g (70 mmol) of the acid chloride 3,6, 9, 12-tetraoxatridecanoic acid in 50 ml of dichloromethane and stirred at 0 ° C for 3 hours. 200 ml of 5% aqueous hydrochloric acid are then added and the mixture is stirred at room temperature for 5 minutes. The organic phase is separated, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel with dichloromethane-acerone (15: 1). 30.94 g (92%) of a colorless viscous oil are obtained.

Analysis:

Calculated: C 40.63, H 4.19, F 31.21, N 5.41, S 3.10; Found: C 40.75%, H 4.08%, F 31.29%, N 5.58%, S 3.25%.

b) 2-N- (3,6,9,12-tetraoxatridecanoyl) lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 53.96 g (52.15 mmol) of the title compound of Example 15a in 500 mL of ethanol was added 6 g of palladium catalyst (10% Pd / C) and the mixture was hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. 43.0 g (100%) of a colorless solid are obtained.

analysis:

H, 4.14; H, 35.86; N, 6.22. S, 3.56. found: 27.60% C, 5.13% H, 39.09% F, 6.68% N, 3.81% S.

c) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -2-N- (3,6,9,12-tetraoxatridecanoyl) lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

21.84 g (24.25 mmol) of the title compound of Example 15b,

2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of the Gd complex 1,4,7-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl) pentanoic acid] -1,4,7,10-tetraazacyclododecane was dissolved in 200 mL of dimethyl sulfoxide with gentle heating. 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide are then added at 10 ° C and the mixture is stirred overnight at room temperature. The solution was then poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on RP-18 silica gel with water-ethanol-acetonitrile (gradient). 28.21 g (81%) of a colorless solid are obtained, containing 11.0% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 36.53, H 4.33, F 21.36, N 8.34, S 2.12, Gd 10.40;

Found: C 31.74, H 4.98, F 22.39, N 8.69, S 2.15,

10.87% Gd.

Example 16

a) 6-N-Benzyloxycarbonyl-2-N- (3-sulfopropyl) lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 50 g (60.20 mmol) of the title compound of Example 1c and 7.10 g (70 mmol) of triethylamine in 250 mL of dry tetrahydrofuran was added dropwise at 50 ° C a solution of 7.33 g (60 mmol) of propanesulfone in 50 mL of tetrahydrofuran. and stirred for 3 hours at 60 ° C. After addition of 200 ml of 5% aqueous hydrochloric acid, it is stirred for 5 minutes at room temperature. The organic phase is separated, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel with dichloromethane-acetone (15: 1). 45.16 g (79%) of a colorless viscous oil are obtained.

analysis:

H, 3.49; F, 33.90; N, 5.88; S, 6.73. Found: C 36.72, H 3.35, F 33.79, N 5.78, S 6.75.

b) 2-N- (3-Sulfopropyl) lysine- [1- (4-perfluorooctyisulfonyl) piperazine] amide

To a solution of 49.68 g (52.15 mmol) of the title compound of Example 16a in 500 mL of ethanol was added 6 g of palladium catalyst (10% Pd / C) and the mixture was hydrogenated at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. 42.69 g (100%) of the product were obtained as a colorless solid.

analysis:

H, 3.32; F, 39.46; N, 6.84; S, 7.83.

Found: C 30.64, H 4.1%, F 39.29%, N 6.68%, S 7.89%.

c) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -2-N- (3-sulfopropyl) lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide, Gd complex

19.85 g (24.25 mmol) of the title compound of Example 16b,

2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of the Gd complex 1,4,7-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl) pentanoic acid] -1,4,7,10-tetraazacyclododecane was dissolved in 200 ml dimethylsulfoxide with gentle heating. At 10 ° C, 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide are added and the mixture is stirred overnight at room temperature. The solution was then poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on RP-18 silica gel with water-ethanol-acetonitrile (gradient) to give 28.13 g (81%) of a colorless solid containing 11.0% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 33.27, H 3.70, F 22.36, N 8.73, S 4.44, Gd 10.89;

Found: C 32.41, H 3.88, F 22.49, N 8.69, S 4.35, Gd 10.97.

