DE102005033903B4 - Perfluoroalkyl-containing complexes, processes for their preparation, and their use and pharmaceutical compositions containing them - Google Patents

Abstract

wobei
R entweder
einen über die 1-OH- gebundenen Mono- oder Oligosaccharidrest darstellt, der optional peralkyliert ist, in diesem Falle hat Q die Bedeutung einer Gruppe ausgewählt aus δ-CO-(CH₂)_n''-ε δ-NH-(CH₂)_n''-ε δ-(CH₂)_m-ε wobei
n'' eine ganze Zahl ist von 1 und 5, und
m eine ganze Zahl ist von 1 und 6, und
wobei δ die Bindungsstelle zum Linker L angibt und ε die Bindungsstelle zum Rest R;
oder
R hat eine der folgenden Bedeutungen, dann hat Q die Bedeutung einer direkten Bindung: R bedeutet einen polaren Rest ausgewählt aus
• den Komplexen K der allgemeinen Formeln II bis VIII', wobei R¹ hier ein Wasserstoffatom oder ein Metallionenäquivalent der Ordnungszahlen 20–29, 31–33, 37–39, 42–44, 49 oder 57–83 bedeutet,
und die Reste R², R³, R⁴, U, U² und U¹ die unten angegebene Bedeutung aufweisen,
oder
• eine...Perfluoroalkyl-containing metal complexes with N-alkyl group of the general formula I.

in which
R either
represents a via the 1-OH bonded mono- or Oligosaccharidrest which is optionally peralkylated, in this case Q has the meaning of a group selected from δ-CO- (CH ₂ ) _{n "} -ε δ-NH- (CH ₂ ) _{n "} -ε δ- (CH ₂ ) _m -ε in which
n '' is an integer of 1 and 5, and
m is an integer of 1 and 6, and
where δ indicates the binding site to the linker L and ε the binding site to the radical R;
or
R has one of the following meanings, then Q has the meaning of a direct bond: R is a polar radical selected from
The complexes K of the general formulas II to VIII ', where R ¹ here denotes a hydrogen atom or a metal ion equivalent of atomic numbers 20-29, 31-33, 37-39, 42-44, 49 or 57-83,
and the radicals R ² , R ³ , R ⁴ , U, U ² and U ^{1 have} the meaning given below,
or
• a ...

Description

The The invention relates to the articles characterized in the claims, namely perfluoroalkyl-containing Metal complexes with N-alkyl group of the general formula I, process for their production and their use in NMR and X-ray diagnostics, Radiodiagnostics and radiotherapy, as well as in MRI lymphography. The perfluoroalkyl-containing metal complexes find application in the Nuclear Magnetic Resonance Imaging (MRI) to display different physiological and pathophysiological structures and thus to Improvement of diagnostic information, namely localization and the degree of illness, selection and success of a targeted Therapy and for prophylaxis.

The Compounds of the invention are in a very special way for the lymphography, for the tumor diagnostics and for infarct and necrosis imaging suitable and characterized by excellent compatibility out.

In the field of nuclear magnetic resonance some fluorine-containing compounds are known which can be used in the field of imaging. In most cases, however, such compounds are proposed only for use in fluorine-19 imaging and are only suitable for this application. Such compounds are described, for example, in US Patent 4,639,364 (Mallinckrodt), DE 4203254 (Max Planck Society), WO 93/07907 (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 can be used for imaging are in US 5,362,478 (VIVORX) US 4,586,511 ; DE 4008179 (Schering), WO 94/05335 and WO 94/22368 (both Molecular Biosystems), EP 292,306 (TERUMO Kabushiki Kaisha), EP 628,316 (TERUMO Kabushiki Kaisha) and DE 4317588 (Schering).

