BRPI0613407A2 - Perfluoralkyl containing complexes, as well as pharmaceutical composition, use and processes for the preparation thereof - Google Patents

Abstract

COMPLEX CONTAINING PERFLUORALQUILA AS WELL AS PHARMACEUTICAL COMPOSITION, USE AND PREPARATION PROCESSES FOR THE SAME. The present invention relates to the objects characterized in the claims, i.e. perfluoralkyl-containing metal complexes containing nitrogen-containing radicals of the general formula I, processes for their preparation and their use in X-ray and NMR diagnosis, radiodiagnosis and radiotherapy, as well as MRT lymphography and balance radioisotopic imaging.

Description

Patent Descriptive Report for "COMPLEXING WITH PERFLUORALKYL, AS A PHARMACEUTICAL COMPOSITION, USE AND PREPARATION PROCESSES".

The present invention relates to the objects characterized in the claims, i.e. the perfluoralkyl-containing metal radicals containing nitrogen-containing radicals of the general formula I, processes for their preparation and their use in the diagnosis by MRI and radiotherapy diagnostic radiotherapy, as well as MRT Iinfography and the equilibrium radioisotopic image. The perfluoralkyl-containing metal complexes are employed in nuclear magnetic resonance tomography (MRT) to represent different physiological and pathophysiological structures and thus to improve diagnostic information such as disease location and degree, choice and successful control of targeted therapy and prophylaxis.

The compounds according to the invention are particularly suitable for lymphography, tumor diagnosis and infarction and necrosis imaging.

In the field of nuclear magnetic resonance, some fluorine-containing compounds are known which can be employed in the field of imaging. In general, these compounds are intended for use only with fluorine-19 imaging and are only suitable for such use. Compounds of this type are described, for example, in U.S. Patent 4,639,364 (Mallinckrodt), DE 4203254 (Max-Planck-Gesellschaft), WO93 / 07907 (Mallinckrodt), US 4,586,511 (Children's Hospital Medical Center), EP 307863 (Air Products), US 4,588,279 (University of Cincinnati, Children's Hospital Research Foundation) and WO 94/22368 (Molecular Biosystems).

Other fluorine-containing compounds that may be employed for imaging are described in US 5,362,478 (VIVORX), U.S. Patent 4,586,511, DE 4008179 (Schering), WO 94/05335 and WO94 / 22368 (both molecular biosystems), EP 292 306 (Kabu-shiki Kaisha Terum), EP 628 316 (Kabushiki Kaisha Terum) and DE 4317588 (Schering).

While in compounds containing the elements fluorine and iodine there is no reciprocal action between the two nuclei, in compounds containing fluorine and paramagnetic centers (radicals, metal ions) there is a strong reciprocal action that is shown to reduce the relaxation time. of the fluorine core. The size of this effect depends on the number of unpaired electrons of the metal ion (Gd3 +> Mn2 +> Fe3 +> Cu2 +) and the distance between the paramagnetic ion and the 19F atom.

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

Reduction of relaxation time as a function of paramagnetic ion distance can be noted in all nuclei with an odd number of spins as well as protons, and gadolinium compounds are therefore widely used as contrast agents in magnetic resonance. nuclear (Magnevist®, Prohance®, Omniscan®, Dotarem®).

In the 1H-RM (1H-RMI) 1 image, however, the T1 or T2 proton detachment time, i.e., especially of the water protons, is measured, not the fluorine nucleus relaxation time and employed for the formation. of image. The quantitative measure for shortening the relaxation time is relaxivity [L / mmol.s]. To shorten the relaxation time, paramagnetic ions are successfully employed. In the following table is

<table> table see original document page 3 </column> </row> <table>

In these compounds occur only reciprocal actions between protons and gadolinium ion. For these contrast agents a relaxivity of approximately 4 [L / mmol.s] is also observed in water.

For MRI imaging, therefore, both fluorine-19 fluorine imaging compounds in which shortened relaxation time of the fluorine core is used as well as non-fluorine-containing compounds in which time is measured are successfully employed. of relaxation of the water tones.

The introduction of a perfluorocarbon-containing radical into a paramagnetic contrast agent, that is, in the combination of properties that until now were known to be suitable only for fluorine imaging compounds, with compounds that have been employed for proton imaging, rises surprisingly fast. also the relaxivity in relation to the protons of water. They here reach values of 10-50 [L / mmol.s] compared to values between 3.5 and 3.8 [L / mmol.s] as already mentioned for some commercial products in the table above.

Perfluoralkyl-containing metal complexes are already known from DE 196 03 033.1, WO 99/01161, DE 19914101, DE 10040381, DE 10040858. These compounds, however, cannot be used satisfactorily for all applications as compatibility is in most cases. insufficient. With this, there still remains a need for MRT contrast agents that have both excellent imaging properties and also simultaneously are excellently compatible to maintain the noninvasive character of the diagnostic method. This is important, for example, when tumors should be diagnosed including satellite metastases and with this a distribution of the contrast agent throughout the body can be obtained.

Malignant tumors cause metastasis in quantity in regional lymph nodes, and can also be divided into various lymph node stations. Thus, lymph node metastases are found in about 50-69% of all patients with malignant tumors (Elke, Lymphographie [lymphography] in: Frommhold, Stender, Thurn (Eds.), Radiologische Diagnostik in Klinik und Praxis [ radiological diagnosis in clinical and practical studies], volume IV, Thieme Verlag Stuttgart, 7th Ed., 434-496, 1984). The diagnosis of a lymph node metastasis attack is of great significance with regard to the therapy and prognosis of malignant diseases. With modern imaging methods (CT, US and MRI) lymphatic metastases from malignant tumors are only poorly recognized, since in most only lymph node size can be used as a diagnostic criterion. As a result, minor metastases in non-enlarged lymph nodes (<2 cm) cannot be distinguished from lymph node hyperplasia without malignant attack (Steinkampet al., Sonographie und Kernspintomographie: Differentialdiagnostik von re-aktiver Lymphknoten-vergrönoten und lymphenperas und lymph nodes). Am Hals 1 Radiol Diagn 33: 158, 1992).

It would be desirable for the use of specific contrast agents to be able to differentiate lymph nodes with metastasis attack and lymph nodes by hyperplasia.

Direct X-ray infography (injection of an oily contrast suspension into a prepared lymphatic vessel) is known as a rarely used invasive method that may represent only a few lymphatic drainage stations.

Experimentally, fluorescence-labeled dextrans were also used in a comanimal experiment in order to be able to observe lymphatic drainage after its interstitial application. After interstitial / intracutaneous application, all markers used to represent the lymphatic pathway and lymph nodes are particulate substances (eg, nano-crystalline emulsions and suspensions) or large polymers (see WO 90/14846). The preparations even now described, however, have not yet been totally appropriate for indirect alinfography, due to their lack of local and systemic compatibility as well as their reduced lymphatic direction, which causes insufficient diagnostic efficiency.

Since visualization of lymph nodes is of fundamental importance for the prior recognition of metastatic attack in cancer patients, there is a great need for lymph-specific contrast agent preparations for the diagnosis of corresponding changes in the lymphatic system, which are characterized by very good compatibility. The lymphatic system within the meaning of the present invention encompasses both lymph nodes and lymphatic vessels. The substances of the present invention are therefore suitable for diagnosing changes in the lymphatic system, preferably for diagnosing changes in the lymph nodes and / or lymphatic vessels, particularly for diagnosing metastases in the lymph nodes.

The highest possible concentration of contrast agent and high stability are equally as desirable as the most uniform lymphatic concentration possible relevant for the diagnosis in various lymphatic stations. The burden throughout the body should be kept reduced by rapid and complete elimination of the contrast agent. A rapid effect, visible within a few hours after contrast application, is of great significance for radiological practice. Good compatibility is required.

Last but not least, it is desirable to have available lymph-specific contrast agents which allow visualization in a diagnostic session of both the primary tumor and possible metastasis of the lymph nodes.

Another important field in medicine is the detection, localization and observation of necrosis or infarction. Thus, myocardial infarction is not a stationary stage, but a dynamic process that extends over a long period (weeks to months). The disease occurs in about three phases that do not severely separate from each other but which are overlapping. The first phase, the development of myocardial infarction spans 24 hours after the infarction, in which destruction progresses as a shock wave (wavefront phenomenon) from the subendocardium to the myocardium. The second phase, the existing infarction, includes the stabilization of the band in which fiber formation (fibrosis) occurs as a healing process. The third phase, the healed infarction, begins after all the damaged tissue has been replaced with scarred fibrous tissue. During this period a major restructuring occurs.

To date, no precise process is known and can make the current phase of a myocardial infarction diagnosed in living patients. For the evaluation of a myocardial infarction, it is decisive to know the size of the fraction of the tissue lost in the infarction and at what point the loss occurred, since this depends on the type of therapy.

Infarctions not only occur in the myocardium, but also in other tissues, particularly in the brain.

While the infarction is curable to a certain extent, only the detrimental consequences for the rest of the body can be prevented or at least moderate in the case of a necrosis, endowed death limited to one location. Necrosis can develop in many ways: from injury, chemicals, oxygen deficit, or radiation. As with infarction, knowing the extent and type of a necrosis is important for a subsequent medical procedure.

Previously, tests have been done to improve the location of infarcts and necroses by the use of contrast agents in noninvasive processes such as scintigraphy or nuclear magnetic tomography. In the literature, tests for porphyrin for necrosis imaging have taken up great space. The results obtained, however, produce a contradictory picture. In addition, porphyrins tend to be stored in the skin, which leads to photosensitization.

Non-porphyrin backbone contrast agents for imaging necrosis and infarction are described in DE 19744003, (Schering AG), DE 19744004 (Schering AG) and WO 99/17809 (EPIX). So far there is still no compound that can be employed in a satisfactory manner as a contrast agent in the infarction and necrosis image and is simultaneously characterized by excellent compatibility.

The same problem occurs in the field of compounds that can be employed to diagnose thrombosis or atherosclerotic plaques: there is no compound that can be satisfactorily employed as a contrast agent to show atherosclerotic thrombosis or plaques and is simultaneously characterized by excellent compatibility.

It was therefore the task of the invention to provide contrast agents which, on the one hand, had excellent imaging properties as MRT contrast agents, and which were particularly suited for the imaging of tumors and necroses and / or for lymphography. and / or for equilibrium radioisotopic imaging and / or to represent atherosclerotic thrombosis or plaques, which are simultaneously characterized by excellent compatibility.

The task of the invention is solved by nitrogen-containing perfluoralkyl-containing complexes of the general formula I

<formula> formula see original document page 8 </formula>

on what

R or represents

a 1-OH-linked monosaccharide or oligosaccharide radical, in which case Q has the meaning of a group selected from:

δ-CO- (CH 2) n »-e

δ-ΝΗ- (ΟΗ2) η ~ ε

δ- (CH2) m-e

on what

n "is an integer from 1 and 5, and

m is an integer from 1 and 6, where δ indicates the binding position with the binding agent L, and ε represents the binding position with the radical R;

or

R has one of the following meanings, since Q has the meaning of a direct bond: R means a polar radical chosen from the complexes K of the general formulas II through V, where R1 signifies a hydrogen atom or a metal ion equivalent of the numbers. 20-29, 31-33, 37-39, 42-44, 49 or 57-83, and the radicals R2, R3, R4, U and U1 have the meaning given below, or

• a carbon chain of 1 -30 C atoms bonded by -CO-, -NR7- or a direct bond with the L-linker, which may be linear or branched, saturated or unsaturated, and eventually 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 groups OH, 1-2 NH2 groups, 1-2 -COOH groups, or 1-2 -SO3H groups, which is eventually substituted by 1-10 -OH groups, 1-5 -COOH groups, 1-2 SO3H groups, 1- NH 2 groups, or 1-5 C 1 -C 4 alkoxy groups, wherein R 7 means H or C 1 -C 4 alkyl,

Rf is a perfluorinated, straight or branched carbon chain of the formula -CnF2nE, where E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen terminal, and η is 4-30,

K represents a metal complex of general formula II,

<formula> formula see original document page 9 </formula>

on what

R1 means a hydrogen atom or a metal ion equivalent of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83, provided that at least two R1 represent equivalent metal ions,

R 2 and R 3, independent of each other, represent hydrogen, C 1 -C 7 alkyl, benzyl, phenyl, -CH 2 OH or -CH 2 OCH 3, and

U represents -C6H4-O-CH2-Co-, - (CH2) 1-SG), a phenylene group, -CH2-NHCO-CH2 -CH (CH2COOH) -C6H4-co-, -C6H4- (OCH2CH2) 0- I -N (CH 2 COOH) -CH 2 -Cd or a C 1 -C 2 alkylene group or - (CH 2) 7. 2-C 6 H 4 O may be interrupted by one or more oxygen atoms, 1 to 3 -NHCO groups, 1 to 3 -CONH groups and / or substituted by 1 to 3 groups- (CH2) 0-5COOH, where ω represents the binding position with -CO-, or of the formula III <formula> formula see original document page 10 </formula>

wherein R1 has the meaning mentioned above, R4 represents hydrogen or one metal ion equivalent mentioned in R1, and U1 represents-C6H4-O-CH2-CD- or a group - (CH2) p-, where ω means the position deletion with -CO- and ρ is an integer between 1 and 4, or of formula IV

<formula> formula see original document page 10 </formula>

wherein R1 and R2 have the meaning mentioned above or of the general formulas V A or V B

<formula> formula see original document page 10 </formula> where R1 has the meaning mentioned above or of the general formula Vl

<formula> formula see original document page 11 </formula>

wherein R1 has the meaning mentioned above or of the general formula V11

<formula> formula see original document page 11 </formula>

wherein R1 and U1 have the meaning mentioned above, where ω means the binding position with -CO-, or of the general formula Vlll

<formula> formula see original document page 11 </formula>

wherein R1 has the meaning mentioned above, and U2 represents a saturated or unsaturated linear or branched C1 -C2 alkylene group, optionally containing imino, phenylene, phenylenoxy, phenylenimino, amide, hydrazide, carbonyl, ester groups, oxygen atom (s), sulfur and / or nitrogen, and optionally substituted by hydroxy, mercapto, oxo, thioxo, carboxy, carboxyalkyl, ester and / or amino group (s),

and free acid groups optionally present in radical K may be present as salts of organic and / or inorganic bases or amino acids or amino acid amides,

and L represents a radical chosen from radicals IXa) through IXc) below: <formula> formula see original document page 12 </formula>

where η 'and m', independent of each other, represent an integer between 0 and 4, and m '+ n'> 1; preferably m '+ n' is equal to 1, 2, or 3, and R8 and R8, independent of each other, are either -H or -OH, with m '+ n'> 1, each grypo - (CR8R8 ') - may be different, and

W is either a direct bond, -O- or a phenylene group, which may be optionally substituted by 1 to 4 hydroxy groups, and q is 1, 2, 3 or 4,

where α signifies the binding position of L with the complex Κ, β is the binding position of L with the radical Qey represents the binding position of L with the radical X, and

X represents a group of formula (VI)

<formula> formula see original document page 12 </formula>

where Y means a direct bond, a -CO- group or an NR6 group, in which

<formula> formula see original document page 12 </formula> where R6 represents -H or a straight or branched, saturated or unsaturated C1-C15 carbon chain that may be interrupted by 1-4 O atoms, 1-3 -NHCO groups, 1-3 -CONH groups, 1-2 -SO 2 groups, 1-2 sulfur atoms (fre, 1-3 -NH groups or 1-2 phenylene groups which may optionally be substituted by 1-2 OH groups, 1-2 NH2 groups, 1-2 -COOH groups or 1-2 -SO3H groups,

and which is optionally substituted by 1-10 OH groups, 1-5 -COOH groups, 1-2 -SO 3 H groups, 1-5 NH 2 groups, 1-5 C 1 -C 4 alkoxy groups, and G means -O- or -SO 2 - ,

if 'independent of each other means 1 or 2, t means O or 1 and r represents the binding position of X with L and ζ represents the binding position of X with Rf.

In a preferred embodiment, R 6 is H or a C 1 -C 6 alkyl group which may be interrupted by 1-3 O atoms and which may be substituted by 1-4 -OH groups.

In a particularly preferred embodiment, R 6 is a C 1 -C 4 alkyl group.

In a preferred embodiment, G means the group -O-.

In a particularly preferred embodiment, t = 0.

In a preferred embodiment W is a direct bond.

In a preferred embodiment, the radical R attached to the L-linking moiety by a -CO-, -NR7- or a direct bond is a 1-30 C-carbon chain which is interrupted by 1 to 10 deoxygen atoms. and / or is substituted by 1-10 OH groups.

In a particularly preferred embodiment, R is a C1-C12 chain attached to L via a -CO-, -NR7- or direct bond, which is interrupted by 1 to 6 oxygen atoms and / or is substituted by 1-6 groups. OH

If the compound according to the invention is employed for NMR diagnosis, then the metal ion of the signaling group must be paramagnetic. These are particularly the bi- and trivalent ions of the atomic number elements 21-29, 42, 44, and 58-70. Suitable ions are, for example, chrome (11), iron (11), cobalt (II), nickel (11), copper (11), praseodymium (11), neodymium (11), samarium (11) and ions. Ytterbium (III). Because of their strong magnetic moment, gadolinium (11), terbium (11), dysprosium (11), holmium (11), erbium (11), iron (11) and manganese (11) ions are particularly preferred.

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

If the compound according to the invention is employed in X-ray diagnosis, then the metal ion is preferably derived from a higher atomic number element in order to obtain sufficient X-ray absorption. For this purpose, diagnostic agents containing a physiologically compatible metal-ion complex salt of atomic number elements 25, 26 and 39 as well as 57-83 are suitable for this purpose.

Preferred are manganese (11), iron (11), iron (11), praseodymium (11), neodymium (11), samarium (11), gadolinium (11), ytterbium (11) or bismuth (11) ions. , particularly dysprosium ions (III) and yttrium ions (III).