Example 17

a) 6-N-Benzyloxycarbonyl-2-N, N-bis (3-sulfopropyl) lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 50 g (60.20 mmol ·) of the title compound of Example 1c and 12.14 g (120 mmol) of triethylamine in 250 ml of dry tetrahydrofuran is added dropwise a solution of 14.65 g (120 mmol) of 1,3- of propane sulfide in 100 ml of tetrahydrofuran and stirred at 60 ° C for 3 hours. Add 400 ml of 5% aqueous hydrochloric acid, stir for 5 minutes at room temperature, add sodium chloride, separate the organic phase, dry over magnesium sulphate and evaporate to dryness in vacuo. The residue is chromatographed on silica gel with dichloromethane-acetone (15: 1). Thus 52.24 g (81%) of a colorless viscous oil are obtained.

analysis:

Calculated: C 35.76, H 3.66, F 30.05, N 5.21, S 8.95; found: 35.75% C, 3.55% H, 30.19% F, 5.08% N, 9.04% S.

b) 2-N, N-Bis (3-sulfopropyl) lysine- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 53.74 g (52.15 mmol) of the title compound of Example 17a in 500 mL of ethanol was added 6 g of palladium catalyst (10% Pd / C) and the mixture was subjected to hydrogenation at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo to give 49.06 g (100%) of a colorless solid.

analysis:

Calculated: C 30.64, H 3.54, F 34.33, N 5.96, S 10.23; Found:% C, 30.69;% H, 3.71;% F, 34.19;% N, 6.08.

c) 6-N- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -2-N, N-bis (3-sulfopropyl) lysine- [1- (4-perfluorooctylsulfonyl) -piperazine] amide, Gd complex, disodium salt

38.76 g (24.25 mmol) of the title compound of Example 17b,

2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of the Gd complex 1,4,7-tris (carboxylatomethyl ·) - 10 - [(3-aza-4-oxo-5-methyl-5-yl) pentanoic acid] -1,4,7,10-tetraazacyclododecane was dissolved in 200 mL of dimethyl sulfoxide with gentle heating. At 10 ° C, 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide are added and the mixture is stirred overnight at room temperature. The solution was then poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on RP-18 silica gel with water-ethanol-acetonitrile (gradient). 31.63 g (81%) of a colorless solid are obtained, containing 11.0% water.

Analysis (calculated on the anhydrous substance):

H, 3.57; F, 20.06; N, 7.83; S, 5.97; Gd, 9.76; Na, 2.86;

found: 31.94% C, 3.48% H, 20.19% F, 7.69% N, 5.85% S, 9.87% Gd, 2.99% Na.

Example 18

(a) N-Trifluoroacetyl-L-glutamic acid 5-benzyl ester

A solution of 100 g (421.5 mmol) of 5-benzyl ester of L-glutamic acid in a mixture of 1000 ml of ethyl trifluoroacetate and 500 ml of ethanol is stirred at room temperature for 24 hours, evaporated to dryness and crystallized from diisopropyl ether. Yield 140.47 g (96%) of a colorless crystalline powder.

analysis:

Calculated: C 50.46, H 4.23, F 17.10, N 4.20;

Found: C 51.35, H 4.18, F 17.03, N 4.28.

b) 2-N-Trifluoroacetyl-L-glutamic acid N-Bis (2-hydroxyethyl) amide-5-benzyl ester

To a solution of the title compound of Example 18a (24.9 g, 24.08 mmol), diethanolamine (2.53 g, 24.08 mmol) and 2.78 g (24.08 mmol).

N-hydroxysuccinimide in 150 ml of dimethylformamide is added at 0 ° C with 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide. The mixture was stirred at 0 ° C for 3 hours and then at room temperature overnight. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo and the residue is chromatographed on silica gel with dichloromethane-ethanol (20: 1). Yield 9.11 g (90%) of a viscous oil.

Analysis:

Calculated: C 51.43, H 5.51, F 13.56, N 6.66.

Found: C 51.22, H 5.41, F 13.40, N. 6.75.

c) N-Trifluoroacetyl-L-glutamic acid N-Bis (2-hydroxyethyl) monoamide

To a solution of 21.92 g (52.15 mmol) of the title compound of Example 18b in 500 mL of ethanol was added 3 g of palladium catalyst (10% Pd / C) and the mixture was subjected to hydrogenation at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield 43.0 g (100%) of a colorless solid.

analysis:

H, 5.19; F, 17.26; N, 8.48.

found: 39.84% C, 5.13% H, 17.09% F, 8.68% N.

d) N-Trifluoroacetyl-A-glutamic acid N-Bis (2-hydroxyethyl) amide-5- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To 10.96 g (33.2 mmol) of the title compound of Example 18a a

18.87 g (33.2 mmol) of 1-perfluorooctylsulfonylpiperazine (prepared according to DE 19603033) in 80 ml of tetrahydrofuran at 0 ° C are added 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-ethyl ester). (i) dihydroquinoline-1-carboxylic acid and stirred overnight at room temperature. After evaporation in vacuo to dryness, the residue is chromatographed on silica gel with dichloromethane-methanol (20: 1). Yield 30.93 g (93%) of a colorless solid.