While compounds containing the elements fluorine and iodine do not interact between the two nuclei, in compounds containing fluorine and paramagnetic centers (radicals, metal ions) an intense interaction takes place, resulting in a shortening of the relaxation time of the fluorine core express. The size of this effect depends on the number of unpaired electrons of the metal ion (Gd ³⁺ > Mn ²⁺ > Fe ³⁺ > Cu ²⁺ ) and on the distance between the paramagnetic ion and the ¹⁹ F atom.

ever more unpaired electrons of the metal ion are present and each closer to this to be brought to the fluorine, the greater the shortening of the Relaxation time of the fluorine core.

The shortening of the relaxation time as a function of distance from the paramagnetic ion becomes all nuclei with an uneven spin number noticeable, as well as the proton, and therefore gadolinium compounds are widely used as contrast agents in magnetic resonance imaging (Magnevist ^®, Prohance ^®, Omniscan ^®, Dotarem ^®) ,

However, the ¹ H-MR imaging ^(1H-MRI) is the relaxation time T ¹ or T ² of the protons, that is measured, mainly the protons of water, and not the reaction time of the fluorine nuclei, and used for imaging. The quantitative measure for the shortening of the relaxation time is the relaxivity [L / mmol · s]. To shorten the relaxation times, complex paramagnetic ions are successfully used. The following table shows the relaxivity of some commercial preparations:

In These compounds only interact with protons and the gadolinium ion. For So these contrast agents in water will have a relaxivity of about 4 [L / mmol · s] observed.

It So be successful for MR imaging has both fluorine compounds for fluorine-19 imaging, in which the shortened Relaxation time of the fluorine core is exploited, as well as not Fluorine-containing compounds in which the relaxation time of the protons of water is used.

at the introduction a perfluorocarbon-containing radical into a paramagnetic Contrast agent, that is in the combination of properties previously only available for fluorine-imaging compounds were known to be suitable, with compounds responsible for proton imaging surprisingly, it also increases the relaxivity concerning the protons of water is rapidly increasing. she now reaches values of 10-50 [L / mmol · s] in Comparison with values between 3.5 and 3.8 [L / mmol · s] as for some Trading products have already been listed in the above table.

Out DE 196 03 033 , WO 99/01161, DE 19914101 . DE 10040381 . DE 10040858 and already known perfluoroalkyl-containing metal complexes. However, these compounds are not satisfactorily applicable for all applications, since the compatibility is usually insufficient. Thus, there is still a need for MRI contrast agents that both have excellent imaging properties and are also excellently compatible to preserve the non-invasive nature of the diagnostic method. This is important, for example, if tumors, including distant metastases, are to be diagnosed and thus a distribution of the contrast agent over the entire body is to be achieved.

Malignant Tumors are frequently metastasized in regional lymph nodes, including several lymph node stations can be involved. Thus, lymph node metastases in about 50-69% of all patients with malignant Tumors found (Elke, Lymphographie, in: Frommhold, Stender, Thurn (eds.), Radiological Diagnosis in Clinic and Practice, Volume IV, Thieme Verlag Stuttgart, 7th ed., 434-496, 1984). The diagnosis of a metastatic Infection of lymph nodes is with regard to therapy and prognosis malignant diseases of great Importance. With the modern imaging methods (CT, US and MRI) lymphoid dislocations of malignant tumors become insufficient recognized, since usually only the size of the lymph node as Diagnostic criterion can be used. These are small metastases in non-enlarged lymph nodes (<2 cm) not of lymph node hyperplasia without distinguishing malignant infestation (Steinkamp et al., Sonography and Magnetic Resonance Imaging: Differential Diagnosis of reactive lymph node enlargement and Lymph node metastases on the neck, Radiol. diagn. 33: 158, 1992).

Desirable would it be, that with use of specific contrast media lymph nodes with metastatic infestation and hyperplastic lymph nodes can be.