Acidic hydrogen atoms optionally present in R1, that is, those which have not been substituted by the central ion, may be entirely or partially substituted by organic and / or inorganic base cations or amino acids or amino acid amides.

Suitable inorganic cations are, for example, lithium ion, potassium ion, calcium ion and particularly sodium ion. Suitable cations of organic bases are, among others, those of primary, secondary or tertiary amines, such as ethanolamine, diethanolamine, morpholine, glucamine, β, β-dimethylglucamine and particularly N-methylglucamine. Suitable amino acid cations are, for example, those of lysine, arginine and ornithine as well as amides of other acidic or neutral amino acids.

Particularly preferred compounds of formula I are those with macrocycle K of formula II.

The radical U in the metal complex K preferably means -CH2- or CeH4-O-CH2-GO, where ω represents the binding position with -CO-.

In a preferred embodiment, U 2 is a C 1 -C 6 alkylene chain optionally interrupted by 1 to 2 -NHCO groups and / or 1 to 2 O atoms, and which may be substituted by 1 to 3 -OH groups.

The radical U2 in the metal complex K particularly particularly means:

- a linear alkylene group of 1 to 6 C atoms, particularly 2, 3 or 4 C atoms, or

- a linear alkylene group of 1 to 6 C atoms, particularly 2, 3 or 4 C atoms, which is interrupted by 1 O atom, or

- a linear alkylene group of 1 to 6 C atoms, particularly 2, 3 or 4 C atoms, which contains an -NHCO group.

In a preferred embodiment, U 2 is an ethylene group.

The alkyl groups R2 and R3 in the macrocycle of general formula II may be straight or branched. As an example, methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl are mentioned. R 2 and R 3 independently of each other preferably mean hydrogen or C 1 -C 4 alkyl.

In a very particularly preferred embodiment R2 represents methyl and R3 represents hydrogen.

The benzyl group or phenyl group R2 or R3 in macrocycle K of general formula II may also be substituted on the ring.

In another preferred embodiment of the invention R is a monosaccharide radical having 5 or 6 C atoms, preferably glycoside, mannose, galactose, ribose, arabinose or xylose or their deoxy sugars such as, for example. , 6-deoxygalactose (fucose) or 6-deoxymanose (rhamnose) or their peralkylated derivatives. Particularly preferred are glucose, mannose and galactose, especially mannose.

In another preferred embodiment of the present invention, R is selected from one of the following radicals:

-C (O) CH2Ot (CH2) 2OlpR'-C (O) CH2OCHiCB2OCH (CH2OFr) 2I2-C (O) CH2OCH2CHtCH2OCH (CH2ORr) 2J2-R-Nt (CH2) 2OlpR'-N (KCH2) 2R1 ' NCH 2 CH H (OH) CH 2 OH-N 1 CH 2 CH (OH) CH 2 OH 2 CH 2 OH (CH 2 OH) CH (OH) CH 2 OH-NICH (CH 2 OH) CH (OH) CH 2 OH I 2 -R''CH [CH 2 OCH 2 CH 2 CH 2 CH [CH 2 OCH (CH2OR) 2] 2-R "NCH2CH2OCHICH2OCH (CH2OR ') 232-R" NCH2C H2OCH2C HfCH2OC H (CH2OR ^ 2J2-NiCHtCH2OCH (CH2OR ^ 2J2) 2-N {CH2CH [CH2pCH (CH2OR J2Mz-OH) CH (OH) CH (OH) CH (OH) CH 2 OH '-NtCH 2 CH (OH) CH (OH) CH (OH) CH (OH) CH 2 OH

and a complex of formula (II), with Q signifying a direct bond, wherein R 11 R 2, R 3 and U are as defined above for formula (II), or 1,2, 3, 4,5, 6, 7 , 8 or 9,

R is either H or CH3, and R "is either H or a C1 to C4-alkyl radical.

ρ is preferably 1, 2, 3, or 4.

The polar radicals indicated herein are commercially available products or are produced according to methods described in the literature.

Cassei et al., Eur. J. Org. Chem., 2001, 5, 875-896. Whitessides et al., JACS, 1994, 5057-5062 Voegtle et al., Liebigs Ann. Chem., 1980, 858-862 Li et al., Chem. Commun., 2002, 594Mitchell et al., Heterocyclic Chem., 1984, 697-699Bartsch et al., J. Org. Chem., 1984, 4076-4078Keana et al., J. Org. Chem., 1983, 2647- 2654

In a most particularly preferred embodiment, R is a radical of the formula: -C (O) CH 20 [(CH 2) 20] p R 'linked to L through -C 0 -. With ρ and R' having the meaning given above, R 'is particularly preferably the CH3 group.

In another preferred embodiment, Q has the meaning of / a group chosen from:

6-CO- (CH2) n "- £

on what

n "is an integer from 1 and 5, and

L simultaneously means a group of formula IXa or IXb.

In another preferred embodiment, Q means a group selected from:

6-NH- (CH 2) n -e

on what

n "is an integer of 1 and 5, and L simultaneously means a group IXc.

Of the compounds of general formula I according to the invention, furthermore, those wherein Rf means -CnF2n + i; that is, and in the formula -CnF2nE means a fluorine atom, η preferably represents numbers 4-15. Most particularly preferred are the radicals -C4F9, -CeF13, -C3F17, -C12F25 and -C14F29 as well as the radicals of the compounds mentioned in the examples.

The nitrogen-containing radical L in formula I, which represents the "backbone", in a preferred embodiment of the invention, means the amino acid (Vc) radical.

In another preferred embodiment, the contendonitrogen L radical in formula I represents a diamine radical of formula (IXb) or (IXa).

The nitrogen-containing perfluoralkyl-containing metal complexes of general formula I

<formula> formula see original document page 17 </formula> with K meaning a metal complex of the general formulas Il through IV and L, Q, X, R, Rf with the meanings mentioned above,

are prepared by reacting, in a known manner, a carboxylic acid of the general formula IIa

<formula> formula see original document page 18 </formula>

wherein R5 means a metal ion equivalent of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83 or a carboxyl protecting group, and R2, R3 and U have the meanings mentioned. above, or a carboxylic acid of general formula IIIa

<formula> formula see original document page 18 </formula>

wherein R4, R5 and U1 have the meaning mentioned,

10. or a carboxylic acid of the general formula IVa

<formula> formula see original document page 18 </formula>

wherein R 5 and R 2 have the meaning mentioned, or a carboxylic acid of the general formula Va or Vb

<formula> formula see original document page 19 </formula>

wherein R5 has the meaning mentioned or a carboxylic acid of the general formula Via

<formula> formula see original document page 19 </formula>

wherein R5 has the meaning mentioned or a carboxylic acid of the general formula Vlla

<formula> formula see original document page 19 </formula>

where R5 and U1 have the meanings mentioned,

<formula> formula see original document page 19 </formula>

where R5 and U2 have the meanings mentioned,

in form possibly activated with an amine of formula Xl <formula> formula see original document page 20 </formula>

wherein L, R, Rf, Q and X have the meanings indicated above in a copulation reaction and eventually subsequent dissociation of protecting groups optionally present to form a metal complex of general formula I

or

when R5 signifies a protecting group upon dissociation by reacting these protecting groups in a subsequent step, as known per se, with at least one metal oxide or metal salt of an atomic number element 21. -29, 31-33, 37-39, 42-44, 49 or 57-83 and then, if desired, by substituting acidic hydrogen atoms optionally with organic and / or inorganic cations, amino acids or amino acid amides .

Such a process for preparing carboxylic acid metal complex amides is known from DE 196 52 386.

The mixture employed in the copulation reaction consisting of a carboxylic acid metal complex IIIb containing carboxy and / or hydroxy groups optionally present in protected form and at least one dissolution promoting substance in an amount of up to 5, preferably 0.5- 2 mol equivalents with respect to the carboxylic acid metal complex can either be prepared in an additional isolated reaction step (for example by concentration by evaporation, lyophilization or spray drying of an aqueous or miscible water solution of the components or by precipitation with an organic solvent of a solution of this type) and then reacted in DMSO with water separating reagent and optionally a copulating auxiliary substance as well as formed of carboxylic acid metal complex, water dissociating reagent and optionally a copulation aid, if necessary by addition of s DMSO suspension-dissolving promoter substance (s). The reaction solution prepared by this process is maintained for pretreatment (acid activation) for 1 to 24, preferably 3 to 12 hours, at temperatures from 0 to 50 °. C, preferably ambient temperature.

The following is an amine of formula Xl

<formula> formula see original document page 21 </formula>

wherein the radicals L, R1 Rf, Q and X have the meanings indicated above, is added without solvent or dissolved, for example, in dimethyl sulfoxide, alcohols such as, for example, methanol, ethanol, isopropanol or mixtures thereof, formamide , dimethylformamide, water or mixtures of solvents mentioned, preferably dimethylsulfoxides, water or solvents mixed with water. For amide copulation, the reaction solution thus obtained is maintained at temperatures of 0 to 70 ° C, preferably 30 to 60 ° C, for 1 to 48 hours, preferably 8 to 24 hours.

In some cases it has been found advantageous to employ aamine in the form of a salt in the reaction, for example as hydrobromide or hydrochloride. For amine release, a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, tripropylamine, tributylamine, lithium hydroxide, lithium carbonate, sodium hydroxide or sodium carbonate is added.

The protection groups that may still be present are thus decoupled.

Isolation of the reaction product takes place according to methods known in the art, preferably by precipitation with organic solvents, preferably acetone, 2-butanone, diethyl ether, acetic ester, methyl t-butyl ether, isopropanol or mixtures thereof. Further purification may be effected, for example, by chromatography, crystallization or ultrafiltration.

Suitable dissolution-promoting substances are alkaline salts, alkaline earth salts, trialkyl ammonium salts, tetraalkylammonium salts, urea, N-hydroxyimides, hydroxyaryl triazoles, and substituted heterocyclic amine phenols. Examples include: delithium chloride, lithium bromide, Iftio1 iodide sodium bromide, sodium iodide, lithium methanesulfonate, sodium methanesulfonate, delirium p-toluenesulfonate, sodium p-toluenesulfonate, potassium bromide, potassium iodide, sodium chloride, magnesium bromide, magnesium chloride, magnesium iodide, tetraethylammonium p-toluenesulfonate, tetramethylammonium p-toluenesulfonate, pyridinium p-toluenesulfonate, p-toluenesulfonate detrietylammonium acid, 2-morpholinophenitrile, 3,5-dinitrophenol, 2,4-dichlorophenol, N-hydroxysuccinimide, N-hydroxyphthalimide, urea, tetramethylurea, N-methylpyrrolidone, formamide as well as cyclic urea, the former being preferred.

Water-dissociating reagents are all agents known to the art. Carbodiimidase onium reagents such as dicyclohexylcarbodiimide (DCCI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) hydroxychloride benzotriazol-1-yloxyamino (dimethylamino) Phosphonium (BOP) and 0- (benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (HBTU) hexafluorophosphate, preferably DCCI.

In the literature, for example, the following appropriate processes are described:

♦ Activation of carboxylic acids. Houben-Weyl, "Me-thoden der Organischen Chemie", volume XV / 2, Georg Thieme Verlag Stutt-gart, 1974 (and J. Chem. Research (S) 1996. 302).

♦ Activation with carbodiimides. R. Schwyzer and H. Kappeler, Helv. 46: 1550 (1963).

♦ E. Wünsch et al., Vol. 100: 173 (1967).

♦ Carbodiimide / hydroxysuccinimide activation: J. Am. Chem.Soe. 86: 1839 (1964) as well as J. Org. Chem. 53: 3583 (1988). Synthesis453 (1972).

♦ "Anhydridmethode, 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydrochinolin": B. Belleau et al., J. Am. Chem. Soc., 90: 1651 (1986), H. Kunz et al., Int. J. Pept. Prot. Res., 26: 493 (1985) and J.R. Voughn. Am. Soc., 73: 3547 (1951).

♦ "Imidazolid-Methode": B.F. Gisin, R.B. Menifield1 D.C. Tosteon, Am. Sound. 91: 2691 (1969).

◆ "Saurechlorid-Methoden, Thionylchlorid": Helv., 42: 1653 (1959).

♦ "Oxalylchlorid": J. Org. Chem., 29: 843 (1964).

Suitable copulation adjuvants to be employed are those known to the art (Houben-Weyl, Methoden der organischen Chemie, Volume XV / 2, Georg Thieme-Verlag, Stuttgart, 1974). As an example, 4-nitrophenol, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 1-hydroxy-7-aza-benzotriazole, 3,5-dinitrophenol and pentafluorfenol are mentioned. 4-nitrophenol and N-hydroxysuccinimide are preferred; Particularly preferred in this case is the first reagent.

The dissociation of the protecting groups takes place according to processes known to the person skilled in the art, for example by hydrolysis, hydrogenolysis, alkali ester saponification with alkali in aqueous-alcoholic solution at temperatures from 0 to 50 ° C, acid saponification with mineral acids or, for example, tert-butyl ether, with the aid of trifluoroacetic acid [Protective Groups in Organic Synthesis, 2nd edition, TW Greene and PGM Wuts, John Wiley and Sons, Inc. New York, 1991 ] in the case of benzyl ethers with hydrogen / palladium / carbon.

The carboxylic acids employed of the general formulas IIa through Vlla are either known compounds or are prepared according to the procedures described in the examples, see DE 10040381 and DE 10040858. Thus, the preparation of the carboxylic acids of the general formula Ila is known from DE 196 52 386. The carboxylic acids of the general formula VIIa employed are prepared as described in WO 95/17451.

The perbenzylated saccharic acids employed as starting substances, when R is a mono- or oligosaccharide, may be prepared analogously to "Lockhoff, Angew. Chem." 1998, 110 n and 24, p. 3634 following. Thus, for example, the preparation of 1-O-acetic acid from perbenzyl glucose occurs by two steps via trichloroacetimidate and reaction with ethyl ester of hydroxyacetic acid, BF3 catalysis in THF and subsequent NaOH saponification in MeOH / THF .

In a more advantageous process, as described in DE 10040381, perbenzylated saccharic acids employed as starting materials may also be prepared by dissolving 1-OHperbenzylated sugars in a non-water miscible organic solvent and reacting with a alkylation reagent of general formula X1

Nu-L-COO-SG (XVIII),

where Nu means a nucleofuge, L is - (CH2) -n, (where η = 1-5), -CH2-CHOH- or -CH (CHOH-CH2OH) -CHOH-CHOH-, and Sg represents a group protection,

in the presence of a base and optionally a phase transfer catalyst. As nucleofuges, for example, the radicals -Cl, -Br, -J1-OTs, -OMs, -OSO2CF3, -OSO2C4F9 or -OSO2C8F17 may be contained in the alkylation agent of the general formula XVIII.

In the protecting groups these are acidic protecting groups. These protecting groups are well known to the art ("Protective Groups in Organic Syntheses", second edition, T.W. Greene and P.G. Wuts, John Wiley & Sons, Inc., New York 1991).

The reaction according to the invention may be carried out at temperatures of 0-50 ° C, preferably from 0 ° C to room temperature. Reaction times are from 10 minutes to 24 hours, preferably 20 minutes to 12 hours.

The base is added in solid form, preferably in fine powder form, or as 10-70% aqueous solution, preferably 30-50%. As preferred bases NaOH and KOH are employed.

As non-water miscible organic solvents may be employed in the alkylation process according to the invention, for example, toluene, benzene, CF3-benzene, hexane, cyclohexane, diethyl ether, tetrahydrofuran, cycloromethane, MTB or mixtures thereof.

As phase transfer catalysts are employed in the process according to the invention, quaternary ammonium or dephosphonium salts known for this purpose or also crown ester such as [15] -choroa-5 or [18] -choroa-6 . Preferably, they are suitable for quaternary ammonium with four equal or different cationic hydrocarbon groups, chosen from methyl, ethyl, propyl, isopropyl, butyl or isobutyl. The hydrocarbon groups in the cation need to be large enough to ensure good solubility of the organic solvent alkylating reagent. Particularly preferably according to the invention is employed N (butyl) 4 + -Cl ", N (butyl) 4 + -HS04" but also N (methyl) 4 + -cr.

Similarly, protected end-protected polyethylene glycol acids may also be prepared.

Compounds of the general formula (XI)

<formula> formula see original document page 25 </formula>

with L meaning

<formula> formula see original document page 25 </formula>

The hydrophilic carboxylic acids R described above are prepared by reacting the above-described amide formation methods known to the art with amines of the general formula (XII) <formula> formula see original document page 26 </formula>

with Sg meaning a protecting group and L, X and Rf with the meanings given above.

The dissociation of the protecting groups takes place according to procedures known to the person skilled in the art, for example by hydrolysis, hydrogenolysis, alkaline ester saponification with alkali in aqueous-alcoholic solution at temperatures from 0 ° to 50 ° C, acid saponification with mineral acids or in the case, for example tert-butyl esters, with the aid of trifluoroacetic acid [Pro-Tective Groups in Organic Synthesis, 2nd Edition, TW Greene and PGMWuts, John Wiley and Sons, Inc. New York, 1991], case of debenzyl ethers with hydrogen / palladium / carbon.

Compounds of general formula (XII) are prepared by reacting monoprotected sediamines of general formula (XIII)

<formula> formula see original document page 26 </formula>

with R8, R8 ', n', Wem 'having the meaning given above and with Sg meaning a perfluor-containing nucleophile protecting group of the general formula (XIV)

<formula> formula see original document page 26 </formula>

with Y, G, s, s' and ζ with the meaning given above, where Nu means a nucleofuge,

in the presence of a base and optionally a phase transfer catalyst. As nucleofuges, for example, the radicals -C1, -Br, -J, -OTs, -OMs1 -OSO2CF3, -OSO2C4F9 or -OSO2C8F17 may be contained in the alkylation reagent of formula XVIII.