analysis:

Calculated: C 39.61, H 2.89, F 35.66, N 6.19, S 3.54; Found: C, 39.68; H, 2.74; F, 35.81; N, 6.13; S, 3.40.

e) L-glutamic acid N-Bis (2-hydroxyethyl) amide-5- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 30.24 g (30.22 mmol) of the title compound from Example 18d in 200 mL of ethanol was added ammonia gas at 0 ° C for 1 hour. The mixture was stirred at 0 ° C for 4 hours, then evaporated to dryness and the residue triturated with water. The solid was filtered off and dried under vacuum at 50 ° C. Yield 26.55 g (97%) of an amorphous solid.

analysis:

Calculated: C 41.12, H 2.89, F 35.66, N 6.19, S 3.54; found: C 41.15%, H 2.83%, F 35.78%, N 6.28%, S 3.71%.

f) N- [1,4,4-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane] N-Bis (2-hydroxyethyl) amide 5- [1- (4-perfluorooctylsulfonyl) piperazine] amide -10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - L-glutamic acid, Gd complex

211.96 g (24.25 mmol) of the title compound of Example 18e,

2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of the Gd complex 1,4,7-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl) pentanoic acid] -1,4,7,10-tetraazacyclododecane was dissolved in 200 ml dimethylsulfoxide with gentle heating. At 10 ° C, 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide are added and the mixture is stirred overnight at room temperature. The solution was then poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on RP-18 silica gel with water-ethanol-acetonitrile (gradient). 27.43 g (81%) of a colorless solid are obtained, containing 11.0% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 34.41, H 3.83, F 23.13, N 9.03, S 2.30, Gd 11.26;

Found: C 34.34, H 3.98, F 23.29, N 9.19, S 2.15, Gd 11.07.

Example 19

a) N-Trifluoroacetyl-L-glutamic acid N-dimethyl-bis (1,1-dihydroxymethyl) amide-5-benzyl ester

To a solution of 8.03 g (24.08 mmol) of the title compound of Example 18a, 3.98 g (24.08 mmol) of dimethyl bis (1,1-dihydroxymethyl) amine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide in 150 ml of dimethylformamide is added at 0 ° C with 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide. The mixture was stirred at 0 ° C for 3 hours and then at room temperature overnight. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo and the residue is chromatographed on silica gel with dichloromethane-ethanol (20: 1). Yield 110.53 g (91%) of a viscous oil.

analysis:

H, 5.66; F, 11.86; N, 7.18.

found: C 50.17, H 5.82, F 11.80, N 7.15.

b) N-Trifluoroacetyl-L-glutamic acid N-dimethyl-bis (1,1-dihydroxymethyl) monoamide

To a solution of 25.05 g (52.15 mmol) of the title compound of Example 19a in 500 mL of ethanol was added 6 g of palladium catalyst (10% Pd / C) and the mixture was subjected to hydrogenation at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield 20.36 g (100%) of a colorless solid.

analysis:

H, 5.42; F, 14.60; N, 7.18.

found: 40.10% C, 5.53% H, 14.69% F, 7.28% N.

c) N-Trifluoroacetyl-L-giutamic acid N- [dimethyl-bis (1,1-dihydroxymethyl)] amide 5- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To 12.96 g (33.2 mmol) of the title compound of Example 19b a

18.87 g (33.2 mmol) of 1-perfluorooctylsulfonylpiperazine (prepared according to DE 19603033) in 800 ml of tetrahydrofuran at 0 ° C are added 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-ethyl ester). (dihydroquinoline-1-carboxylic acid) was added and the mixture was stirred overnight at room temperature. After evaporation in vacuo to dryness, the residue is chromatographed on silica gel with dichloromethane-methanol (20: 1). Yield 28.42 g (91%) of a colorless solid.

analysis:

Calculated: C 31.93, H 3.00, F 40.40, N 5.96, S 3.41. Found: C 32.08%, H 2.94%, F 40.57%, N 5.88%, S 3.31%.

d) A-glutamic acid N- [dimethyl-bis (1,1-dihydroxymethyl)] amide 5- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 28.41 g (30.2 mmol) of the title compound of Example 19c in 200 mL of ethanol was added ammonia gas at 0 ° C for 1 hour. After stirring at 0 ° C for 4 hours, it is evaporated to dryness and the residue is triturated with water. The solid was filtered off and dried under vacuum at 50 ° C. Yield 24.74 g (97%) of an amorphous solid.