Known is the direct X-ray lymphography (Injection of an oily Contrast agent suspension in a prepared lymphatic vessel) as one only rarely used invasive method, the few lymph drainage stations can represent.

experimental In animal experiments, fluorescence-labeled dextrans are also used, to observe the lymphatic drainage after their interstitial application to be able to. All common Markers for the presentation of lymphatic and lymph nodes after interstitial / intracutaneous Application is so common that it is substances with particulate character ("particulates", e.g., emulsions and nanocrystal suspensions) or large polymers (see WO 90/14846). The preparations described so far proved however, due to their lack of local and systemic compatibility as well as their low Lymphgängigkeit, which causes insufficient diagnostic efficiency, as yet not optimal for the indirect lymphography suitable.

There the appearance of lymph nodes central to early detection metastatic infestation in cancer patients, there is a great need at lymph-specific contrast agent preparations for the diagnosis of corresponding changes of the lymphatic system, which are characterized by very good tolerability. The lymphatic system according to the present invention comprises both the lymph nodes as well as the lymphatic vessels. The substances of the present Invention are therefore for the diagnosis of changes in the lymphatic system suitable, preferably for the diagnosis of changes in the lymph nodes and / or of the lymphatic vessels, in particular Diagnosis of metastases in the lymph nodes.

Highest possible contrast agent loading and high stability are just as desirable as diagnostically relevant, as even as possible lymphatic enrichment across multiple lymphatic stations. The burden on the whole organism should be kept low by rapid and complete excretion of the contrast agent. A rapid onset of action as early as possible within a few hours after the administration of contrast medium is of importance for radiological practice. Good systemic compatibility is needed dig.

Not last it is desirable have lymph-specific contrast agents available that allow in a diagnostic session both the primary tumor and a possible lymph node metastasis to show.

One Another important area in medicine is detection, localization and monitoring of necrosis or infarction. So the myocardial infarction is not one stationary Process but a dynamic process that is about one longer Period (weeks to months). The disease runs in about three Phases that are not sharply separated, but overlapping are. The first phase, the development of myocardial infarction, includes the 24 hours after the infarction, in which the destruction like a shock wave (Wave front phenomenon) from the subendocardium to the myocardium progresses. The second phase, the already existing infarct, includes the stabilization of the area, in the fiber formation (fibrosis) takes place as a healing process. The third Phase, the healed infarction, begins after all destroyed tissue by fibrous Scar tissue is replaced. While This period will be a major restructuring.

To today is not a precise one and reliable Procedures known that the current stage of myocardial infarction makes diagnosable at the living patient. For the assessment of a myocardial infarction It is crucial to know how big the share is of the tissue lost at the heart attack and at which point the loss occurred because of this knowledge depends on the type of therapy.

infarctions not only in the myocardium, but also in other tissues, especially in the brain.

During the Infarction is curable to some extent, can cause necrosis, the localized tissue death, only the harmful consequences for the residual organism prevented or at least mitigated. Necroses can on In many ways arise: injuries, chemicals, oxygen deficit or by radiation. As with the infarction, the knowledge of extent and kind of necrosis important for the further medical Action.

Early on, therefore, attempts were made to improve the localization of infarcts and necroses by using contrast agents in non-invasive procedures such as scintigraphy or magnetic resonance imaging. In the literature, attempts to use porphyrins for necrosis imaging occupy a large space. The results obtained, however, give a contradictory picture. In addition, porphyrins tend to deposit in the skin, resulting in photosensitization. Sensitization can last for days, even weeks. This is an undesirable side effect of using porphyrins as diagnostics. In addition, the therapeutic index for the porphyrins is very small, since, for example, for Mn-TPPS an effect only starts at a dose of 0.2 mmol / kg, but the LD ₅₀ is already at 0.5 mmol / kg. Non-porphyrin scaffold-derived contrast agents for necrosis and infarct imaging are known in US Pat DE 19744003 (Schering AG), DE 19744004 (Schering AG) and WO 99/17809 (EPIX). So far, however, there are no compounds that can be satisfactorily used as a contrast agent in infarction and necrosis imaging.