Known perfluor containing nucleophiles of general formula (XIV) as well as other perfluoralkyl containing substances and their preparation are described in the following publications: J. G. Riess, Journal of Drug Targeting, 1994, Vol. 2, p. 455-468; J. B. Nivet et al., Eur. J. Med. Chem., 1991, Vol. 26, p. 953-960; M.-P. Krafftetal., Angew. Chem., 1994, Vol. 106, Ng 10, pp. 1146-1148; M. Lanier et al., Tetrahedron Letters, 1995, Vol. 36, Ne. 2491-2492; F. Guillod et al., Carbohydrate Research, 1994, Vol. 261, pp. 37-55;

S. Achilefu et al., Journal of Fluorine Chemistry, 1995, Vol. 70, p. 19-26; L. Clary et al., Tetrahedron, 1995, Vol. 51, No. 47, p. 13073-13088; F. Szoni et al., Journal of Fluorine Chemistry, 1989, Vol. 42, p. 59-68; H. Wu et al., Supramolecular Chemistry, 1994, Vol. 3, p. 175-180; F. Guileri et al., Angew. Chem. 1994, Vol. 106, No. 14, p. 1583-1585; M.-P. Krafftet al., Eur. J. Med. Chem., 1991, Vol. 26, p. 545-550; J. Greiner et al., Journal of Fluorine Chemistry, 1992, Vol. 56, p. 285-293; A. Milius et al., Carbohydrate Research, 1992, Vol. 229, p. 323-336; J. Riess et al., Colloids and Surfaces A, 1994, Vol. 84, pp. 33-48; G. Merhi et al., J. Med. Chem., 1996, Vol. 39, p. 4483-4488;

V. Cirkva et al., Journal of Fluorine Chemistry, 1997, Vol. 83, p. 151-158; A. Ould Amanetoullah et al., Journal of Fluorine Chemistry, 1997, Vol. 84, pp.149-153;

J. Chen et al., Inorg. Chem., 1996, Vol. 35, pp. 1590-161; L. Clary et al., Tetrahedron Letters, 1995, Vol. 36, No. 4, pp. 539-542;

Μ M. Chaabouni et al., Journal of Fluorine Chemistry, 1990, Vol. 46, pp.307-315;

A. Milius et al., New J. Chem., 1991, Vol. 15, p. 337-344; M.-P. Krafftetal., New J. Chem., 1990, Vol. 14, p. 869-875; J.-B. Nivetetal., New J. Chem., 1994, Vol. 18, pp. 861-869; C. Santaella et al., New J. Chem., 1991, Vol. 15, p. 685-692; C. Santaella et al., New J. Chem., 1992, Vol. 16, pp. 399-404; A. Milius et al., New J. Chem., 1992, Vol. 16, p. 771-773; F. Szonyi et al., Journal of Fluorine Chemistry, 1991, Vol. 55, p. 85-92; C. Santaella et al., Angew. Chem., 1991, Vol. 103, No. 5, pp. 584-586; M.-P. Krafft et al., Angew. Chem., 1993, Vol. 105, No. 5, pp. EP 0 548 096 B1. Compounds of general formula (XI) with L meaning

<formula> formula see original document page 28 </formula>

with q ', α, β and γ with the meaning given above,

are produced by reacting perfluoro-containing carboxylic acids of formula (XV)

<formula> formula see original document page 28 </formula>

with X and Rf with meaning given above according to the amide formation methods known to the art, with amines of the general formula (XVI)

<formula> formula see original document page 28 </formula>

with q ', β with the meaning given above and Sg meaning a protection group.

The dissociation of the protecting groups takes place according to known procedures in the art, for example by hydrolysis, hydrogenesis, alkaline ester saponification with alkali in aqueous-alcoholic solution at temperatures of 0 ° C to 50 ° C, acid saponification with mineral acids or, in the case of, for example tert-butyl esters with the aid of trifluoroacetic acid [Protective Groups in Organic Synthesis, 2nd Edition, TW Greeneand PGM Wuts, John Wiley and Sons, Inc., New York, 1991] in the case of benzyl ethers with hydrogen / palladium / carbon.

The preparation of compounds of the general formula (XV) is described in the literature listed above for preparation of compounds containing perfluor.

Compounds of the general formula (XVI) <formula> formula see original document page 29 </formula>

with q ', β with the meaning given above and with Sg meaning a protection group

The hydrophilic R amines described above are prepared by reacting with the amide formation methods known to the art carboxylic acids of formula (XVII).

<formula> formula see original document page 29 </formula>

with q 'with the meaning indicated above and with Sg and Sg' meaning a protecting group, where Sg and Sg 'may be dissociated differently.

The dissociation of the protecting groups takes place according to the known procedures of the art, for example by hydrolysis, hydrogenolysis, alkaline saponification of alkali esters in aqueous-alcoholic solution at temperatures from 0 ° to 50 ° C, acid saponification with mineral acids or in the case of, for example, tert-butyl esters with the aid of trifluoroacetic acid [Protective Groups in Organic Synthesfer-2nd Edition, TW'Greene and PGM Wuts, John Wiley and Sons, Inc. New York, 1991]. benzyl ethers with hydrogen / palladium / carbon.

Such amino acids of the general formula (XVII) protected twice are commercially available products (Bachem).

The compounds according to the invention are particularly suitable for use in NMR and X-ray diagnostics, radiotherapy and radiotherapy, as well as MRT infrared and balance-balanced radioisotopic imaging. Perfluoralkyl-containing metal complexes are particularly suitable for use in nu-clear magnetic resonance tomography (MRT) for visualization of different physiological and duck physiological structures and thus for improving diagnostic information, for example location and grade. of disease, for choosing and controlling the success of an objectified therapy and for the prophylaxis of diseases and disorders.

In a particularly preferred embodiment, the substances according to the invention are employed for MRT lintography.

In another particularly preferred embodiment, substances in accordance with the invention are employed for the blood pool image.

Appropriate diseases and disorders include tumors, especially detection and characterization of primary tumors, satellite metastases, lymph node metastases as well as necroses, cardiovascular diseases, particularly changes in vascular diameter such as stenosis aneurysms, atherosclerosis by detecting atherosclerotic plaques. , thromboembolic diseases, stroke, necrosis, inflammation, particularly arthritis, osteomyelitis, ulcerative colitis, as well as nerve involvement.

In a particularly preferred embodiment, the substances according to the invention are employed for imaging necrosis or tumors.

Objects of the invention are also pharmaceutical compositions containing at least one physiologically compatible compound according to the invention, optionally with the usual additives in galenics.

The compounds of the present invention are characterized by excellent compatibility and at the same time excellent imaging properties. Thus, they are particularly well-suited for MRT systemic use, particularly in MRT lymphography and tumor imaging.

The preparation of the pharmaceutical compositions according to the invention is carried out in a manner known per se by suspending or dissolving in aqueous medium the complexes according to the invention - possibly with addition of the usual additives in the galenics - and eventually sterilize the suspension or solution. Suitable additives are, for example, physiologically harmless buffers (such as tromethamine), complex-forming additives or weak complexes (such as, for example, diethylene triamine-pentaacetic acid or metal complexes corresponding to the invention). ) or - if necessary - electrolytes such as sodium chloride or - if necessary - antioxidants such as ascorbic acid.

If suspensions or solutions in water or physiological hydrochloric solution of the compositions according to the invention are desired for enteral or parenteral administration or for other purposes, they are mixed with one or more usual adjunct (s) in galenics. [e.g. methyl cellulose, lactose, mannitol] and / or surfactant (e.g. lecithins, Tween®, Myrj®] and / or flavor correction atomizer (s) [e.g. etheric oils].

In principle, it is also possible to prepare the pharmaceutical compositions according to the invention without isolating the complexes. In each case special care is required to effect chelate formation such that the complexes according to the invention are practically free of non-complex metal ions with toxic effect.

This can be ensured, for example, with the aid of color indicators, such as xylenol orange, by means of control titration during the preparation process. The invention therefore also relates to processes for preparing the complexes and their salts. As a final safety, a purification of the isolated complex is restored.

In the in vivo application of the compositions according to the invention, they may be administered together with a suitable carrier such as serum or sodium chloride physiological solution, and together with another protein such as albumin. of human serum (HSA).

The compositions according to the invention are usually applied parenterally, preferably i.v. They may also be applied via intravascular or interstitial / intracutaneous, depending on whether vessel or body tissue should be examined.

The pharmaceutical compositions according to the invention preferably contain 0.1 μιτιοΙ - 2 mol / l of the complex and are generally dosed in amounts of 0.001 - 5 mmol / kg.

The compositions according to the invention fulfill the various requirements to serve as a contrast agent for nuclear magnetic tomography. After oral or parenteal application, they are then extremely suitable for enhancing the image information strength obtained with the aid of nuclear magnetic tomography by increasing signal intensity. In addition, they have the great efficacy that is required to carry the body with the smallest possible amount of foreign substances, and the excellent compatibility that is required to maintain the noninvasive nature of the examination.

The good water solubility and low osmolality of the compositions according to the invention allow the preparation of highly concentrated solutions to keep the volume charge of the circulatory system within reasonable limits and to compensate for dilution by body liquids. In addition, the compositions according to the invention have not only high in vitro stability but also surprisingly high in vivo stability, so that a release or exchange of the ions themselves - which are bound to the compounds. complex, occurs only extremely slowly during the time when the new contrast medium is completely eliminated again.

Generally, the compositions according to the invention are suitable for use as NMR diagnostic agents in amounts of 0.0001-5 mmol / kg, preferably 0.005-0.5 mmol / kg.

The complexes according to the invention may advantageously be employed as susceptibility reagents and as shift reagents for in vivo NMR spectroscopy.

Because of their favorable radioactive properties and very good stability of the complexes contained therein, the compositions according to the invention are also suitable as radiodiagnostic agents. Details of use and dosage of this type are described, for example, in "Ra-diotracers for Medical Applications". , "CRC Press, Boca Raton, Florida.

The compounds and compositions according to the invention may also be employed in positron-emitting tomography using positron-emitting isotopes such as 43Sc, 44Sc, 52Fe, 55Co, 68Ga and 86Y (Heiss, WD; Phelps, E). Positron Emission Tomography of Brain, Springer Verlag Berlin, Heidelberg, New York 1983).

Histological studies confirm a regional microvascular hyperpermeability.

Thus, it is possible to employ the contrast agent according to the invention also to visualize abnormal capillary permeability.

The compounds according to the invention are characterized above all by the fact that they are completely eliminated from the body and thus tolerated. Thus, the excellent imaging properties can be employed and the noninvasive character of the diagnosis can be maintained.

Since the substances according to the invention accumulate in malignant tumors (no diffusion in healthy tissue, but high permeability of tumor vessels), they may also assist in radiation therapy of malignant tumors. It differs from the corresponding diagnosis only in the amount and type of isotope employed. The goal here is the destruction of tumor cells by the irradiation of high energy short waves with the smallest possible range. To this end, interactions of the metals contained in the complexes (such as, for example, iron or gadolinium) with ionizing radiation (eg X-ray) or neutron radiation are employed. By this effect, the local radiation dose at the location of the metal complex (eg, in tumors) is significantly increased. In order to produce the same radiation dose in malignant tissue, in the use of such metal complexes, the irradiation burden on healthy tissue can be considerably reduced and thereby painful side effects for patients can be avoided. The metal complex conjugates according to the invention are therefore also suitable as radiosensitizing substances for malignant tumor irradiation therapy (e.g., use of Mosbauer effects or neutron capture therapy). Suitable β-emitting ions are, for example, 46Sc, 47Sc, 48Sc, 72Ga, 73Ga and 90Y. α-emitting ions which exhibit suitable short transformation times are, for example, 211Bi, 212Bi, 213Bi, and 214Bi, with 212Bi being preferred. An appropriate photon and electron emitter ion is 158Gd, which can be obtained from 157Gd by neutron capture.

If the composition according to the invention is employed as a variant of the irradiation therapy proposed by R. L. Mills et al. [NatureVol. 336, (1988), p. 787], then the central ion must be derived from a MóBbauer isotope, such as, for example, 57Fe or 151Eu.

In the in vivo application of the compositions according to the invention, they may be administered together with a suitable carrier such as sodium chloride saline or physiological solution and together with another protein such as sodium albumin. human serum. The dosage here depends on the type of cell disorder, the metal ion employed and the type of imaging method.

Compositions according to the invention are usually applied parenterally, preferably i.v. They may also - as already discussed - be applied intravascularly or interstitially / intracutaneously, depending on whether the vessel or body tissue is to be examined.

The compositions according to the invention are extremely well suited as an X-ray contrast agent, and it should be especially emphasized that with them there can be no trace in the biochemical-pharmacological studies of any known ana-phylactic reactions known to the agents. Contrast containing iodine. Because of their favorable absorption properties in high vascular tension bands, they are particularly valuable for digital subtraction techniques.

In general, for use as an X-ray contrast agent, similarly to, for example, meglumine diatrizoate, the compositions according to the invention are dosed in amounts of 0.1 - 5 mmol / kg, preferably 0.25 - 0.5 mmol. 1 mmol / kg.

The term "metal ion equivalent" as used herein is a usual term known in the art of complex chemistry. A metal ion equivalent is an equivalent of demetal ions that can bind to, for example, a carboxylate group rather than hydrogen. For example, a Gd3 + may bond to 3 carboxylate groups, that is, 1/3 of Gd3 + corresponds to the metal ion equivalent R1 in formula (II), (III), (IV) or (V) when the metal is gadolinium.

Examples

Example 1

a) 1-N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-aza-per-fluortridecylamine

23.31 G (120 mmol) of N-benzyloxycarbonylethylenediamine (At-well et al., Synthesis, 1984, 1032-1033) and 10.2 g (100 mmol) of triethylamine added to 54.22 g (100 mmol) ) of (1H, 1H, 2H, 2H-perfluordecyl) methanesulfonic acid ester (Bartsch et al., Tetrahedron, 2000, 3291-3302) in 500 ml of acetonitrile, and is stirred for 48 hours at 60 ° C. Insoluble components are separated by filtration of the reaction solution, concentrated by evaporation in vacuo to dryness and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 32.8 g (51% of theory) of a colorless wax

Elemental Analysis:

Calc .: C 37.51 H 2.68 N 4.37 F 50.44

Enc .: C 37.82 H 2.74 N 4.29 F 50.27

b) N- [2- (Benzyloxycarbonyl) -aminoethyl-N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2- [1-0-ad- (2,3,4,6-tetra-0 benzyl) mannopyranosyl] acetamide

8.05 G (39.04 mmol) dicyclohexylcarbodiimide are added at 0 ° C to a solution of 20 g (31.23 mmol) of the title compound of example 1a and 18.70 g (31.23 mmol) ) of 1-O-ad-carbonylmethyl- (2,3,4,6-tetra-0-benzyl) mannopyranose (prepared according to WO 99/01160 A1) and 3.59g (31.23 mmols) of N- hydroxysuccinimide in 200 ml of dimethylformamide is stirred for 3 hours at 0 ° C and then for 16 hours at room temperature. Precipitated urea is filtered off, the filtrate is concentrated by evaporation in vacuo and the residue is then chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 29.8 g (78% of theory) of a colorless viscous oil. Elemental Analysis:

<table> table see original document page 36 </column> </row> <table>

c) N- (2-aminoethyl) -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2- (1-O-oc-d-mannopyranosyl) acetamide, methanesulfonic acid salt

2.29 g (23.75 mmols) of methanesufonic acid as well as 4.0 g of palladium catalyst (10% Pd / C) are added to a solution of 29 g (23.75 mmols) of the title compound of example 1b in 500 ml of ethanol is hydrogenated for 24 hours at room temperature. The catalyst is filtered off, and the filtrate is evaporated in vacuo to dryness.

Yield: 19.5 g (quantitative) of a colorless solid. Elemental analysis:

<table> table see original document page 36 </column> </row> <table>

d) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetracyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] - 2-aminoethyl} -N- (1 H, 1 H, 2H, 2H-perfluor-decyl) -2- (1-ad-mannopyranosyl) acetamide, Gd complex

18.7 g (22.72 mmol) of the title compound of Example 1c, 2.61 g (22.72 mmol) of N-hydroxysuccinimide, 1.93 g (45.44 mmol) of lithium chloride and 14.31 g (22.72 mmoles) 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7, 10-Tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (Example 1)) are dissolved in 200 ml dimethyl desulfoxide under gentle heating. At 10 ° C, 5.86 g (28.4 mmols) of dicyclohexylcarbodiimide as well as 2.30 g (22.72 mmols) of triethylamine are added and stirred for 16 hours at room temperature. The solution is poured into 2000 ml of acetone and stirred for a further 10 min. The precipitated solid is filtered off and then chromatographically purified (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 22.3 g (68% of theory) of a colorless solid.Water content (Karl-Fischer): 7.0% Elemental analysis (relative to anhydrous substance):

Calc .: C 35.01 H 3.84N 7.33F 24.14 Gd 11.75

Enc .: C 35.21 H 3.89N 7.27F 24.09 Gd 11.61

Example 2

a) 1 -N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7 10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] perfluortridecylamine, Gd complex

10.0 G (15.62 mmols) of the title compound of Example 1a, 1.80 g (15.62 mmoles) of N-hydroxysuccinimide, 1.33 g (31.34 mmols) lithium decloride and 9.84 g (15.62 mmol) 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7, 10-Tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (Example 1)) is dissolved in 150 ml of dimethyl sulfoxide under gentle heating. At 10 ° C, 4.03 g (19.52 mmol) of dicyclohexylcarbodiimide is added and stirred for 16 hours at room temperature. The solution is poured into 2000 ml of diethyl ether and stirred for a further 10 minutes. The precipitated solid is filtered off and then the residue is chromatographed on silica gel (eluent: 10: 5: 1 dichloromethane / methanol / aqueous ammonia).

Yield: 16.4 g (79% of theory) of a colorless solid.