analysis:

Calculated: C 32.71, H 3.46, F 38.24, N 6.63, S 3.80; Found: C, 32.75; H, 3.33; F, 38.38; N, 6.68; S, 3.81%.

e) 2-N- [1,4,7-tris (carboxylatomethyl) -1-N- [dimethyl-bis (1,1-dihydroxymethyl)] amide 5- [1- (4-perfluorooctylsulfonyl) piperazine] amide, 4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - L-glutamic acid, Gd complex

20.48 g (24.25 mmol) of the title compound of Example 19d,

2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of the Gd complex 1,4,7-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl) pentanoic acid] -1,4,7,10-tetraazacyclododecane was dissolved in 200 ml dimethylsulfoxide with gentle heating. 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide are added at 10 ° C and the mixture is stirred overnight at room temperature. The solution is then poured into 3000 ml of ace70 tone and stirred for 10 minutes. The precipitated solid was filtered off and purified by chromatography on RP-18 silica gel with water-ethanol-acetonitrile (gradient). This gave 29.05 g (83%) of a colorless solid containing 11.0% water.

Analysis (calculated on the anhydrous substance):

H, 3.91; F, 22.38; N, 8.73; S, 2.22; Gd, 10.90;

Found: C 34.24, H 3.98, F 22.39, N 8.69, S 2.15, Gd 10.87.

Example 20

a) N-Trifluoroacetyl-L-glutamic acid 5-benzyl ester [1- (4-perfluorooctylsulfonyl) piperazine] amide

To 11.06 g (33.2 mmol) of the title compound of Example 18a a

18.87 g (33.2 mmol) of 1-perfluorooctylsulfonylpiperazine (prepared according to DE 19603033) in 80 ml of tetrahydrofuran at 0 ° C are added 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-ethyl ester). (dihydroquinoline-1-carboxylic acid) is added and the mixture is stirred overnight at room temperature. After evaporation to dryness in vacuo, the residue is chromatographed on silica gel with dichloromethane-methanol (20: 1). 27.28 g (93%) of a colorless solid are obtained.

analysis:

Calculated: C 35.35, H 2.40, F 43.01, N 4.76, S 3.63; found: C 35.48, H 2.51, F 42.87, N 4.73, S 3.50.

b) N-Trifluoroacetyl-L-glutamic acid [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 21.92 g (52.15 mmol) of the title compound of Example 20a in 500 mL of ethanol was added 3 g of palladium catalyst (10% Pd / C) and the mixture was subjected to hydrogenation at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield 41.37 g (100%) of a colorless solid.

analysis:

Calculated: C 28.76, H 1.91, F 47.89, N 5.30, S 4.04; found: C 28.84, H 2.03, F 47.79, N 5.28, S 4.19.

c) N-Trifluoroacetyl-L-glutamic acid N-Bis (2-hydroxyethyl) amide 5- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of the title compound of Example 20b (24.9 g, 24.08 mmol), diethanolamine (2.53 g, 24.08 mmol) and 2.77 g (24.08 mmol).

N-hydroxysuccinimide in 150 ml of dimethylformamide is added at 0 ° C with 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide. The mixture was stirred at 0 ° C for 3 hours and then at room temperature overnight. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo and the residue is chromatographed on silica gel with dichloromethane-ethanol (20: 1). 9.11 g (90%) of a viscous oil are obtained.

analysis:

Calculated: C 31.37, H 2.75, F 43.15, N 6.36, S 3.64. Found: C 31.22, H 2.61, F 43.30, N 6.25, S 3.81.

d) L-glutamic acid N-Bis (2-hydroxyethyl) amide-5- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 26.61 g (30.22 mmol) of the title compound of Example 20c in 200 mL of ethanol was added ammonia gas at 0 ° C for one hour. The mixture was stirred at 0 ° C for 4 hours, evaporated to dryness and the residue was triturated with water. The solid is filtered off with suction and dried under vacuum at 50 ° C. Yield 23.93 g (97%) of an amorphous solid.

analysis:

Calculated: C 30.89, H 3.09, F 39.56, N 6.86, S 3.93; Found: C 30.75, H 3.13, F 39.78, N 6.75, S 3.81.

e) N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10- [1- (4-perfluorooctylsulfonyl) piperazine] amide N-Bis (2-hydroxyethyl) amide (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - L-glutamic acid, Gd complex