The same problem exists in the range of compounds used can be to diagnose thrombi or atherosclerotic plaques: it There are no compounds satisfactorily used as a contrast agent Representation of thrombi or atherosclerotic plaques used can be and at the same time characterized by excellent compatibility.

task The invention was therefore to contrast media available on the one hand, outstanding imaging properties as MRI have contrast agents, and in particular for the tumor and necrosis imaging and / or lymphography and / or blood pool imaging and / or imaging of thrombi or atherosclerotic Plaques are suitable, and at the same time characterized by excellent compatibility distinguished.

wobei
R entweder
einen über die 1-OH- gebundenen Mono- oder Oligosaccharidrest darstellt, der optional peralkyliert ist,
in diesem Falle hat Q die Bedeutung einer Gruppe ausgewählt aus δ-CO-(CH₂)_n''-ε δ-NH-(CH₂)_n''-ε δ-(CH₂)_m-ε wobei
n'' eine ganze Zahl ist von 1 und 5, und
m eine ganze Zahl ist von 1 und 6, und
wobei δ die Bindungsstelle zum Linker L angibt und ε die Bindungsstelle zum Rest R;
oder
R hat eine der folgenden Bedeutungen, dann hat Q die Bedeutung einer direkten Bindung: R bedeutet einen polaren Rest ausgewählt aus

• • den Komplexen K der allgemeinen Formeln II bis VVIII', wobei R¹ hier ein Wasserstoffatom oder ein Metallionenäquivalent der Ordnungszahlen 20–29, 31–33, 37–39, 42–44, 49 oder 57–83 bedeutet, und die Reste R², R³, R⁴, U und U¹ die unten angegebene Bedeutung aufweisen, oder
• • eine über -CO-, -NR⁶- oder eine direkte Bindung an den Linker L gebundene Kohlenstoffkette mit 1–30 C-Atomen,
• – die geradlinig oder verzweigt, gesättigt oder ungesättigt sein kann,
• – und die gegebenenfalls unterbrochen ist durch 1–10 Sauerstoffatome, 1–5 -NHCO-Gruppen, 1–5 -CONH-Gruppen, 1–2 Schwefelatome, 1–5 -NH-Gruppen oder 1-2 Phenylengruppen, die gegebenenfalls mit 1–2 OH-Gruppen, 1–2 NH₂-Gruppen, 1–2 -COOH-Gruppen, oder 1–2 -SO₃H-Gruppen substituiert sein können,
• – und die gegebenenfalls substituiert ist mit 1–10 -OH-Gruppen, 1–5 -COOH-Gruppen, 1–2 -SO₃H-Gruppen, 1–5 NH₂-Gruppen, 1–5 C₁-C₄-Alkoxygruppen, wobei R⁶ H oder C₁-C₄-Alkyl bedeutet,

R_f eine perfluorierte, geradkettige oder verzweigte Kohlenstoffkette mit der Formel -C_nF_2nE ist, in der E ein endständiges Fluor-, Chlor-, Brom-, Jod- oder Wasserstoffatom darstellt und n für die Zahlen 4–30 steht,
X für eine Gruppe der Formel (XI) steht ρ-Y-(CH₂)_s-(G)_t-(CH₂)_s'-ζ (XI)und G entweder -O- oder -SO₂- bedeutet,
s und s' unabhängig voneinander entweder 1 oder 2 bedeuten, t entweder 0 oder 1 bedeutet und
ρ die Bindungsstelle von X zu L darstellt und ξ die Bindungsstelle von X zu R_f darstellt.The object of the invention is achieved by perfluoroalkyl-containing complexes with N-alkyl group of the general formula I.