Water content (Karl-Fischer): 5.4%

Elemental analysis (on anhydrous basis):

Calc .: C 37.41 H 3.62 N 7.83 F 25.80 Gd 12.56

Enc .: C 37.69 H 3.56 N 7.91 F 25.64 Gd 12.37

b) 1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N - (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - perfluortridecylamine, Gd complex, methanesulfonic acid salt

1.16 g (12.08 mmol) of methanesulfonic acid as well as 2.0 g of palladium catalyst (10% Pd / C) are added to a solution of 16 g (12.08 mmol) of the title compound of example 2a in 300 ml of ethanol, and is hydrogenated for 24 hours at room temperature. The catalyst is filtered off and the filtrate is concentrated by fresh evaporation. Yield: 15.8 g (quantitative) of a colorless solid

Water content (Karl-Fischer): 7.0%

Elemental analysis (on anhydrous basis):

Calc .: C 31.66 H 3.57 N 8.08 F 26.60 Gd 12.95

Enc .: C 31.88 H 3.59 N 8.14 F 26.42 Gd 12.69

c) 1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N - (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - perfluortridecyl-N-2- (1-0-ad-mannopyranosyl) acetamide, Gd complex

1.72 g (8.33 mmoles) dicyclohexylcarbodiimide as well as 674mg (6.66 mmols) triethylamine are added at 0 ° C to a solution of 8.9 g (6.66 mmols) of the title compound of example 2b and 3.99 g (6.66mmols) of 1-0-ad-carbonylmethyl- (2,3,4,6-tetra-0-benzyl) mannopyranose (prepared according to WO 99/01160 A1) and 767 mg (6.66 mmoles) N-hydroxysuccinimide in 100 ml dimethylformamide is stirred for 3 hours at 0 ° C and then for 16 hours at room temperature. Precipitated urea is filtered off and the filtrate is concentrated by novacetic evaporation to dryness. The residue is dissolved in 100 ml methanol, mixed with 2.0 g palladium catalyst (10% Pd / C) and hydrogenated for 24 hours at room temperature. The catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo to dryness. The residue is taken up in low water, insoluble components are filtered off, and the filtrate is then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 6.1 g (64% of theory) of a colorless solid.

Water content (Karl-Fischer): 6.2%

Elemental analysis (on anhydrous basis):

Calc .: C 35.01 H 3.84 N 7.33 F24.14 Gd 11.75

Enc .: C 35.23 H 3.88 N 7.27 F 24.01 Gd 11.59

Example 3

a) [1,3-Bis- (2-benzyloxy-1-benzyloxymethyl-ethoxy) -prop-2-yl] -acetic acid

14.62 g (75 mmol) of bromoacetic acid tert-butyl ester are added to 30.02 g (50 mmol) of 1,3-bis- (2-benzyloxy-1-benzyloxymethyl-ethoxy) -propan-2-ol ( Cassei et al., Eur. J. Org. Chem., 2001, 5, 875-896) and 5.6 g (100 mmols) of fine powdered potassium hydroxide as well as a catalytic amount (1 g) of hydrogen tetra-n-butylammonium sulfate in 250 ml of toluene at 0 ° C, and is stirred for two hours at this temperature as for 12 hours at room temperature. The reaction solution is mixed with 500 ml of ethyl acetate and 300 ml of water. The organic phase is separated and washed twice with 300 ml of water each time, then dried with magnesium sulfate and concentrated by evaporation in vacuo to dryness. The residue is suspended in a mixture consisting of 400 ml methanol and 0.5 M 2: 1 sodium hydroxide solution and then heated for 12 hours at 60 ° C. The reaction mixture is neutralized for processing by mixing with Amberlite IR 120 cation exchange resin (H + form), the exchanger is filtered off, concentrated by evaporation to dryness and chromatographed on silica gel (eluent: acid ethylester). acetic acid / hexane 1: 3).

Yield: 23.5 g (71% of theory) of a colorless wax

Elemental Analysis:

Calc .: C 71.10 H 7.04

Enc .: C 71.29 H 7.21

b) N- [2- (benzyloxycarbonyl) -aminoethyl-N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2- [1,3-bis- (2-benzyloxy-1-benzyloxymethyl-ethoxy) -benzamide prop-2-oxy] acetamide

8.05 g (39.04 mmol) dicyclohexylcarbodiimide are added at 0 ° C to a solution of 20 g (31.23 mmol) of the title compound of example 1a and 20.57 g (31.23 mmol) ) of the title compound of Example 3a and 3.59g (31.23 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide is stirred for 3 hours at 0 ° C and then for 16 hours at room temperature. Precipitated urea is filtered off, the filtrate is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 28.7 g (72% of theory) of a colorless viscous oil. Elemental Analysis:

Calc .: C 55.32 H 4.80 N 2.19 F 25.21

Enc .: C 55.56 H 4.87 N 2.13 F 26.07

c) N- (2-aminoethyl) -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2- [1,3-bis- (2-hydroxy-1-hydroxymethyl-ethoxy) -prop-2 -oxy] -acetamide, methanesulfonic acid salt

1.96 g (20.29 mmols) of methanesulfonic acid as well as 4.0 g decatalyst (10% Pd / C) are added to a 26 g (20.29 mmols) solution of the title compound of example 3b in 500 ml of ethanol is hydrogenated for 24 hours at room temperature. The catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo to dryness.

Yield: 17.9 g (quantitative) of a colorless solid.

Elemental Analysis:

Calc .: C 32.66 H 4.00 N 3.17 F 36.59

Enc .: C 32.89 H 4.10 N 3.11 F 36.41

d) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] -2-Aminoethyl} -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2- [1,3-bis- (2-hydroxy-1-hydroxymethyl-ethoxy) -prop-2-oxy ] -acetamide, Gd complex

16.8 g (19.07 mmol) of the title compound of Example 3c, 2.19 g (19.07 mmol) of N-hydroxysuccinimide, 1.62 g (38.14 mmol) of lithium chloride and 14.31 g (19.07 mmoles) 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10 tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (example 1)) are dissolved in 200 ml dimethyl desulfoxide under slight heating. At 10 ° C, 4.92 g (23.84 mmols) of dicyclohexylcarbodiimide as well as 1.93 g (19.07 mmols) of triethylamine are added and stirred for 16 hours at room temperature. The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile). 6 g (72% of theory) of a colorless solid.Water content (Karl-Fischer): 6.7% Elemental analysis (with respect to anhydrous substance):

<table> table see original document page 41 </column> </row> <table>

Example 4

a) N-1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10 1,4,7- {tris (carboxylatomethyl) - N - (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - perfluortridecylamide} -1,4,7,10-tetraazacyclododecane 10 - [(3-aza-4-oxohexan-5-yl), complex Gd8.1 g (6.31 mmol) of the title compound of example 2b, 726 mg (6.31 mmol) of N-hydroxysuccinimide Delionium chloride, 535 mg (12.62 mmols) and 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo, 3.97 g (6.31 mmols) -5-methylpentan-5-yl] -1,4,7,10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (example 1)) are dissolved in 100 ml dimethyl desulfoxide under gentle heating. At 10 ° C, 1.63 g (7.89 mmoles) of dicyclohexylcarbodiimide as well as 693 mg (6.31 mmoles) detriethylamine are added and stirred for 16 hours at room temperature. The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 6.5 g (56% of theory) of a colorless solid.Water content (Karl-Fischer): 5.8% Elemental analysis (with respect to anhydrous substance):

<table> table see original document page 41 </column> </row> <table>

Example 5

a) N- [2- (Benzyloxycarbonyl) aminoethyl-N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2- [2- (2-methoxyethoxy) ethoxy] acetamide

8.05 g (39.04 mmol) dicyclohexylcarbodiimide is added at 0 ° C to a solution of 20 g (31.23 mmol) of the title compound of example 1a and 5.57 g (31.23 mmol) ) of [2- (2-methoxyethoxy) ethoxy] acetic acid (Aldrich) and 3.59 g (31.23 mmols) of N-hydroxysuccinimide in 200 ml dimethylformamide is stirred for 3 hours at 0 ° C and 1 then for 16 hours at room temperature. Precipitated urea is filtered off, the filtrate is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 19.8 g (79% of theory) of a colorless viscous oil

Elemental Analysis:

Calc .: C 40.51 H 3.65 N 3.50 F 40.35

Enc .: C 40.62 H 3.68 N 3.53 F 40.09

b) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H-perfluordecyl) -2- [2- (2-methoxyethoxy) ethoxy] acetamide, methanesulfonic acid salt

2.28 g (23.73 mmols) of methanesulfonic acid as well as 4.0 g of palladium catalyst (10% Pd / C) are added to a solution of 19 g (23.73 mmols) of the title compound of example 5a in 500 µl. ml of ethanol and is hydrogenated for 24 hours at room temperature. The catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo to dryness.

Yield: 18.1 g (quantitative) of a colorless solid.

Elemental Analysis:

Calc .: C 31.51 H 3.57 N 3.67 F 42.36

Enc .: C 31.77 H 3.59 N 3.54 F 42.05

c) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-

10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -2-aminoethyl} -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2- [2 - (2-methoxyethoxy) ethoxy] acetamide, Gd complex

17.2 g (22.51 mmol) of the title compound of Example 5b, 2.59 g (22.51 mmol) of N-hydroxysuccinimide, 1.91 g (45.02 mmol) of lithium chloride and 14.18 g 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4oxo-5-methylpentan-5-yl] -1,4,7,10-tetraazacyclododecane (22.51 mmol) Gd complex (WO 98/24775, Schering AG, (example 1)) are dissolved in 200 ml dimentyl desulfoxide under slight heating. At 10 ° C, 5.81 g (28.14 mmol) of dicyclohexylcarbodiimide as well as 2.28 g (22.51 mmol) of triethylamine are added and stirred for 16 hours at room temperature. The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP18; eluent: gradient consisting of water / acetonitrile).

Yield: 21.5 g (70% of theory) of a colorless oil.

Water content (Karl-Fischer): 6.4%

Elemental analysis (for anhydrous substance):

Calc .: C 35.71 H 4.02 N 7.67 F 25.72 Gd 12.30

Enc .: C 35.79 H 4.07 N 7.59 F 25.63 Gd 12.27

Example 6

a) 1 -N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 5H, 5H, 7H, 7H, 8H, 8H-3-aza-4-oxa-6-oxo-perfluorhexadecylamine

17.8 g (140 mmol) of oxalyl chloride is added to 52.22 g (100 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluortridecanoic acid (produced according to EP 01 08498) in 500 ml of dichloromethane and stirred for 14 hours at room temperature. It is concentrated by evaporation in vacuo to dryness, the residue is dissolved in 400 ml of dichloromethane, mixed at 0 ° C with 23.31 g (120 mmols) of N-benzyloxycarbonylethylenediamine (Atwell et al., Synthesis, 1984, 1032-25). 1033) and 10.2 g (100mmols) of triethylamine and is stirred for a further 24 hours at room temperature. The reaction solution is mixed with 400 ml 1Ne hydrochloric acid and mixed well for 15 minutes. The organic phase is separated, dried with magnesium sulfate and concentrated by evaporation in vacuo to dryness. The residue is chromatographed on silica gel (eluent: ethyl acetate / hexane 1: 2).

Yield: 49.7 g (71% of theory) of a colorless wax

Elemental Analysis:

Calc .: C 37.84 H 2.74 N 4.01 F 46.25

Enc .: C 38.02 H 2.76 N 3.97 F 46.12

b) 1 -N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H, 7H, 7H, 8H, 8H-3-aza-6-oxo-perfluorhexadecylamine

48.5 g (69.45 mmol) of the title compound of Example 6a in

150 ml of THF are mixed with 50 ml of 10 M boranedimethylsulfide (in THF) and heated for 5 hours under reflux. It is cooled to 0 ° C, 100 ml of methanol is added by dripping, stirred for one hour at room temperature and then concentrated by evaporation in vacuo to dryness. The residue is taken up in a mixture of 300 ml ethanol / 50 ml 1 M hydrochloric acid and stirred for 14 hours at 40 ° C. It is concentrated by evaporation in vacuo to dryness, the residue taken up in 300 ml of 5% sodium hydroxide solution and extracted three times, each with 300 ml of dichloromethane. The combined organic phases are dried with magnesium sulfate, concentrated by evaporation in vacuo to dryness and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).

Yield: 39.8 g (84% of theory) of a colorless solid.

Elemental Analysis:

Calc .: C 38.61 H 3.09 N 4.09 F 47.19

Enc .: C 38.88 H 3.14 N 4.06 F 46.87

c) N- [2- (benzyloxycarbonyl) aminoethyl-N-1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-

3-oxa-perfluortridecyl) -2- [2- (2-methoxyethoxy) ethoxy] acetamide

7.54 g (36.53 mmol) dicyclohexylcarbodiimide are added at 0 ° C to a solution of 20 g (29.22 mmol) of the title compound of example 6b and 5.21 g (29.22 mmol) ) of [2- (2-methoxyethoxy) ethoxy] -acetic acid (Aldrich) and 3.36 g (29.22 mmols) of N-hydroxysuccinimide in 200 ml of dimethylformamide is stirred for 3 hours at 0Â °. C and then for 16 hours at room temperature. Precipitated urea is filtered off, the filtrate is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 18.3 g (74% of theory) of a colorless viscous oil

Elemental Analysis:

Calc .: C 41.24 H 3.94 N 3.32 F 38.24

Enc .: C 41.42 H 3.98 N 3.33 F 38.21

d) N- (2-Aminoethyl) -N- (1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluortridecyl) -2- [2- (2-methoxyethoxy) ethoxy ] -acetamide, methanesulfonic acid salt

2.0 g (20.72 mmol) of methanesulfonic acid as well as 3.0 g of palladium catalyst (10% Pd / C) are added to a solution of 17.5 g (20.72 mmol) of the title compound of the example. 6c in 300 ml ethanol, is hydrogenated for 24 hours at room temperature. The catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo to dryness.

Yield: 16.7 g (quantitative) of a colorless solid.

Elemental Analysis:

<table> table see original document page 45 </column> </row> <table>

e) N - {[1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] - 2-aminoethyl} -N- (1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluortridecyl) -2- [2- (2-methoxyethoxy) ethoxy] - acetamide, Gd complex

14.8 g (18.30 mmol) of the title compound of Example 6d, 2.11 g (18.30 mmol) of N-hydroxysuccinimide, 1.55 g (36.60 mmol) of lithium chloride and 11.52 g (18.30 mmol) 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10 tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (example 1)) are dissolved in 200 ml dimethyl desulfoxide under slight heating. At 10 ° C, 4.72 g (22.88 mmol) dicyclohexylcarbodiimide as well as 1.85 g (18.30 mmol) triethylamine are added and stirred for 16 hours at room temperature. The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 16.6 g (64% of theory) of a colorless solid.Water content (Karl-Fischer): 6.9%

Elemental analysis (on anhydrous basis):

<table> table see original document page 45 </column> </row> <table>

Example 7

a) 6-N-benzyloxycarbonyl-2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluortridecanoyl) - L-lysine25 g (31.31 mmols) of 6-N-benzyloxycarbonyl-2 methylester -N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluortridecanoyl) -L-lysine (produced according to EP 03/07274) are dissolved in 200 ml of methanol and 50 ml of 2N potassium hydroxide solution. and is stirred for 18 hours at room temperature. It is acidified with 2N hydrochloric acid, concentrated by evaporation to dryness and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).

Yield: 22.4 g (91% of theory) of a colorless solid.

Elemental Analysis:

Calc .: C 39.81 H 3.21 N 3.57 F 41.17

Enc .: C 40.07 H 3.27 N 3.49 F 41.05

b) [1-O-α-d- (2,3,4,6-Tetra-0-benzyl) mannopyranosyl] acetamide

11.45 g (90 mmol) of oxalyl chloride is added to 40 g (66.81 mmol) of 1-O-d-carbonylmethyl- (2,3,4,6-tetra-0-benzyl) mannopyranose (produced according to WO 99/01160 A1) in 300 ml of dichloromethane and is stirred for 14 hours at room temperature.

It is concentrated by evaporation in vacuo to dryness, the residue is dissolved in 400 ml of dichloromethane, ammonia gas is introduced into the solution at 0 ° C for approximately two hours and stirred for a further 4 hours at room temperature. The reaction solution is mixed with 400 ml 1N hydrochloric acid and mixed well for 15 minutes. The organic phase is separated, dried with magnesium sulfate and concentrated by evaporation to dryness. The residue is chromatographed on silica gel (eluent: 1: 2 ethyl acetate / hexane).

Yield: 34.1 g (85% of theory) of a colorless oil

Elemental Analysis:

Calc .: C 72.34 H 6.58 N 2.34

Enc .: C 72.69 H 6.54 N 2.39

c) 2- [1-O-α-d- (2,3,4,6-tetra-0-benzyl) mannopyranosyl] ethylamine

33 g (55.21 mmol) of the title compound of Example 7b in 100 mL of THF are mixed with 30 mL of 10 M boranedimethylsulfide (in THF) and heated at reflux for 5 hours. It is cooled to 0 ° C, 100 ml of methanol is added dropwise, stirred for one hour at room temperature and then concentrated by evaporation in vacuo to dryness.

The residue is taken up in a mixture of 200 ml ethanol / 100 ml ethanamine and stirred for 14 hours at 60 ° C. It is concentrated by evaporation to dryness to dryness, the residue taken up in 300 ml of 5% sodium hydroxide solution and extracted three times each with 300 ml of dichloromethane. The unified organic phases are dried with magnesium sulfate, concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).