16.43 g (24.25 mmol) of the title compound of Example 20d,

2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of the Gd complex 1,4,7-tris (carboxylatomethyl) -10 - [(3-aza-4-oxo-5-methyl-5-yl) pentanoic acid] -1,4,7,10-tetracyclododecane was dissolved in 200 mL of dimethyl sulfoxide with gentle heating. 8.25 g (40 mmol) of N, N-dicyclohexylcarbodiimide are then added at 10 ° C and stirred overnight at room temperature. The solution was poured into 3000 mL of acetone and stirred for 10 minutes. The precipitated solid is filtered off with suction and purified by chromatography on RP-18 silica gel with water-ethanol-acetonitrile (gradient). 28.10 g (83%) of a colorless solid are obtained, containing 11.0% water.

Analysis (calculated on the anhydrous substance):

Calculated: C 34.41, H 3.83, F 23.13, N 9.03, S 2.30, Gd 11.26;

Found: C 34.44, H 4.98, F 23.19, N 8.89, S 2.15, Gd 11.17.

Example 21

a) N-Trifluoroacetyl-F-glutamic acid 5-benzyl ester [1- (4-perfluorooctylsulfonyl) piperazine] amide

To 11.06 g (33.2 mmol) of the title compound of Example 18a a

18.87 g (33.2 mmol) of 1-perfluorooctylsulfonylpiperazine (prepared according to DE 19603033) in 80 ml of tetrahydrofuran at 0 ° C are added 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-ethyl ester). (dihydroquinoline-1-carboxylic acid) was added and the mixture was stirred overnight at room temperature. After evaporation in vacuo to dryness, the residue is chromatographed on silica gel with dichloromethane-methanol (20: 1). 27.28 g (93%) of a colorless solid are obtained.

analysis:

Calculated: C 35.35, H 2.40, F 43.01, N 4.76, S 3.63; Found: C 35.48, H 2.54, F 42.87, N 4.73, S 3.40.

b) N-trifluoroacetyl-L-glutamic acid 5- [1- (4-perfluorooctylsulfonyl) piperazine] amide

To a solution of 21.92 g (52.15 mmol) of the title compound of Example 21a in 500 mL of ethanol was added 3 g of palladium catalyst (10% Pd / C) and the mixture was subjected to hydrogenation at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Yield 41.37 g (100%) of a colorless solid.

analysis:

Calculated: C 28.76, H 1.91, F 47.89, N 5.30, S 4.04; Found: C 28.84, H 1.81, F 47.79, N 5.28, S 4.16.

Example 22

Contrast composition of Example 3 according to the invention in various organs (including tumor enrichment and lymph node) in rats with prostate cancer

The rats (Cop-Inzucht) implanted with Dunning R3327 MAT-Lu prostate cancer 12 days ago were injected intravenously with the resulting compound of Example 3 at a dose of 100 μπιοί of total gadolinium / kg body weight. The metal content of the various organs, both tumor and lymph nodes (pooled as mesenteric and peripheral lymph nodes) was then determined 10 minutes, 1 hour and 24 hours after application (mean ± standard deviation, n = 3).

rThe title compound of the example

% Total tissue dose H & Ό ABOUT JZ CN 5.37 ± 0.63 0.25 ± 0.01 0.18 ± 0.01 n · about about +1 WHAT WHAT and t 0.56 ± 0.03 0.15 ± 0.03 0.03 ± 0.00 0.03 ± 0.01 OJ tr about +1 kD tr about 0.26 ± 0.01 0.09 ± 0.01 0.11 ± 0.02 ! 0.27 ± 0.03 1.63 ± 0.15 9.58 ± 1.02 31.05 ± 4.60 36, 38 ± 2.36 8.91 ± 2.29 50.95 ± 4.52 about- tr what +1 tr OJ kD oh | 1 hr p.i. 3.93 ± 0.20 0.23 ± 0.01 0.23 ± 0.07 2.00 ± 0.21 1.27 ± 0.05 0.33 ± 0.01 0.10 ± 0.02 0.08 ± 0.01 0.40 ± 0.12 0.50 ± 0.02 0.10 ± 0.01 0.19 ± 0.03 0.50 ± 0.06 1.85 ± 0.27 30.63 ± 1.05 1 +1 1 1 +1 1 1 +1 1 kD about- i-1 +1 OK Γ- rh tr 1 Ή | 10 min p.i. 3.79 ± 1.12 0.25 ± 0.07 0.25 ± 0.08 cn what about +1 about 1-1 1.30 ± 0.33 0.40 ± 0.11 0.09 ± 0.02 0.12 ± 0.04 0.20 ± 0.07 0.50 ± 0.06 0.11 ± 0.04 0.13 ± 0.03 R-L ABOUT +1 sr about 2.48 ± 0.56 35.18 ± 7.43 1 +1 1 1 +1 1 1 +1 1 WHAT ch ch +! LO WHAT kD tr 1 +1 1 Gd concentration [μιυοΐ / l] | 24 h p.i. kD +1 OJ r- i-l 161 ± 19 55 ± 7 292 ± 18 146 ± 19 65 ± 12 about +1 iD 13 ± 2 100 ± 6 33 ± 1 127 ± 7 108 ± 6 48 ± 8 101 ± 12 169 ± 16 103 ± 7 60 ± 19 561 ± 28 Sum of authorities * * * balance H and Ό 0 £ 1-1 136 ± 1 161 ± 3 95 ± 15 I-1 +1 tr WHAT 321 ± 16 151 ± 7 16 ± 3 tr +1 about tr 126 ± 10 LO +1 tr kD 160 ± 5 186 ± 6 93 ± 3 130 ± 7 534 ± 12 1 +1 1 1 +1 1 [ +1 1  H and C ε about t-1 137 ± 39 WHAT tn +1 tr what 1 d 99 ± 26 359 ± 88 LiO +1 tT tT WHAT kD tr +1 r- r- I ^- ) 16 ± 5 OJ i — i +1 t-1 tr 82 ± 32 61 ± 10 ABOUT tr +1 10 µO i-1 115 ± 27 ¹ 90 + 26 WHAT Ή kD tr i-1 621 ± 137 1 +1 1 1 +1 1 1 +1 1 liver spleen pancreas kidney lungs Heart Brain -k -k <—1 m> ω tumor Thigh-bone 0) J w Q) 2 Perif. LU Stomach (empty) Intestine (emptied) -K > i-l The rest of the body Urine 0-24 hrs Stool 0-24 hrs

□ 1 - 1 m> o about r: -about C C -1-1 0 4— ¹ r- | (0 ABOUT 0 JZ C 4> 0 0 r: £ Ό JC > , -1 about about Φ Q. C ω ABOUT Φ > 1-1 H d) C ΙΌ CP about: 4-1 22 4J • H Ό > > -IN • 1 — f i-1 rh 03 E what C ω lO I-i -k -k

sum of organs 10 min and 60 min p.i. without the other body.

Claims (21)