Yield: 26.2 g (81% of theory) of a colorless solid. ι

Elemental Analysis:

Calc .: C 74.08 H 7.08 N 2.40

Enc .: C 74.55 H 7.19 N 2.31

d) 6-N-benzyloxycarbonyl-2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluortri-decanoyl) -L-lysine- {2- [1 -0-ad- (2,3 4,6-tetra-0-benzyl) mannopyranyl] ethyl} amide

4.93 g (23.90 mmols) of dicyclohexylcarbodiimide are added at 0 ° C to a solution of 15 g (19.12 mmols) of the title compound of example 7a and 11.16 g (19.12 mmols). ) of the title compound of Example 7c and 2.20 g (19.12 mmols) of N-hydroxysuccinimide in 200 ml of dimethylformamide is stirred for 3 hours at 0 ° C and then for 16 hours at room temperature. ambient temperature. Precipitated urea is filtered off, the filtrate is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 19.2 g (74% of theory) of a colorless viscous oil

Elemental Analysis:

Calc .: C 55.15 H 4.78 N 3.11 F 23.92

Enc .: C 55.32 H 4.82 N 3.09 F 23.74

e) 2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluortridecanyl) -L-lysine- [2- {1-0-α-d-mannopyranosyl) -ethyl] -amide

2.0 g of palladium catalyst (10% Pd / C) is added to a solution of 18.5 g (13.70 mmols) of the title compound of example 7d in 200 ml of ethanol and is hydrogenated for 24 hours at room temperature. The catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo to dryness.

Yield: 11.8 g (quantitative) of a colorless solid

Elemental Analysis:

Calc .: C 36.50 H 4.01 N 4.91 F 37.75

Enc .: C 36.79 H 3.98 N 4.87 F 37.84

f) 6-N- [1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluortridecanoyl) -L-lysine [2- {1-ad-mannopyranosyl) ethyl] amide, Gd complex

11.0 g (12.86 mmol) of the title compound of Example 7e, 1.48 g (12.86 mmol) of N-hydroxysuccinimide, 1.09 g (25.72 mmol) of lithium chloride and 8.10 g 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10 (12.86 mmol) tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (example 1)) are dissolved in 100 ml dimethyl desulfoxide under gentle heating. At 10 ° C, 3.32 g (16.08 mmol) of dicyclohexylcarbodiimide is added and stirred for 16 hours at room temperature. The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (FtP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 13.0 g (64% of theory) of a colorless solid.

Water content (Karl-Fischer): 6.9%

Elemental analysis (on anhydrous basis):

Calc .: C 36.84 H 4.26 N 7.64 F 22.01 Gd 10.72

Enc .: C 37.03 H 4.31 N 7.59 F 21.95 Gd 10.62

Example 8

a) 6-N-benzyloxycarbonyl-2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluortri-decanoyl) -L-lysine - {[N- (2S, 3R, 4R, 5R) - 2,3,4,5,6-pentahydroxyhexyl] -N-methyl} -amide

4.93 g (23.90 mmols) of dicyclohexylcarbodiimide are added at 0 ° C to a solution of 15 g (19.12 mmols) of the title compound of example 7a and 5.6 g (28.68 mmols). ) of N-methylglucamine (Aldrich) and 2.20 g (19.12 mmols) of N-hydroxysuccinimide in 200 ml of dimethylformamide is stirred for 3 hours at 0 ° C and then 16 hours at room temperature. It is filtered off, the filtrate is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 5: 1).

Yield: 9.4 g (51% of theory) of a colorless viscous oil.

Elemental Analysis:

Calc .: C 41.22 H 4.19 N 4.37 F 33.58

Enc .: C 41.47 H 4.30 N 4.29 F 33.35

b) 2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluortridecanoyl) -L-lysine - {[N- (2S, 3R, 4R, 5R) -2,3,4,5, 6-pentahydroxyhexyl] -N-methyl} -amide

1.0 g of palladium catalyst (10% Pd / C) is added to a solution of 9.0 g (9.39 mmols) of the title compound of example 8a in 100 ml of ethanol and is hydrogenated for 24 hours at room temperature. room temperature. The catalyst is filtered off and the filtrate is concentrated by evaporation to dryness.

Yield: 7.8 g (quantitative) of a colorless solid.

Elemental Analysis:

Calc .: C 36.29 H 4.14 N 5.08 F 39.03

Enc .: C 36.44 H 4.17 N 4.98 F 38.86

c) 6-N- [1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododeca-n-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-1 5-yl)] -2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluortridecanoyl) -L-lysine - {[N- (2S, 3R, 4R, 5R) -2.3, 4,5,6-pentahydroxyhexyl] -N-methyl} -amide, Gd complex

7.0 g (8.46 mmol) of title compound of example 8b, 974 mg (8.46 mmol) of N-hydroxysuccinimide, 717 mg (16.92 mmol) of delium chloride and 5.33 g (8, 46 mmol) 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (example 1)) are dissolved in 100 ml dimethyl desulfoxide under slight heating. At 10 ° C, 2.18 g (10.57 mmol) of dicyclohexylcarbodiimide is added and stirred for 16 hours at room temperature. The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and further purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 7.4 g (57% of theory) of a colorless solid.

Water content (Karl-Fischer): 6.1%

Elemental analysis (on anhydrous basis):

Calc .: C 36.72 H 4.34 N 7.79 F 22.44 Gd 10.93

Enc .: C 36.87 H 4.36 N 7.72 F 22.48 Gd 10.94

Example 9

a) 6-N-Benzyloxycarbonyl-2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluor-tridecanoyl) -L-lysine- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -ethyl) -amide

4.93 g (23.90 mmols) of dicyclohexylcarbodiimide are added at 0 ° C to a solution of 15 g (19.12 mmols) of the title compound of example 7a and 3.97 g (19.12 mmols). ) of (2- {2- [2- (2-Methoxyethoxy) -ethoxy] -ethoxy} -ethyl) -amine (Whitessides et al., JACS, 1994, 5057-5062) and 2.20 g (19.12mmols ) of N-hydroxysuccinimide in 200 ml of dimethylformamide is stirred for 3 hours at 0 ° C and then for 16 hours at room temperature. Precipitated urea is filtered off, the filtrate is concentrated by vacuum evaporation to dryness. and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).

Yield: 12.2 g (82% of theory) of a colorless viscous oil

Elemental Analysis:

Calc .: C 43.17 H 4.55 N 4.32 F 33.17

Enc .: C 43.36 H 4.61 N 4.27 F 33.00

b) 2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluortridecanoyl) -L-lysine- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -ethyl ) -amide

1.0 g of palladium catalyst (10% Pd / C) is added to a solution of 11.5 g (11.81 mmols) of the title compound of example 9a in 100 ml of ethanol and is hydrogenated for 24 hours at room temperature. The catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo to dryness.

Yield: 9.95 g (quantitative) of a colorless solid. Elemental Analysis:

<table> table see original document page 51 </column> </row> <table>

c) 6-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluortridecanoyl) -L-lysine- (2- {2- [2- (2-methoxyethoxy) ethoxy] -ethoxy} -ethyl) -amide, Gd complex

9.0 g (10.72 mmol) of the title compound of Example 9b, 1.23 g (10.72 mmol) of N-hydroxysuccinimide, 909 mg (21.44 mmol) of lithium chloride and 6.75 g ( 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10- tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (example 1)) are dissolved in 100 ml dimethyl desulfoxide under slight heating. At 10 ° C, 2.76 g (13.4 mmol) of dicyclohexylcarbodiimide is added and stirred for 16 hours at room temperature. The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 10.1 g (62% of theory) of a colorless solid.Water content (Karl-Fischer): 6.0% Elemental analysis (on anhydrous basis):

<table> table see original document page 51 </column> </row> <table>

Example 10

a) 2H, 2H, 4H, 4H, -3Oxa-perfluordodecanoic acid 64.96 g (333.26 mmol) of bromoacetic acid tert-butyl ester are added at 0 ° C to 100 g (222.17 mmol) of 1H 1H-perfluor-1-nonanol (ApoIIo) and 24.9 g (444 mmols) of fine powdered potassium hydroxide as well as a catalytic amount (2 g) of detetra-n-butylammonium hydrogen sulfate in 800 ml of toluene and It is stirred for two hours at this temperature as well as for 12 hours at room temperature. The reaction solution is mixed with 1500 ml of ethyl acetate and 800 ml of water. The organic phase is separated and washed twice with 500 ml of water each time, then dried with magnesium sulfate and concentrated by evaporation in vacuo to dryness. The residue is suspended in a mixture consisting of 1200 ml of methanol and 0.5 Mem sodium hydroxide solution at a ratio of 2: 1 and then heated for 12 hours at 60 ° C. Reaction mixture is neutralized by mixing with cation-exchange resin (H + form) Amberlite IR 120 for processing, exchanger is filtered off, concentrated by evaporation to dryness and chromatographed on silica gel (eluent: ethyl acetate / hexane 1: 3).

Yield: 87 g (77% of theory) of a colorless wax

Elemental Analysis:

Calc .: C 26.00 H 0.99 F 63.56

Enc .: C 26.22 H 1.01 F 63.42

b) 1-N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 5H, 5H, 7H, 7H-3-aza-4-oxa-6-oxo-perfluorpentyldecylamine

17.8 g (140 mmol) of oxalyl chloride is added to 50.81 g (100 mmol) of the title compound of Example 10a in 500 mL of dichloromethane and stirred for 14 hours at room temperature. Concentrated by evaporation in vacuo to dryness, the residue is dissolved in 400 ml of dichloromethane, mixed at 0 ° C with 23.31 g (120 mmol) of N-benzyloxycarbonylethylenediamine (Atwell et al., Synthesis, 1984, 1032-1033) and 10.2 g (100 mmol) of triethylamine and is stirred for a further 24 hours at room temperature. The reaction solution is mixed with 400 ml of 1N hydrochloric acid and mixed well for 15 minutes. The organic phase is separated, dried with magnesium sulfate and concentrated by novacetic evaporation. The residue is chromatographed on silica gel (eluent: ethyl acetate / hexane 1: 2).

Yield: 46.5 g (68% of theory) of a colorless waxElemental analysis:

Calc .: C 36.86 H 2.50 N 4.09 F 47.19

Enc .: C 37.00 H 2.52 N 4.11 F 46.97

c) 1-N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H, 7H, 7H-3-aza-6-oxo-perfluorpentadecylamine

45.5 g (66.40 mmol) of the title compound of Example 10b in 150 mL of THF are mixed with 50 mL of 10 M boranedimethyl sulfide (in THF) and heated for 5 hours under reflux. It is cooled to 0 ° C, 100 ml of methanol are added by dripping, stirred for one hour at room temperature and then concentrated by novacetic evaporation to dryness. The residue is taken up in a mixture consisting of 300 ml ethanol / 50 ml 1 M hydrochloric acid and stirred for 14 hours at 40 ° C. It is concentrated by evaporation in vacuo to dryness, the residue taken up in 300 ml of 5% sodium hydroxide solution and extracted three times with 300 ml of dichloromethane each time. The combined organic phases are dried with magnesium sulfate, concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).

Yield: 35.2 g (79% of theory) of a colorless solid.

Elemental Analysis:

Calc .: C 37.63 H 2.86 N 4.18 F 48.18

Enc .: C 37.87 H 2.90 N 4.17 F 48.00

d) N- [2- (benzyloxycarbonyl) aminoethyl-N- (1 H, 1 H, 2H, 2H, 4H, 4H-3-oxa-perfluordodecenyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetamide

7.69 g (37.29 mmols) of dicyclohexylcarbodiimide are added at 0 ° C to a solution of 20 g (29.83 mmols) of the title compound of example 10c and 6.63 g (29.83 mmols). (2- [2- (2-Methoxyethoxy) ethoxy] - [ethoxy] acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) and 3.43 g (29.83 mmols) of N-hydroxysuccinimide in 200 ml of dimethylformamide is stirred for 3 hours at 0 ° C and then for 16 hours at room temperature. Precipitated urea is filtered off, the filtrate is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 20.1 g (77% of theory) of a colorless viscous oil

Elemental Analysis:

<table> table see original document page 54 </column> </row> <table>

e) N- (2-Aminoethyl) -N- (1 H, 1 H, 2H, 2H, 4H, 4H-3-oxa-perfluordodecyl) -2- {2- [2- (2-methoxyethoxy) ethoxy] -ethoxy} -acetamide, methanesulfonic acid salt

2.09 g (21.72 mmols) of methanesulfonic acid as well as 3.0 g palladium catalyst (10% Pd / C) are added to a solution of 19.0 g (21.72 mmols) of the title compound of example 10d. in 300 ml ethanole is hydrogenated for 24 hours at room temperature. The catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo to dryness.

Yield: 18.2 g (quantitative) of a colorless solid. Elemental Analysis:

<table> table see original document page 54 </column> </row> <table>

f) N - {[1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] - 2-aminoethyl} -N- (1 H, 1 H, 2H, 2H, 4H, 4H, -3-oxa-perfluordodecyl) -2- {2- [2- (2-methoxyethoxy) ethoxy] - ethoxy} -acetamide, Gd complex

15.8 g (18.9 mmols) of the title compound of Example 10e, 2.18 g (18.9 mmols) of N-hydroxysuccinimide, 1.60 g (37.80 mmols) of delithium chloride and 11.90 g (18.30 mmol) 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10 -tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (example 1)) are dissolved in 200 ml dimethyl desulfoxide under gentle heating. At 10 ° C, 4.87 g (23.63 mmoles) of dicyclohexylcarbodiimide as well as 1.91 g (18.9 mmols) detriethylamine are added, and it is stirred for 16 hours at room temperature. The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes.

The precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: water / acetonitrile gradient). Yield: 16.7 g (61% of theory) of a colorless solid.

Water content (Karl-Fischer): 6.9%

Elemental analysis (on anhydrous basis):

Calc .: C 36.42 H 4.25 N 7.25 F 23.89 Gd 11.63

Enc .: C 36.71 H 4.32 N 7.19 F 23.67 Gd 11.51

Example 11

a) 1 -N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 5H, 5H, 7H, 7H, 8H, 8H-3-aza-4-oxa-6-oxo-perfluorhexadecylamine

17.8 g (140 mmol) of oxalyl chloride is added to 52.21 g (100 mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluortridecanoic acid (e.g. 39 g EP 01 / 08498) in 500 ml of dichloromethane and is stirred for 14 hours at room temperature. It is concentrated by evaporation in vacuo to dryness, the residue is dissolved in 400 ml of dichloromethane, mixed at 0 ° C with 23.31 g (120 mmols) of N-benzyloxycarbonylethylenediamine (Atwell et al. , Synthesis, 1984, 1032-1033) and 10.2 g (100 mmol) of triethylamine and stirred for a further 24 hours at room temperature. The reaction solution is mixed with 400 ml of 1N hydrochloric acid and mixed well for 15 minutes. The organic phase is separated, dried with magnesium sulfate and concentrated by evaporation in vacuo to dryness. The residue is chromatographed on silica gel (eluent: ethyl acetate / hexane 1: 2).

Measure: 49.6 g (71% of theory) of a colorless wax

Elemental Analysis:

Calc .: C 37.84 H 2.74 N 4.01 F 46.25

Enc .: C 37.99 H 2.81 N 4.05 F 45.96

b) 1 -N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H, 7H, 7H, 8H, 8H-3-aza-6-oxo-perfluorhexadecylamine

48.0 g (68.73 mmol) of the title compound of Example 11a in 150 mL of THF are mixed with 50 mL of 10 M boranedimethyl sulfide (in THF) and heated for 5 hours under reflux. It is cooled to 0 ° C, 100 ml of methanol is added dropwise, stirred for one hour at room temperature and then concentrated by evaporation in vacuo to dryness. The residue is taken up in a mixture of 300 ml of ethanol / 50 ml of 1 M hydrochloric acid and stirred for 14 hours at 40 ° C. Concentrated by evaporation in vacuo to dryness, the residue is taken up in 300 ml of 5% sodium hydroxide solution and extracted three times with 300 ml each of dichloromethane. The combined organic phases are dried with magnesium sulfate, concentrated by evaporation in vacuo to dryness and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).

Yield: 30.2 g (64% of theory) of a colorless solid.

Elemental Analysis:

Calc .: C 36.61 H 3.09 N 4.09 F 47.19

Enc .: C 36.77 H 3.14 N 4.02 F 46.99

c) N- [2- (benzyloxycarbonyl) -aminoethyl-N- (1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluortridecyl) -2- {2- [2- ( 2-methoxyethoxy) ethoxy] ethoxy} acetamide

7.42 g (36.59 mmols) of dicyclohexylcarbodiimide are added at 0 ° C to a solution of 20 g (29.22 mmols) of the title compound of example 11b and 6.49 g (29.22 mmols). {2- [2- (2-Methoxyethoxy) -ethoxy] -ethoxy} -acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) and 3.29 g (29.22 mmol) ) of N-hydroxysuccinimide in 200 ml of dimethylformamide is stirred for 3 hours at 0 ° C and then for 16 hours at room temperature. Precipitated urea is filtered off, the filtrate is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 20.3 g (78% of theory) of a colorless viscous oil

Elemental Analysis:

Calc .: C 41.90 H 4.20 N 3.15 F 36.35

Enc .: C 42.16 H 4.28 N 3.12 F 36.21

d) N- (2-aminoethyl) -N- (1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluortridecyl) -2- {2- [2- (2-methoxyethoxy ) -ethoxy] -ethoxy} -acetamide, acid methanesulfonic acid salt

2.06 g (21.38 mmoles) of methanesulfonic acid as well as 3.0 g of palace catalyst (10% Pd / C) are added to a solution of 19.0 g (21.38 mmols) of the title compound of Example 11c. in 300 ml ethanole is hydrogenated for 24 hours at room temperature. The catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo. Yield: 18.2 g (quantitative) of a colorless solid.