PATENT CLAIMS 1. Perfluoroalkylated complexes containing polar radicals of the general formula I (K) 1G - (Z-Rf) m (D (R) _P ) wherein: R f is a perfluorinated, unbranched or branched hydrocarbon chain of the formula -C _n F _{2 n} E, wherein E is a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n is a number from 4 to 30, K is a metal complex of formula II wherein R ¹ is a hydrogen atom or a metal ion equivalent having atomic number 21-29, 31-33, 37-39, 42-44, 49 or 57-83, provided that at least two R ¹ are metal ion equivalents, R ² and R ³ independently of one another are hydrogen, C 1 -C ₇ -alkyl, benzyl, phenyl, -CH ₂ OH or -CH ₂ OCH ₃ , and U is-C _s H ₄ -O-CH ₂ -U group, - _(CH2) -, - 5-ω, a phenylene group, a group --CH2 NHCO-CH 2 -CH (CH ₂ COOH) -CsHd-ω- , -C ₆ H ₄ - (OCH 2 CH 2) 0-1 -N (CH ₂ COOH) -CH ₂ -C 1, or C 1 -C ₁₂ -alkylene or C ₇ -C ₁₂ -C ₅ H ₄ -O-, the last two groups are optionally interrupted by one or more oxygen atoms, one to three groups -NHCO-, one to three groups -CONH-, and / or substituted by one to three groups - (CH _{2) 0-5} COOH, wherein ω represents the point of attachment to -CO-, or is a radical of formula III wherein R ¹ is as previously defined, R ⁴ is a hydrogen atom or a metal ion equivalent defined for R ^1, and U ¹ is -C 6 H ₄ -O-CH ₂ -m-, where ω is the point of attachment to -CO-, or wherein R ¹ and R ² are as previously defined, or is a radical of formula VA or VB CO • COOR ¹ ROOC / \ _n -coor ¹ XO = COOR ¹ • Wv * -C COOR ¹ COOR ¹ COOR ¹ COOR ¹ (V3) wherein R ¹ is as previously defined, or is a radical of formula VI WHAT- ROOC COOR ¹ wherein R ¹ is as defined above, or is a radical of formula (VII) ROOC ROOC ROOC ROOC: N O (VII) wherein R ¹ is as defined above and U ¹ is -C 6 H ₄ -O-CH ₂ -o, where ω is the point of attachment to -CO-, and the free acid groups optionally present in K may optionally exist as salts of organic and / or inorganic bases or amino acids or amides amino acids, G is at least three times a functionalized moiety selected from the group of moieties a) to i) NH β (B) NH (c) (d) (e) (f) Y -N- (CH 2) _{4 -} > N - CO - C - (CH 2 -N 4 - β π I n NH β (G) HN NH β γ-CO- (CH ₂ ) ₂ ; _3-J? H CO - ^ / 3 NH OÚ β CO- (CH ₂ ) ₂ : ₃ -CH-CO- ^ γ I H H where a is the point of attachment of the residue G to the complex K, β is the point of attachment of the residue G to the residue R and γ is the point of attachment of the residue G to the rest of Z, Z is a group Y - N - SO 3 - or a group of γ-C (O) CH ₂ O (CH ₂ ) 2 -ε where γ represents the point of attachment of the Z residue to the G residue and ε represents the point of attachment of the Z to perfluorinated residue Rf R is a polar moiety selected from the group of K complexes of formulas II to VII, wherein R ¹ is hydrogen or metal ion equivalent with atomic number 20-29, 31-33, 37-39, 42-44, 49 or 57- 83, and the radicals R ² , R ³ , R ⁴ , U and U ¹ are as previously defined, and when G is a radical (c) or (d) and R is a complex selected from formulas II and V, it may not be R identical to the remainder of K in formula I when Z is δ-C (O) CH ₂ O (CH ₂ ) ₂ -ε, or a folic acid residue or a straight or branched, saturated or unsaturated hydrocarbon chain of 2- 30 carbon atoms which is bonded to the remainder of G through -CO-, -SO ₂ - or by a direct bond and which is optionally interrupted by 1-10 oxygen atoms, 1-5 -NHCO- groups, 1-5 -CONH- groups, 1-2 sulfur atoms, 1-5 -NH- groups or 1-2 phenylene groups which may be optionally substituted by 1-2 OH groups, 1-2 NH ₂ groups, 1-2 groups i -COOH or 1-2 -SO ₃ H groups, or optionally substituted with 1-8 OH groups, 1-5 -COOH groups, 1-2 -SO ₃ H groups, 1-5 NH ₂ or 1-5 Ci groups -C 1-6 -alkoxy groups; 1. m, p independently of each other are integers 1 or 2. Metal complexes according to claim 1, characterized in that the equivalent of the metal ion R ¹ in residue K is an element with atomic number 21-29, 39, 42, 44 or 57-83. Metal complexes according to claim 1, characterized in that the equivalent of the metal ion R ¹ in residue K is an element with atomic number 27, 29, 31-33, 37-39, 43, 49, 62, 64, 70, 75 and 77th Metal complexes according to one of Claims 1 to 3, characterized in that K is a metal complex of the formula II, III, VB or VII. vyznávšecbecného Metal complexes according to one of Claims 1 to 4, characterized in that the polar residue R has the meaning of n and of the complex K. Metal complexes according to claim 5, characterized in that the polar residues R are of the formula II, III, VA or VII. characterized by complexes K in general Metal complexes according to claim 5 or 6, characterized in that R ¹ is a metal ion equivalent having an atomic number of 20, 25 or 64. Metal complexes according to one of Claims 1 to 4, characterized in that the polar radical R has the following meanings: -C (O) CH ₂ CH ₂ SO ₃ H, -C (O) CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ OH, -C (O) CH ₂ OCH ₂ CH ₂ OH, -C (O) CH2OCH2CH (OH) CH ₂ OH, C (O) CH ₂ NH-C (O) CH ₂ COOH, -C (O) CH ₂ CH (OH) CH ₂ OH, -C (O) CH ₂ OCH ₂ COOH, -so ₂ ch ₂ ch ₂ cooh -C (O) -C ₆ H ₃ - (m-COOH) 2, -C (O) CH ₂ O (CH ₂ ) 2 -C ₆ H ₃ - (m-COOH) 2, -C (O) CH ₂ OC ₆ H ₄ -m-SO ₃ H, -C (O) CH ₂ NHC (O) CH ₂ NHC (O) CH ₂ OCH ₂ COOH, -C (O) CH ₂ OCH ₂ CH ₂ OCH ₂ COOH, -C (O) CH ₂ OCH ₂ CH (OH) CH ₂ O-CH ₂ CH ₂ OH, -C (O) CH ₂ OCH ₂ CH (OH) CH ₂ OCH ₂ -CH (OH) -CH ₂ OH, -C (O) CH ₂ SO ₃ H, -C (O) CH ₂ CH ₂ COOH, -C (O) CH (OH) CH (OH) CH ₂ OH, -C (O) CH ₂ O [(CH ₂ ) ₂ O] ₁ . ₉ -CH ₃ , -C (O) CH ₂ O [(CH ₂ ) ₂ O] -C (O) CH ₂ OCH (CH ₂ OH) 2, -C (O) CH ₂ OCH (CH ₂ OCH ₂ COOH) 2, -C (O) -C ₆ H ₃ - (m-OCH ₂ COOH) 2, -CO-CH ₂ O- (CH ₂ ) ₂ 0 (CH ₂ ) ₂ 0- (CH ₂ ) ₂ 0 (CH ₂ ) ₂ and ₃ , in particular -C (O) CH ₂ O [(CH ₂ ) ₂ O ₄ -CH ₃ . Metal complexes according to one of Claims 1 to 4, characterized in that the polar residue R is a folic acid residue. Metal complexes according to one of Claims 1 to 9, characterized in that G in formula I is a lysine residue (a) or (b). Metal complexes according to one of Claims 1 to 10, characterized in that, in the metal complex K, the group is -CH ₂ - or -C 6 H ₄ -O-CH _{2 -} >, wherein ω denotes the point of attachment to -CO- . Use of the metal complexes according to claim 2 for the preparation of contrast agents for use in NMR and X-ray diagnostics. Use of metal complexes according to claim 12 for the preparation of contrast agents for imaging infarction and necrosis. Use of the metal complexes according to claim 3 for the preparation of contrast agents for application in radiodiagnostics and radiotherapy. Use of metal complexes according to claim 2 for the preparation of contrast agents for lymphography in order to diagnose changes in the lymphatic system. Use of metal complexes according to claim 2 for the preparation of contrast agents for application in indirect lymphography. Use of metal complexes according to claim 2 for the preparation of contrast agents for administration in intravenous lymphography. Use of metal complexes according to claim 2 for the preparation of contrast agents for imaging of the vascular bed. Use of metal complexes according to claim 2 for the preparation of contrast agents for tumor imaging. Pharmaceutical compositions comprising at least one physiologically acceptable compound according to claims 1 to 11, optionally with customary galenic additives. A process for the preparation of perfluoroalkylated complexes containing polar moieties of the general formula I (K) - (ZR _f ) _m (I) (R) _P wherein K, G, R, Z, R _f , 1, maps are defined in claim 1 characterized in that the carboxylic acid of the formula IIIa ABOUT U 1 OH (IIIa) or a carboxylic acid of the formula IIIa wherein R ⁵ is the metal ion equivalent with atomic number 21-29, 31-33, 37-39, 42-44, 49 or 57-83, or a carboxyl protecting group, and R ² , R ³ and U have the meanings given above, IIIa) wherein R ⁴ , R ⁵ and U ¹ are as defined above, or a carboxylic acid of formula IVa (IVa) wherein R ⁵ and R ² are as defined above, or a carboxylic acid of formula Va or Vb ^The OOC R '\ —N / COOH -COOR ⁵ COOR ⁵ COOR ⁵ N _N - ^c ° 0R ^'N ^ ^p -COOR HOOC / COOR ⁵ COOR ⁵ (Va) wherein R ⁵ is as defined above, or a carboxylic acid of Formula VIa R ⁵ OOC- _x / CO-OH R ^Z OOC-- ^ COOR ⁵ wherein R ⁵ is as defined above, or a carboxylic acid of formula Villa (Vb) (Via) R ^S OOC R ^S OOC R ⁵ OOC R ^with OOC OH (VIIa) wherein R ⁵ and U ¹ have the above-mentioned meanings, optionally in activated form, subjected to a condensation reaction with an amine of the general formula VIII H - G - (ZR _f ) _m t (VIII) (R) p wherein G, R, Z, R _f , maps are as defined above, then optionally removing any protecting groups present to form a metal complex of formula I, or when R ⁵ is a protecting group, after cleavage of these protecting groups, they are reacted in known manner with at least one metal oxide or metal salt of atomic number 21-29, 31-33, 37-39, 42-44, 49 or 57 in a known manner -83, and finally, if desired, any acidic hydrogen atoms present are replaced by cations of inorganic and / or organic bases, amino acids or amino acid amides.