Elemental Analysis:

<table> table see original document page 57 </column> </row> <table>

e) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] - 2-aminoethyl} -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluortridecyl) -2- {2- [2- (2-methoxyethoxy) ethoxy] -ethoxy} -acetamide, Gd complex

15.8 g (18.55 mmol) of the title compound of Example 11 d, 2.14 g (18.55 mmol) of N-hydroxysuccinimide, 1.57 g (37.10 mmol) of lithium decloride and 11, 68 g (18.55 mmol) 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7 10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (example 1)) are dissolved in 200 ml of dimethyl sulfoxide under gentle heating. At 10 ° C, 4.78 g (23.19 mmol) of dicyclohexylcarbodiimide as well as 1.88 g (18.55 mmol) of triethylamine are added and stirred for 16 hours at room temperature. The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: gradient consisting of water (water / acetonitrile).

Yield: 19.8 g (73% of theory) of a colorless solid.Water content (Karl-Fischer): 6.5% Elemental analysis (on anhydrous basis):

<table> table see original document page 57 </column> </row> <table>

Example 12

a) N- [2- (Benzyloxycarbonyl) -aminoethyl-N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy } -ethoxy) -acetamide

8.05 g (39.04 mmol) dicyclohexylcarbodiimide are added at 0 ° C to a solution of 20 g (31.23 mmol) of the title compound of example 1a and 8.32 g (31.23 mmol) (2- {2- [2- (2-Methoxyethoxy) -ethoxy] -ethoxy} -ethoxy) -acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) and 3.59 g (31.23 mmol) N-hydroxysuccinimide in 200 ml dimethylformamide is stirred for 3 h at 0 ° C and then 16 hours at room temperature. Precipitated urea is filtered off, the filtrate is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 22.1 g (80% of theory) of a colorless viscous oil

Elemental Analysis:

Calc .: C 41.90 H 4.20 N 3.15 F 36.35

Enc .: C 42.14 H 4.26 N 3.11 F 36.12

b) N- (2-aminoethyl) -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2- (2- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} ethoxy ) -acetamide, methanesulfonic acid salt

2.28 g (23.63 mmol) of methanesulfonic acid as well as 4.0 g of palace catalyst (10% Pd / C) is added to a solution of 21 g (23.63 mmol) of the title compound of example 12a in 500 ml of ethanol is hydrogenated for 24 hours at room temperature. The catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo to dryness.

Yield: 20.1 g (quantitative) of a colorless solid.

Elemental Analysis:

Calc .: C 33.89 H 4.15 N 3.29 F 37.97

Enc .: C 34.08 H 4.19 N 3.17 F 37.65

c) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] - 2-aminoethyl} -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2- (2- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} ethoxy) - acetamide, with complex Gd

16.9 g (19.88 mmol) of the title compound of example 12b, 2.29 g (19.88 mmol) of N-hydroxysuccinimide, 1.68 g (39.76 mmol) lithium decloride and 12.52 g (19.88 mmol) 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7, 10-Tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (Example 1)) is dissolved in 200 ml of dimethyl sulfoxide under slight heating. At 10 ° C, 5.13 g (24.85 mmol) of dicyclohexylcarbodiimide as well as 2.01 g (19.88 mmol) of triethylamine are added and stirred for 16 hours at room temperature. The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 18.1 g (62% of theory) of a colorless solid.Water content (Karl-Fischer): 6.8%

Elemental analysis (on anhydrous basis):

<table> table see original document page 59 </column> </row> <table>

Example 13

a) N- [2- (Benzyloxycarbonyl) aminoethyl-N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2-methoxy acetamide

8.05 g (39.04 mmol) dicyclohexylcarbodiimide are added at 0 ° C to a solution of 20 g (31.23 mmol) of the title compound of example 1a and 2.81 g (31.23 mmol) ) of 2-methoxyacetic acid (Aldrich) and 3.59 g (31.23 mmols) of N-hydroxysuccinimide in 200 ml of dimethylformamide is stirred for 3 hours at 0 ° C and then for 16 hours at room temperature. -Environment break. Precipitated urea is filtered off, the filtrate is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 17.1 g (77% of theory) of a colorless viscous oilElemental analysis:

<table> table see original document page 59 </column> </row> <table>

b) N- (2-aminoethyl) -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2-methoxyacetamide, methanesulfonic acid salt

2.23 g (23.16 mmol) methanesulfonic acid as well as 4.0 g palladium catalyst (10% Pd / C) are added to a solution of 16.5 g (23.16 mmol) of the title compound of Example 13a. in 500 ml ethanole is hydrogenated for 24 hours at room temperature. The catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo to dryness.

Yield: 15.1 g (quantitative) of a colorless solid.

Elemental Analysis:

Calc .: C 28.50 H 2.84 N 4.15 F 47.89

Enc .: C 28.79 H 2.96 N 4.09 F 47.53

c) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] - 2-aminoethyl} -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2-methoxyacetamide, Gd complex

11.7 g (17.29 mmol) of the title compound of Example 13b, 1.99 g (17.29 mmol) of N-hydroxysuccinimide, 1.46 g (34.58 mmol) lithium decloride and 10.89 g (17.29 mmol) 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7, 10-Tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (example 1)) are dissolved in 200 ml of dimethyl sulfoxide under slight heating. At 10 ° C, 4.46 g (21.6 mmol) of dicyclohexylcarbodiimide as well as 1.75 g (17.29 mmol) of triethylamine are added and stirred for 16 hours at room temperature.

The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 12.9 g (59% of theory) of a colorless solid.

Water content (Karl-Fischer): 6.0%

Elemental analysis (on anhydrous basis):

Calc .: C 34.32 H 3.64 N 8.24 F 27.14 Gd 13.21

Enc .: C 34.59 H 3.69 N 8.18 F 26.98 Gd 13.14

Example 14

a) N- [2- (benzyloxycarbonyl) aminoethyl-N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] -ethoxy} acetamide

8.05 g (39.04 mmol) dicyclohexylcarbodiimide is added at 0 ° C to a solution of 20 g (31.23 mmol) of the title compound of example 1a and 6.94 g (31.23 mmol) {2- [2- (2-Methoxyethoxy) -ethoxy] -ethoxy} -acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) and 3.59 g (31.23 mmol) ) of N-hydroxysuccinimide in 200 ml of dimethylformamide is stirred for 3 hours at 0 ° C and then for 16 hours at room temperature. Precipitated urea is filtered off, the filtrate is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 22.3 g (85% of theory) of a colorless viscous oilElemental analysis:

<table> table see original document page 61 </column> </row> <table>

b) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H-perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetamide, acid salt methanesulfonic

2.40 g (24.86 mmol) of methanesulfonic acid as well as 4.0 g palladium catalyst (10% Pd / C) are added to a solution of 21 g (24.86 mmol) of the title compound of example 14a in 500 ml of ethanol is hydrogenated for 24 hours at room temperature. The catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo to dryness.

Yield: 20.1 g (quantitative) of a colorless solid. Elemental Analysis:

<table> table see original document page 61 </column> </row> <table>

c) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] - 2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetamide, Gd11.4 g complex (14.08 mmol) of the title compound of example 14b, 1.62 g (14.08 mmol) of N-hydroxysuccinimide, 1.19 g (28.12 mmol) lithium decloride and 8.87 g (14, 08 mmol) 1,4,7-tris- (carboxymethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG (example 1)) are dissolved in 200 ml of dimethyl sulfoxide under slight heating. At 10 ° C, 3.63 g (17.6 mmol) of dicyclohexylcarbodiimide as well as 1.43 g (14.08 mmol) of triethylamine are added and stirred for 16 hours at room temperature. The solution is poured in 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 13.9 g (71% of theory) of a colorless solid.

Water content (Karl-Fischer): 5.7%

Elemental analysis (on anhydrous basis):

Calc .: C 36.34 H 4.19 N 7.42 F 24.43 Gd 11.89

Enc .: C 36.57 H 4.22 N 7.44 F 24.29 Gd 11.77

Example 15

a) N- [2- (benzyloxycarbonyl) aminoamethyl-N- (1H, 1H, 2H, 2H-perfluordecyl) -2- (2-methoxyethoxy) acetamide

8.05 g (39.04 mmol) dicyclohexylcarbodiimide are added at 0 ° C to a solution of 20 g (31.23 mmol) of the title compound of example 1a and 4.19 g (31.23 mmol) ) (2-methoxyethoxy) acetic acid (Aldrich) and 3.59 g (31.23 mmols) of N-hydroxysuccinimide in 200 ml dimethylformamide are stirred for 3 hours at 0 ° C and then for 16 hours at room temperature. Precipitated urea is filtered off, the filtrate is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 17.5 g (74% of theory) of a colorless viscous oil

Elemental Analysis:

Calc .: C 39.70 H 3.33 N 3.70 F 42.70

Enc .: C 40.01 H 3.42 N 3.66 F 42.54

b) N- (2-aminoethyl) -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2- (2-methoxyethoxy) acetamide, methanesulfonic acid salt

2.17 g (22.47 mmols) of methanesulfonic acid as well as 3.0 g of palace catalyst (10% Pd / C) are added to a solution of 17 g (22.47 mmols) of the title compound of example 15a in 500 ml of ethanol is hydrogenated for 24 hours at room temperature. The catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo to dryness.

Yield: 16.2 g (quantitative) of a colorless solid. Elemental Analysis:

Calc .: C 30.09 H 3.23 N 3.90 F 44.96

Enc .: C 30.33 H 3.25 N 3.84 F 44.77

c) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] - 2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluordecyl) -2- (2-methoxyethoxy) acetamide, Gd complex

11.5 g (16.07 mmol) of the title compound of Example 15b, 1.85 g (16.07 mmol) of N-hydroxysuccinimide, 1.36 g (32.14 mmol) Iftio decloride and 10.12 g (16.07 mmol) 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7, 10-Tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (example 1)) are dissolved in 200 ml of dimethyl sulfoxide under slight heating. At 10 ° C, 4.14 g (20.08 mmol) of dicyclohexyl carbodiimide as well as 1.63 g (16.07 mmol) of triethylamine are added and stirred for 16 hours at room temperature. The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 14.2 g (67% of theory) of a colorless solid.

Water content (Karl-Fischer): 6.0%

Elemental analysis (on anhydrous basis):

Calc .: C 35.04 H 3.84 N 7.95 F 26.17 Gd 12.74

Enc .: C 35.38 H 3.88 N 7.91 F 25.99 Gd 12.63

Example 16

a) 1-N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 3H, 3H, 4H, 4H, 6H, 6H, -4-aza-perfluortetradecylamine

25.0 G (120 mmol) of N-benzyloxycarbonylpropylenediamine (Atwell et al., Synthesis, 1984, 1032-1033) and 10.2 g (100 mmol) of triethylamine are added to 54.22 g (100 mmol) of methanesulfonic acid- (1H, 1H, 2H, 2H-perfluordecyl) ester (Bartsch et al., Tetrahedron, 2000, 3291-3302) in 500 ml of acetonitrile and is stirred for 48 hours at 60 ° Ç. Insoluble components are separated by filtration of the reaction solution, concentrated by evaporation in vacuo to dryness and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 40.7 g (62% of theory) of a colorless waxElemental analysis:

<table> table see original document page 64 </column> </row> <table>

b) N- [3- (benzyloxycarbonyl) aminopropyl-N- (1 H, 1 H, 2H, 2H-perfluoroyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy } -acetamide

7.99 G (38.74 mmol) dicyclohexylcarbodiimide is added at 0 ° C to a solution of 20 g (30.99 mmol) of the title compound of example 16a and 6.89 g (30.99 mmol) (2- [2- (2-Methoxyethoxy) ethoxy] ethoxy acetic acid) (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) and 3.56 g (30.99 mmols) of N-hydroxysuccinimide in 200 ml of dimethylformamide is stirred for 3 hours at 0 ° C and then for 16 hours at room temperature. Precipitated urea is filtered off, the filtrate is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 21.5 g (81% of theory) of a colorless viscous oil. Elemental Analysis:

<table> table see original document page 64 </column> </row> <table>

c) N- (3-aminopropyl) -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetamide methanesulfonic acid salt 2.25 g (23.29 mmol) methanesulfonic acid as well as 4.0 g palladium catalyst (10% Pd / C) are added to a solution of 20 g (23.29 mmol) of the Example 16b in 500 ml of ethanol and is hydrogenated for 24 hours at room temperature. The catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo to dryness.

Yield: 19.2 g (quantitative) of a colorless solid. Elemental Analysis:

<table> table see original document page 64 </column> </row> <table> d) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,1O-tetraazacyclododecane-10- N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] -3-aminopropyl} -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2 - {-2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetamide, Gd complex

11.3 G (13.80 mmol) of the title compound of Example 16c, 1.59 g (13.80 mmol) of N-hydroxysuccinimide, 1.17 g (27.60 mmol) lithium decloride and 8.79 g (13.80 mmol) 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7, 10-Tetraazacyclododecan, Gd complex (WO 98/24775, Schering AG, (example 1)) are dissolved in 200 ml of dimethyl sulfoxide under gentle heating. At 10 ° C, 3.59 g (17.4 mmol) of dicyclohexylcarbodiimide as well as 1.40 g (13.80 mmol) of triethylamine are added and stirred for 16 hours at room temperature.

The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 12.9 g (66% of theory) of a colorless solid.Water content (Karl-Fischer): 6.0%

Elemental analysis (on anhydrous basis):

<table> table see original document page 65 </column> </row> <table>

Example 17

a) 1-N- (benzyloxycarbonyl) -1H, 1H, 2H, 2H, 3H, 3H, 4H, 4H, 6H, 6H, 7H, 7H-5-aza-perfluoro-pentadecylamine

26.67 g (120 mmol) of N-benzyloxycarbonyl butylenediamine (Atwell et al., Synthesis, 1984, 1032-1033) and 10.2 g (100 mmol) of triethylamine are added to 54.22 g (100 mmols) of methanesulfonic acid (1H, 1H, 2H, 2H, 2H-perfluordecyl) ester (Bartsch et al., Tetrahedron, 2000, 3291-3302) in 500 ml of acetonitrile and is stirred for 48 hours at 60 ° C. Insoluble components are separated by filtration of the reaction solution, concentrated by evaporation in vacuo to dryness and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 39.6 g (59% of theory) of a colorless wax Elemental Analysis: Calc .: C 39.53 H 3.17 N 4.19 F 48.32

Enc .: C 39.74 H 3.21 N 4.17 F 48.17

b) N- [4- (benzyloxycarbonyl) aminobutyl-N- (1 H, 1 H, 2H, 2H-perfluoroyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy } -acetamide

7.71 G (37.4 mmols) of dicyclohexylcarbodiimide are added at 0 ° C to a solution of 20 g (29.92 mmols) of the title compound of Example 17a and 6.65 g (29.92 mmols). {2- [2- (2-Methoxyethoxy) -ethoxy] -ethoxy} -acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) and 3.44 g (29.92 mmol) ) of N-hydroxysuccinimide in 200 ml of dimethylformamide is stirred for 3 hours at 0 ° C and then for 16 hours at room temperature. Precipitated urea is filtered off, the filtrate is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 26.0 g (79% of theory) of a colorless viscous oil.

Elemental Analysis:

Calc .: C 42.67 H 4.27 N 3.21 F 37.01

Enc .: C 42.85 H 4.30 N 3.16 F 36.87

c) N- (4-aminobutyl) -N- (1H, 1H, 2H, 2H-perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetamide

4.0 g of palladium catalyst (10% Pd / C) is added to a solution of 20 g (22.92 mmols) of the title compound of example 17b in 500 ml of ethanol and is hydrogenated for 24 hours at room temperature.

The catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo to dryness.

Yield: 17.0 g (quantitative) of a colorless solid.

Elemental Analysis:

Calc .: C 37.41 H 4.23 N 3.79 F 43.73

Enc .: C 37.59 H 4.29 N 3.74 F 43.61

d) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] - 4-Aminobutyl} -N- (1H, 1H, 2H, 2H-perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetamide, Gd10 G complex (13 , 54 mmol) of the title compound of example 17c, 1.56 g (13.54 mmol) of N-hydroxysuccinimide, 1.14 g (26.08 mmol) of lithium chloride and 8.69 g (13.54 mmol) 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (Example 1)) are dissolved in 200 ml of dimethyl sulfoxide under slight heating. At 10 ° C, 3.53 g (17.07 mmol) dicyclohexylcarbodiimide is added and stirred for 16 hours at room temperature. The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and further purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 11.7 g (60% of theory) of a colorless solid.Water content (Karl-Fischer): 6.5% Elemental analysis (on anhydrous basis):

<table> table see original document page 67 </column> </row> <table>

Example 18

a) N- [2- (benzyloxycarbonyl) aminoethyl-N- (1 H11 H, 2H, 2H, 4H, 4H-3-oxa-perfluordodecyl) -2- [2- (2-methoxyethoxy) ethoxy] acetamide

7.69 g (37.29 mmol) dicyclohexylcarbodiimide are added at 0 ° C to a solution of 20 g (29.83 mmol) of the title compound of example 10c and 5.32 g (29.83 mmol) ) of [2- (2-methoxyethoxy) ethoxy] acetic acid (Aldrich) and 3.43 g (29.83 mmols) of N-hydroxysuccinimide in 200 ml dimethylformamide is stirred for 3 hours at 0 ° C and then for 16 hours at room temperature. Precipitated urea is filtered off, the filtrate is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 17.9 g (72% of theory) of a colorless viscous oil. Elemental Analysis:

<table> table see original document page 67 </column> </row> <table>

b) N- (2-aminoethyl) -N- (1 H, 1 H, 2H, 2H, 4H, 4H-3-oxa-perfluordodecyl) -2- [2- (2-methoxyethoxy) ethoxy] acetamide, methanesulfonic acid salt 1.98 g (20.50 mmols) methanesulfonic acid as well as 3.0 g palladium catalyst (10% Pd / C) are added to a solution of 17.0 g (20.50 mmols) of the title compound. Example 18c in 300 ml ethanole is hydrogenated for 24 hours at room temperature. The catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo to dryness.

Yield: 16.3 g (quantitative) of a colorless solid.

Elemental Analysis:

Calc .: C 31.83 H 3.69 N 3.53 F 40.75

Enc .: C31.57 H 3.78 N 3.44 F 40.51

c) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] - 2-aminoethyl} -N- (1H, 1H, 2H, 2H, 4H, 4H-3-oxa-perfluordodecyl) -2- [2- (2-methoxyethoxy) ethoxy] acetamide, Gd complex

14.5 g (18.30 mmols) of the title compound of example 18d, 2.11 g (18.30 mmols) of N-hydroxysuccinimide, 1.55 g (36.60 mmols) lithium decloride and 11.52 g (18.30 mmol) 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7, 10-Tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (example 1)) are dissolved in 200 ml of dimethyl sulfoxide under slight heating. At 10 ° C, 4.72 g (22.88 mmol) of dicyclohexylcarbodiimide as well as 1.85 g (18.30 mmol) of triethylamine are added and stirred for 16 hours at room temperature. The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 17.6 g (69% of theory) of a colorless solid.

Water content (Karl-Fischer): 6.1%

Elemental analysis (on anhydrous basis):

Calc .: C 35.81 H 4.06 N 7.50 F 24.69 Gd 12.02

Enc .: C 36.04 H 4.11 N 7.49 F 24.52 Gd 11.94

Example 19

a) 1 -N- (tert-butyloxycarbonyl) -1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H, 7H, 7H, 8H, 8H-6-aza-3-oxaperfluorhexaadecylamine

6.13 G (30 mmol) of N-tert-Butyloxycarbonyl-3-oxa-pentylenediamine (Koenig et al., Eur. J. Org. Chem., 2002, 3004-3014) and 2.55 µg (25 mmol ) of triethylamine are added to 13.56 g (25 mmol) of methanesulfonic acid (1H, 1H, 2H, 2H-perfluordecyl) ester (Bartsch et al., Tetrahedron, 2000, 3291-3302) in 150 ml acetonitrile and is stirred for 48 hours at 60 ° C. Insoluble components are separated by filtration of the reaction solution, concentrated by evaporation in vacuo to dryness and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 10.9 g (67% of theory) of a colorless wax.

Elemental Analysis:

<table> table see original document page 69 </column> </row> <table>

b) N- [5- (tert-Butyloxycarbonyl) amino-3-oxapentyl-N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) - ethoxy] ethoxy} acetamide

3.97 g (19.23 mmols) of dicyclohexylcarbodiimide are added at 0 ° C to a solution of 10 g (15.38 mmols) of the title compound of example 19a and 3.42 g (15.38 mmols). {2- [2- (2-Methoxyethoxy) -ethoxy] -ethoxy} -acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) and 1.77 g (15.38 mmol) ) of N-hydroxysuccinimide in 200 ml of dimethylformamide is stirred for 3 hours at 0 ° C and then for 16 hours at room temperature. Precipitated urea is filtered off, the filtrate is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 9.9 g (75% of theory) of a colorless viscous oil. Elemental Analysis:

<table> table see original document page 69 </column> </row> <table>

c) N- (5-amino-3-oxapentyl) -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy} -acetamide

50 ml of trifluoroacetic acid is added at 0 ° C to a solution of 9.5 g (11.12 mmols) of the title compound of example 19b in 100 ml of dichloromethane and stirred for 3 hours at room temperature. It is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).

Yield: 7.8 g (93% of theory) of a colorless solid.

Elemental Analysis:

Calc .: C 36.62 H 4.14 N 3.71 F 42.81

Enc .: C 36.88 H 4.21 N 3.55 F 43.25

d) N - {[1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-1β-10N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 5-amino-3-oxapentyl} -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetamide, Gd complex

7g (9.28mmol) of the title compound of Example 19c, 1.07g (9.28mmol) of N-hydroxysuccinimide, 787mg (18.56mmol) of delium chloride and 5.84g (9, 28 mmol) 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (example 1)) are dissolved in 100 ml dimethyl desulfoxide under slight heating. At 10 ° C, 2.39 g (11.6 mmol) of dicyclohexylcarbodiimide is added and stirred for 16 hours at room temperature. The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 8.8 g (65% of theory) of a colorless solid.

Water content (Karl-Fischer): 6.5%

Elemental analysis (on anhydrous basis):

Calc .: C 36.92 H 4.35 N 7.18 F 23.64 Gd 11.51

Enc .: C 37.04 H 4.39 N 7.15 F 23.57 Gd 11.47

Example 20

a) 1 -N- (tert-butyloxycarbonyl) -1 H, 1 H, 2H, 3H, 4H, 4H, 6H, 7H, 7H-5-aza- [2,3- (2,2-dimethyl [1,3] -dioxolanyl)] - perfluorpentadecylamine

7.81 G (30 mmol) of N-tert-Butyloxycarbonyl- [2,3- (2,2-dimethyl- [1,3] dioxolanyl)] butylenediamine [produced from (5-aminoethyl-2, 2-Dimethyl- [1,3] dioxolan-4-yl) methylamine (ACROS) analogously to the preparation of N-tert-butyloxycarbonyl-3-oxa-pentylenediamine (Koenig et al., Eur. J. Org.Chem., 2002, 3004-3014)] and 2.55 g (25 mmol) of triethylamine are added to 13.56 g (25 mmol) of (1 H, 1 H, 2H, 2H-perfluordecyl) methyl ester. -tansulfonic acid (Bartsch et al., Tetrahedron, 2000, 3291-3302) in 150 ml deacetonitrile and is stirred for 48 hours at 60 ° C. Insoluble components are filtered off the reaction solution, concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 12.5 g (71% of theory) of a colorless wax.

Elemental Analysis:

Calc .: C 37.40 H 3.85 N 3.97 F 45.72

Enc .: C 37.66 H 3.94 N 3.88 F 45.61

b) N- {4- (tert-butyloxycarbonyl) amino- [2,3- (2,2-dimethyl- [1,3] dioxolanyl)] butyl} -N- (1 H11 H, 2H, 2H -perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetamide

3.65 G (17.7 mmoles) of dicyclohexylcarbodiimide is added at 0 ° C to a solution of 10 g (14.16 mmols) of the title compound of example 20a and 3.15 g (14.16 mmols). {2- [2- (2-Methoxyethoxy) -ethoxy] -ethoxy} -acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) and 1.63 g (14.16 mmol) ) of N-hydroxysuccinimide in 200 ml of dimethylformamide is stirred for 3 hours at 0 ° C and then for 16 hours at room temperature. Precipitated urea is filtered off, the filtrate is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).

Yield: 8.9 g (69% of theory) of a colorless viscous oil.

Elemental Analysis:

Calc .: C 40.89 H 4.76 N 3.08 F 35.47

Enc .: C 40.97 H 4.85 N 3.00 F 35.37

c) N- (4-amino-2,3-dihydroxybutyl) -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] - ethoxy} -acetamide

50 ml of trifluoracetic acid is added at 0 ° C to a solution of 8.2 g (9.00 mmols) of the title compound of example 20b in 100 ml of dichloromethane and stirred for 3 hours at room temperature.

It is concentrated by evaporation in vacuo to dryness and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1 to 2: 1).

Yield: 6.68 g (96% of theory) of a colorless solid.

Elemental Analysis:

Calc .: C 35.85 H 4.06 N 3.64 F 41.92

Enc .: C 36.05 H 4.11 N 3.60 F 41.77

d) N - {[1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] - (4-amino-2,3-dihydroxybutyl) -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy } -acetamide, Gd complex

6 G (7.79 mmol) of the title compound of Example 20c, 897 mg (7.79 mmol) of N-hydroxysuccinimide, 660 mg (15.58 mmol) delium chloride and 4.90 g (7.79 mmol) 1,4,7-tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1,4,7,10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (Example 1)) are dissolved in 100 ml dimethyl desulfoxide under gentle heating. At 10 ° C, 2.01 g (9.74 mmol) of dicyclohexylcarbodiimide is added and stirred for 16 hours at room temperature. The solution is poured into 2000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and further purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 6.9 g (59% of theory) of a colorless solid.

Water content (Karl-Fischer): 7.7%

Elemental analysis (on anhydrous basis):

Calc .: C 36.50 H 4.30 N 7.09 F 23.37 Gd 11.38

Enc .: C 36.71 H 4.35 N 7.02 F 23.41 Gd 11.29

Example 21

a) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (butanoyl-4- (R) -carboxylate-4-yl)] - 2 -aminoethyl} -N- (1H, 1H, 2H, 2H-perfluor-decyl) -2 - {- 2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetamide, Gd and N-complex monosodium salt - ({1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododeca-n-10-N- (ethane- [2- (R) -carboxylateethyl] -yl)} -2- aminoethyl} -N- (1 H, 2H, 2H, 2H-per-fluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetamide, Gd complex monosodium salt

2.84 G (3.52 mmol) of the title compound of Example 14b, 448 mg (4.4 mmol) of triethylamine and 3.51 g (4.4 mmol) of 2- (R) -2- acid monopentafluorphenyl ester [4,7,10-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclodo-decan-1-yl] pentanedicarboxylic, Gd complex (WO 2005/0014154, EPIXPHARMACEUTICALS, INC., (Example 9: EP- 2104-15-Pfp)) are dissolved in 50 ml of dimethyl sulfoxide, mixed with 356 mg (3.52 mmols) diethylamine and mixed for 16 hours at room temperature. The solution is poured into 1000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile). Fractions containing the product are concentrated by evaporation, dissolved in water, neutralized with 0.1 Nea sodium hydroxide solution and then lyophilized.

Yield: 2.03 g (39% of theory) of a colorless solid. as dermal-isomers mixture 3: 2.

Water content (Karl-Fischer): 9.2%

Elemental analysis (on anhydrous basis):

Calc .: C 35.72 H 3.97 N 6.25 F 24.01 Gd 11.69

Enc .: C 36.01 H 4.06 N 6.29 F 23.89 Gd 11.46

Example 22

a) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (butanoyl-4- (R) -carboxylate-4-yl)] - 2 -aminoethyl} -N- (1 H, 1 H, 2H, 2H-perfluor-decyl) -2- (1-0-ad-mannopyranosyl) -acetamide, Gd and N - monosodium salt ({1,4,7 -tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (ethane- [2- (R) -carboxylateethyl] -yl)} -2-aminoethyl) -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2- (1-ad-mannopyranosyl) acetamide, Gd complex monosodium salt

2.83 G (3.44 mmol) of the title compound of Example 1c, 436mg (4.3 mmol) of triethylamine and 3.43 g (4.3 mmol) of 2- (R) -2- acid monopentafluorphenyl ester Dicarboxylic [4,7,10-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclo-dodecan-1-yl] pentane, Gd complex (WO 2005/0014154, EPIXPHARMACEUTICALS, INC., (Example 9: EP -2104-15 Pfp))) are dissolved in 50 ml of dimethyl sulfoxide, mixed with 348 mg (3.44 mmols) detriethylamine and stirred for 16 hours at room temperature. The solution is poured into 1000 ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile). Fractions containing product are concentrated by evaporation, dissolved in water, neutralized with 0.1 N sodium hydroxide solution and then lyophilized.

Yield: 1.64 g (32% of theory) of a colorless solid. as dermal-isomers mixture 3: 2.

Water content (Karl-Fischer): 8.8%

Elemental analysis (on anhydrous basis):

Calc .: C 34.42 H 3.63 N 6.17 F 23.73 Gd 11.55

Enc .: C 34.66 H 3.60 N 6.09 F 23.78 Gd 11.39

Example 23

a) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] - 2-aminoethyl} -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetamide, trisodium salt 10 G (7.13 mmols) of the title compound of example 14c are dissolved in a mixture of 100 ml water and 30 ml isopropanol, mixed with 2.25 g (24.96 mmols) of oxalic acid and heated for 5 hours to 100 ° C. After cooling to room temperature the precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile). The product-containing fractions concentrated by evaporation, dissolved in water, adjusted to pH 10 with 0.1 N sodium hydroxide solution then lyophilized.

Yield: 7.39 g (77% of theory) of a colorless solid.

Water content (Karl-Fischer): 8,2% Elemental analysis (on anhydrous basis):

Calc .: C 38.94 H 4.49 N 7.95 F 26.18

Enc .: C 39.03 H 4.44 N 7.98 F 25.89

b) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] - 2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetamide, Dy complex

2.0 G (1.49 mmol) of the title compound of Example 23a are dissolved in 50 mL of water and 1 mL of acetic acid, mixed with 441 mg (1.64 mmol) of dysprosium chloride and stirred for 6 hours at 80 ° C. It is neutralized with ammonia, concentrated by evaporation to dryness and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 1.78 g (84% of theory) of a colorless solid.

Water content (Karl-Fischer): 6.2%

Elemental analysis (on anhydrous basis):

Calc .: C 36.19 H 4.18 N 7.39 F 24.33 Dy 12.24

Enc .: C 36.32 H 4.24 N 7.30 F 24.19 Dy 12.16

Example 24

a) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] - 2-aminoethyl} -N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetamide, Yb complex

2.0 G (1.49 mmol) of the title compound of Example 23a are dissolved in 50 mL of water and 1 mL of acetic acid, mixed with 458 mg (1.64 mmol) of ytterbium chloride and stirred for 6 hours at 80 ° C. It is neutralized with ammonia, concentrated by evaporation to dryness and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 1.84 g (86% of theory) of a colorless solid.

Water content (Karl-Fischer): 6.9%

Elemental analysis (on anhydrous basis):

Calc .: C 35.91 H 4.14 N 7.33 F 24.14 Yb 12.93

Enc .: C 36.05 H 4.19 N 7.31 F 24.00 Yb 12.79Example 25

a) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl )] - 2-aminoethyl} -N- (1H, 1H, 2H, 2H-perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetamide, Y complex

2.0 G (1.49 mmol) of the title compound of Example 23a are dissolved in 50 mL of water and 1 mL of acetic acid, mixed with 320 mg (1.64 mmol) of yttrium chloride and stirred for 6 hours at 80 ° C. ° C. It is neutralized with ammonia, concentrated by evaporation to dryness and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 1.56 g (79% of theory) of a colorless solid.Water content (Karl-Fischer): 5.5% Elemental analysis (on anhydrous basis):

<table> table see original document page 76 </column> </row> <table>

Example 26

a) 10- (5-Oxo-tetrahydrofuran-2-ylmethyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

8.3 G (207.6 mmol) of sodium hydroxide is added to 12.0 g (34.6 mmol) of 1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclodode-barrel ( D03A) in 50 ml of water. A solution of 5.02 g (43.25 mmol) of 3-oxiranylpropionic acid (Dakoji et al., J. Am. Chem. Soc., 1996, 10971-10979) in 50 ml n-butanol / 50 ml 2 -propanol is added dropwise and the solution is heated for 24 hours to 80 ° C. The reaction solution is concentrated by evaporation in vacuo to dryness, the residue is mixed with 300 ml of water and adjusted to pH 3 with 3N hydrochloric acid.

Subsequently, it is extracted three times with 200 ml of n-butanol each time, the combined butanol phases are evaporated in vacuo to dryness and the residue is purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile ).

Yield: 13.6 g (79% of theory) of a colorless solid.Water content (Karl-Fischer): 10.4% Elemental analysis (on anhydrous basis):

Calc .: C 51.34 H 7.26 N 12.60

Enc .: C 51.63 H 7.05 N 12.44

b) 10- (5-Oxo-tetrahydrofuran-2-ylmethyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane, Gd complex

12.0 G (24.2 mmol) of the title compound of Example 26 are dissolved in 100 mL of water and 1 mL of acetic acid, mixed with 4.39 g (12.1 mmol) of gadolinium oxide and stirred for 6 hours. at 80 ° C. The solution is filtered, concentrated by evaporation to dryness and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 13.8 g (89% of theory) of a colorless solid.

Water content (Karl-Fischer): 6.5%

Elemental analysis (on anhydrous basis):

Calc .: C 38.12 H 4.88 N 9.36 Gd 26.26

Enc .: C 38.26 H 4.89 N 9.21 Gd 26.09

c) N - {[1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-4-hydroxy-5-yl)] -2-aminoethyl} - N- (1 H, 1 H, 2H, 2H-perfluordecyl) -2 - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetamide, Gd complex

2.84 G (3.52 mmols) of the title compound of example 14b and 3.38 g (5.28 mmols) of the title compound of example 26b are dissolved in 50 ml of methanol, mixed with 356 mg (3.52 mmols). ) of triethylamine stirred for 48 hours at a temperature of 50 ° C. It is concentrated by evaporation to dryness and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 3.27 g (66% of theory) of a colorless solid.

Water content (Karl-Fischer): 6.9%

Elemental analysis (on anhydrous basis):

Calc .: C 36.70 H 4.31 N 6.42 F 24.67 Gd 12.01

Enc .: C 36.77 H 4.38 N 6.33 F 24.59 Gd 11.96Example 27

a) 1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3-N- [1,4,7-Tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N - (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - perfluortridecyl-N - {- 2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetamide, Gd complex

2.58 G (12.5 mmol) dicyclohexylcarbodiimide as well as 1.01 g (10 mmol) triethylamine is added at 0 ° C to a solution of 12.14 g (10 mmol) of the title compound of Example 2b and 2.22 g (10 mmol) {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetic acid (Voegtle et al., Liebigs Ann.Chem., 1980, 858-862) and 1, 15 g (10m N) of N-hydroxysuccinimide in 100 ml of dimethylformamide is stirred for 3 hours at 0 ° C and then for 16 hours at room temperature. Precipitated urea is filtered off and the filtrate is concentrated by evaporation in vacuo to dryness. The residue is taken up in a little water, insoluble components are filtered off, and the filtrate is then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 8.2 g (58% of theory) of a colorless solid.

Water content (Karl-Fischer): 6.2%

Elemental analysis (on anhydrous basis):

Calc .: C 36.34 H 4.19 N 7.42 F 24.43 Gd 11.89

Enc .: C 36.55 H 4.27 N 7.33 F 24.21 Gd 11.70

Example 28

a) 1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N - (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - perfluortridecyl-N - {- 2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetamide, trisodium salt

10 G (7.11 mmol) of the title compound of Example 27a are dissolved in a mixture of 100 mL water and 30 mL isopropanol, mixed with 2.25 g (24.96 mmol) oxalic acid and heated for 5 hours at 100 ° C. After cooling to room temperature, the precipitated solid is filtered off and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile). The product-containing fractions are evaporative concentrated, dissolved in water, adjusted to pH 8 with 0.1 N sodium hydroxide solution and then lyophilized. Yield: 8.64 g (91% of theory) of a colorless solid.

Water content (Karl-Fischer): 7.5%

Elemental analysis (on anhydrous basis):

Calc .: C 38.94 H 4.49 N 7.95 F 26.18

Enc .: C 38.88 H 4.40 N 7.65 F 25.77

b) 1 H, 1 H, 2H, 2H, 4H, 4H, 5H, 5H-3-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N - (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)] - perfluortridecyl-N - {- 2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetamide, Y2 complex, The G (1.50 mmol) of the title compound of Example 28a is dissolved in 50 mL of water and 1 mL of acetic acid, mixed with 320 mg (1.64 mmol) of yttrium chloride and stirred for 6 hours at 80 ° C. . It is neutralized with ammonia, concentrated by evaporation to dryness and then purified by chromatography (RP-18; eluent: gradient consisting of water / acetonitrile).

Yield: 1.43 g (72% of theory) of a colorless solid.

Water content (Karl-Fischer): 5.0%

Elemental analysis (on anhydrous basis):

Calc .: C 38.32 H 4.42 N 7.82 F 25.76 Y 7.09

Ene .: C 38.48 H 4.55 N 7.75 F 25.66 Y 6.96

Example 29: Relaxation

The relaxation times T1 and T2 of water and plasma (bovine) with increasing concentrations of gadolinium complexes of the substances of Examples 1 d, 5c, 14c, 15c contained therein were determined at 40 ° C using a Minispec NMR pulse spectrometer. PC 20) at 0.47 T. The results are shown in table 1.

Example 30: Acute toxicity after intravenous application to rats (guiding)

Following intravenous application of the gadolinium complexes of the title substances of examples 1d, 5c, 14c, 15c in rats (n = 3; injection speed: 2 ml / min), the acute systemic compatibility (LD50) was determined as follows: guiding mode. In each case, various dosages with an observation period of 7 days were analyzed. The acute acute toxicities can be seen in table 1.

Example 31: Elimination after intravenous application in rats

Following intravenous application of 50 μιτιοΙ total gadolinium / kg body weight of gadolinium complexes of the title substances of examples 1 d, 5c, 14c, 15c in rats (n = 3), the metal content was determined in fractions up to 14 days after application. by means of Atomic Emission Spectrometry (ICP-AES) on urine and feces excretion media as well as on the body (on the rest of the body). The results are presented in table 1.

Example 32: Plasma kinetics after intravenous application in rats

Following intravenous application of 50 μτηοΙ total gadolinium / kg body weight of the gadolinium complexes of the title substances of examples id, 5c, 14c, 15c in rats (n = 3), blood samples were taken via a catheter in the In the carotis communis artery at different times (8 hours up to 24 hours pi), the metal content was determined by atomic emission spectrometry (ICP-AES) and converted to plasma values by means of a conversion factor (0.625). Elimination transformation time was calculated using special software (WinNonIin) from plasma concentrations. The results are presented in table 1.

Example 33: Visualization (MRT) of lymph node metastases and primary tumors following intravenous contrast agent administration in VX2 tumor-bearing rabbits

The illustrations in Figures 1 and 2 show lymph node pre-contrast MRI images as well as up to 24 hours after intravenous application of 50 μηιοΙ Gd / kg body weight of the title substance of example 1d) in rabbits with im implanted VX2 tumor The Ti-evaluated turbo-spin-echo images illustrate the strong signal increase in healthy lymph node tissue at certain times following the application of a contrast agent (15 to 60 minutes p.i.). Zones without increased lymph node signaling were diagnosed as metastases and histologically confirmed (H / E staining of lymph node section) (Figure 1).

Surprisingly, immediately after application, a clear enhancement in the primary tumor (particularly in the periphery) could also be observed (Figure 2). At later times (24 hours p.i.)> This enhancement also propagates toward the center of the tumor.

Example 34: MRT visualization of atherosclerotic plaques after intravenous contrast agent application in rats

The illustrations in Figure 3 show MR images of the aorta 6 or 24 hours after intravenous application of 50 μιηοΙ Gd / kg body weight of the title substances of example 1d) and example 14c in Watanabe rabbits (WHHL rabbits; genetically induced arteriosclerosis) and animals. of control without arteriosclerosis (white New Zealanders). T1 inversion and recovery images (IR-TFL, TR / TE / TI = 300 / 4.0 / 120 m, α 20 °) illustrate a strong signal increase in the atherosclerotic plaques of the WHHL rabbits, but not in the basal images or does not appear vascular in healthy control animals. Plaque location, particularly in the aortic arch as well as in the vascular passages, was confirmed by dyeing with Sudan-3. With this test, the utility of the compounds according to the invention as markers for atherosclerotic plaques could be shown.

Example 35: MRT visualization of inflammatory lesions and necrotic areas after intravenous contrast agent application in rats

By way of example, the illustrations in Figure 4 show MR images of inflammatory muscle lesions as well as necrotic areas at different times after intravenous application of 50 μηιοΙ Gd / kg body weight of the title substance of Example 14c in rats. Inflammation / necrosis was induced by intravenous application of Rose Bengal (20mg / kg; 24 hours before contrast medium application) and subsequent 20-minute irradiation with a xenon lamp. The turbo-spin-echo images analyzed Ti (1.5 T; sequence: T1-TSE; TR 451 ms, TE 8.7 ms) illustrate the strong signal increase in inflammation-modified tissue in short moments (up to 60 minutes pi) as well as the retar-given signal increase in central necrosis at time 24 hours pi

Example 36: MRT visualization of lymph nodes after intravenous contrast agent application in rats

By way of example, the illustrations show MR popliteal lymph node images at different times following intravenous application of 50 μιτιοΙ Gd / kg body weight of the title substance of example 5c), the title substance of example 14c) and the title substance. 15c) in rats. The turbo-spin-echo images analyzed Ti (1.5T; sequence: T1-TSE; TR 451 ms, TE 8.7 m) illustrate the strong desinal increase in functional tissue of lymph nodes in short moments (up to 60 minutes p.i.).

Table 1: Experimental and physicochemical data with reference to the example substances.

<table> table see original document page 82 </column> </row> <table>

R1 (w) = R1-water relaxivity; R1 (p) = R1 (w) = R1-relaxivity in plasma R2 (w) = R2-relaxivity in water; R 2 (p) = R 1 (w) = R 2 -plasma relaxivity;

Claims (22)

1. Complexes, characterized in that they contain perfluoroalkyl with a nitrogen-containing binding structure of the general formula I <formula> formula see original document page 83 </formula> in which R represents a 1-OH linked monosaccharide or oligosaccharide radical, in this case Q has the meaning of a group chosen from: δ-CO- (CH2) n »-eδ-ΝΗ- (ΟΗ2) η" -εδ- (CH2) m- £ where "is an integer of 1 and 5, em is an integer from 1 and 6, where δ indicates the binding position with the binding agent L, and ε represents the binding position with the radical R, or R has one of the following meanings because Q has the meaning of a direct bond: R means a polar radical chosen from the complexes K of the general formulas II through V, where R1 here signifies a hydrogen atom or metal ion equivalent of atomic numbers 20-29, 31- 33, 37-39, 42-44, 49 or 57-83, and the radicals R2, R3, R4, U and U1 have the ind meaning below, or • a 1-30 C-carbon chain bonded by -CO-, -NR7- or a direct bond to the L-linker, which may be straight or branched, saturated or unsaturated, and which is eventually 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 eventually be substituted by 1-2-OH1 groups 1-2 -NH2 groups, 1-2 -COOH groups, or 1-2 -SO3H1e groups which may eventually be substituted by 1-10 -OH1 groups 1-5 1-5 -COOH groups, -1 -2 groups SO 3 H, 1-5 -NH 2 groups, or 1-5 C 1 -C 4 alkoxy groups, wherein R 7 is H or C 1 -C 4 alkyl, R f is a perfluorinated, straight or branched carbon chain with the formula -CnF 2nE 1 wherein E represents a terminal atom fluorine, decolor, bromine, iodine or hydrogen, and η represents the numbers 4-30, K represents a metal complex of the general formula II, <formula> formula see original document page 84 </formula> R1 means to a hydrogen atom or metal ion equivalent of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83, provided that at least two R1 represent equivalent metal ions , R 2 and R 3, independent of each other, represent hydrogen, C 1 -C 7 -alkyl, benzyl, phenyl, -CH 2 OH or -CH 2 OCH 3, and U represent -C 6 H 4 -O-CH 2 -C-, - (CH 2) 1.5-ω, a phenyl group. -leno, -CH 2 -NHCO-CH 2 -CH (CH 2 COOH) -C 6 H 4 -i-, -C 6 H 4 - (OCH 2 CH 2) 0-IN (CH 2 COOH) -CH 2 -a> or a C 1 -C 12 alkylene group or - (CH 2) 712- C6H4-O is eventually interrupted by one or more oxygen atoms, 1 to 3 -NHCO groups, 1 to 3 -CONH groups and / or substituted by 1 to 3 groups- (CH2) o-5COOH, where ω represents the binding position with -CO-, or of the general formula III wherein R1 has the meaning mentioned above, R4 represents hydrogen or one metal ion equivalent mentioned in R11 and U1 represents-C6H4-O -CH2-CO- or a group - (CH2) p-, where ω means is the deletion position with -CO- and ρ is an integer between 1 and 4, or of the general formula IV <formula> formula see original document page 85 </formula> where R1 and R2 have the meaning mentioned above or of the general formulas VA or VB <formula> formula see original document page 85 </formula> where R1 has the meaning mentioned above, or the general formula Vl <formula> formula see original document page 86 </formula> above, or of the general formula Vll <formula> formula see original document page 86 </formula> wherein R1 and U1 have the meaning mentioned above, where ω means the binding position with -CO-, or the general formula Wherein R1 has the meaning mentioned above, and U2 represents a linear or branched, saturated or unsaturated C1 -C2 alkylene group optionally containing imino, phenylene, phenylenoxy, phenylenimino, amide, hydrazide, carbonyl, est groups r, oxygen, sulfur and / or nitrogen atom (s) and optionally substituted by niooxy, mercapto-, oxo-, thioxo-, carboxy-, carboxyalkyl, ester and / or amino groups and free acid groups optionally present in radical K may be present as organic and / or inorganic base salts or amino acids or amino acid amides, and L represents a radical chosen from radicals IXa) through (cc) below: <formula> formula see original document page 87 < / formula> where η 'and m', independent of each other, represent an integer between 0 and 4, in '+ n'> 1, and R8 and R8 ', independent of each other, are either -H or With m '+ n'> 1, each group - (CR8R8 ') - may be the same or different, and W is either a direct bond, -O- or a phenylene group, which may optionally be substituted by 1 to 4 hydroxy groups, eq 'is either 1, 2, 3 or 4, where α means the binding position of L with the complex Κ, β is the binding position of L with Qey represents the binding position of L with radical X, and X represents a group of formula (VI) wherein Y means a direct bond, a group -CO- or an NR6 group, wherein R6 represents -H or a straight or branched, saturated or unsaturated C1 -C15 carbon chain that may be interrupted by 1-4 O atoms, 1-3 -NHCO groups, 1-3 -CONH groups, 1-2 groups -SO 2, 1-2 sulfur atoms, 1 -3 -NH groups or 1 -2 phenylene groups, which may optionally be substituted by 1-2 OH groups, 1-2 NH 2 groups, 1 -2 -COOH groups or 1 -2 -SO 3 H groups, and which are optionally substituted by 1-10 OH groups, 1-5 -COOH groups, 1-2 -SO 3 H groups, 1-5 NH 2 groups, 1-5 C 1 -C 4 alkoxy groups, and G means - O- or -SO2-, if 's independent of each other means 1 or 2, t means O or 1 and r represents the binding position of X with L and ζ represents the binding position of X with Rf. Metal complexes according to claim 1, characterized in that the metal ion equivalent R1 is an atomic number element 21-29, 39, 42, 44 or 57-83. Metal complexes according to claim 1, characterized in that the metal ion equivalent R1 is an atomic number element 27, 29, 31-33, 37-39, 43, 49, 62, 64 , 70, 75 and 77. Metal complexes according to any one of claims 1 to 3, characterized in that R represents a monosaccharide radical of 5 to 6 carbon atoms or its deoxy compound, preferably glucose, mannose or galactose. Metal complexes according to any one of claims 1 to 3, characterized in that R is a radical chosen from: -C (0) CH20 [{CH2) 20} PR · -C (0) CH20CH [CH20CH (CH20R ') 2] 2-C (O) C H2OCH2C HICNjOCH1CHaOR' kh-R-iNt (CH2) 2OlpR'-N {[{CH2) 2OpR} 2-R '' NCH2C H (OH) CH2O H -NCH 1 CH (OH) CHaOH I 2 -R "NCH (CH 2 OH) CH (OH) CH 2 OH-NfCH (CH 2 OH) CH (OH) CHzOH I 2 -R-NCH 1 CH 2 OCH (CH 2 ORr) 2 I" RCH "CH 2 CH (CH 20 R ') 232-R" NCH2CH2OCH [CH2OCH (CH2OR ') 2] 2-R "NCH2CH2OCH2CHtCH2OCH (CH2OR') 2J2-NCHlCHaOCHINCOROR ^ zk-N {CH2CH [CH2OCH (CH2OR-) 2I} 2-R" NCH2CH (OH) ) CH (OH) CH 2 OH-N t CH 2 CH (OH) CH (OH) CH (OH) CH (OH) CH 2 OHhe a complex of formula (II), wherein R 11 R 2, R 3 and U are as defined in claim 1, and ρ is 1 , 2, 3, 4, 5, 6, 7, 8 or 9. Metal complexes according to any one of claims 1 to 5, characterized in that K represents a metal complex of the general formula II. Metal complexes according to claim 6, characterized in that R 2 and R 3 independent of each other means hydrogen or C 1 -C 4 alkyl. Metal complexes according to any one of claims 1 to 7, characterized in that E in the formula -CnF2nE means a fluorine atom. Metal complexes according to any one of claims 1 to 8, characterized in that L in the general formula I represents the radical Iysine (Vc). Metal complexes according to any one of Claims 1 to 8, characterized in that L in the general formula I represents a diamine radical (Va) or (Vb). Metal complexes according to any one of claims 1 to 10, characterized in that U in the metal complex K represents -CH2- or -C6H4-O-CH2-U, where ω represents the binding position with -C0-. Use of metal complexes as defined in claim 2, characterized in that it is for the preparation of contrast agents for use in NMR and X-ray diagnostics. Use of metal complexes according to claim-12, characterized in that it is for the preparation of contrast agents for infarction and necrosis imaging. Use of metal complexes as defined in claim 3, characterized in that it is for the preparation of contrast agents for use in radiodiagnosis and radiotherapy. Use of metal complexes as defined in claim-2, characterized in that it is for the preparation of contrast agents for lymphography to diagnose changes in the lymphatic system. Use of metal complexes as defined in claim-2, characterized in that it is for the preparation of contrast agents for the diagnosis of inflammatory diseases. Use of metal complexes as defined in claim 2, characterized in that it is for the preparation of contrast agents for the visualization of atherosclerotic plaques. Use of metal complexes as defined in claim-2, characterized in that it is for the preparation of contrast agents for the diagnosis of cardiovascular disease. Use of metal complexes as defined in claim-2, characterized in that it is for the preparation of contrast agents for tumor imaging. Use of metal complexes as defined in claim 2, characterized in that it is for the preparation of contrast agents for equilibrium radioisotopic imaging. Pharmaceutical composition, characterized in that it contains at least one physiologically compatible compound as defined in claims 1 to 11, possibly with the usual additives in galenic formulations. A process for preparing perfluoroalkyl-containing complexes with a nitrogen-containing binding structure of formula I with K signifying a metal complex of formulas II through IV as defined in claim 1, and L1 Q1 X1 R, Rf with the meanings as defined in claim 1, said process being characterized by reacting a carboxylic acid of the general formula IIa <formula> formula see original document page 91 </formula> wherein R5 means a metal ion equivalent of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83 or a carboxyl protecting group, and R2, R3 and U have the meanings mentioned. , or a carboxylic acid of the general formula IIIa wherein R4, R5 and U1 have the meaning mentioned above, or a carboxylic acid of the general formula IVa wherein R5 and R2 have the meaning mentioned, or a carboxylic acid of the general formula Va or Vb <formula> formula see original document page 92 </formula> where R5 has the meaning mentioned or a carboxylic acid of the general formula Vla <formula> formula see original document page 92 </formula> R5 has the meaning mentioned or a carboxylic acid of the general formula Vlla <formula> formula see original document page 92 </formula> where R5 and U1 have the mentioned meanings <formula> formula see original document page 93 </formula> R5 has the meaning mentioned above, and U2 is as defined in claim 1, optionally activated with an amine of the formula wherein L, R1 Rf, Q and X have the meanings given in claim-1 in a copulation reaction and eventually subsequent dissociation of protecting groups which may be present to form a metal complex of the general formula wherein R5 means a after dissociation, if these protecting groups are reacted in a subsequent step, as is known per se, with at least one metal oxide or metal salt of an element atomic numbers 21-29, 31- 33, 37-39, 42-44, 49 or 57-83 and, if desired, substitute acidic hydrogen atoms which may be present with organic and / or inorganic cations, amino acids or amino acid amides.