in which
R either
represents a mono- or oligosaccharide radical attached via the 1-OH, which is optionally peralkylated,
in this case, Q has selected the meaning of a group δ-CO- (CH ₂ ) _{n "} -ε δ-NH- (CH ₂ ) _{n "} -ε δ- (CH ₂ ) _m -ε in which
n '' is an integer of 1 and 5, and
m is an integer of 1 and 6, and
where δ indicates the binding site to the linker L and ε the binding site to the radical R;
or
R has one of the following meanings, then Q has the meaning of a direct bond: R is a polar radical selected from

• The complexes K of the general formulas II to VVIII ', where R ¹ here represents a hydrogen atom or a metal ion equivalent of atomic numbers 20-29, 31-33, 37-39, 42-44, 49 or 57-83, and the radicals R ² , R ³ , R ⁴ , U and U ^{1 have} the meaning given below, or
• • a carbon chain with 1-30 C atoms bonded via -CO-, -NR ⁶ - or a direct bond to the linker L,
• - which may be straight or branched, saturated or unsaturated,
• - and which is optionally interrupted by 1-10 oxygen atoms, 1-5 -NHCO groups, 1-5 -CONH groups, 1-2 sulfur atoms, 1-5 -NH groups or 1-2 phenylene groups, optionally with 1 -2 OH groups, 1-2 NH ₂ groups, 1-2 -COOH groups, or 1-2 -SO ₃ H groups may be substituted,
• - 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, where R ^{6 is} H or C ₁ -C ₄ -alkyl,

R _{f is} a perfluorinated, straight-chain or branched carbon chain of the formula -C _n F _2n E, in which E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n represents the numbers 4-30,
X represents a group of the formula (XI) ρ-Y- (CH ₂ ) _s - (G) _t - (CH ₂ ) _s' - (XI) and G is either -O- or -SO ₂ -,
s and s' independently of one another are either 1 or 2, t is either 0 or 1 and
ρ represents the binding site from X to L and ξ represents the binding site from X to R _f .

in der
R¹ ein Wasserstoffatom oder ein Metallionenäquivalent der Ordnungszahlen 21–29, 31–33, 37–39, 42–44, 49 oder 57–83 bedeutet,
mit der Maßgabe, dass mindestens zwei R¹ für Metallionenäquivalente stehen
R² und R³ unabhängig voneinander Wasserstoff, C₁-C₇-Alkyl, Benzyl, Phenyl, -CH₂OH oder -CH₂OCH₃ darstellen und
U -C₆H₄-O-CH₂-ω-, -(CH₂)_1-5-ω, eine Phenylengruppe, -CH₂-NHCO-CH₂-CH(CH₂COOH)-C₆H₄-ω-, -C₆H₄-(OCH₂CH₂)_0-1-N(CH₂COOH)-CH₂-ω oder eine gegebenenfalls durch ein oder mehrere Sauerstoffatome, 1 bis 3 -NHCO-, 1 bis 3 -CONH-Gruppen unterbrochene und/oder mit 1 bis 3-(CH₂)_0-5COOH-Gruppen substituierte C₁-C₁₂-Alkylen- oder -(CH₂)_7-12-C₆H₄-O-Gruppe darstellt,
wobei ω für die Bindungsstelle an -CO- steht,
oder
der allgemeinen Formel III

in der R¹ die oben genannte Bedeutung hat, R⁴ Wasserstoff oder ein unter R¹ genanntes Metallionenäquivalent darstellt und U¹ -C₆H₄-O-CH₂-ω- oder eine Gruppe -(CH₂)_p'- darstellt, wobei ω die Bindungsstelle an -CO- bedeutet und p' eine ganze Zahl ist zwischen 1 und 4,
oder der allgemeinen Formel IV

in der R¹ und R² die oben genannte Bedeutung haben
oder der allgemeinen Formel VA oder VB

in der R¹ die oben genannte Bedeutung hat,
oder der allgemeinen Formel VI

in der R¹ die oben genannte Bedeutung hat,
oder der allgemeinen Formel VII

in der R¹ und U¹ die oben genannte Bedeutung haben, wobei ω die Bindungsstelle an -CO- bedeutet
oder der allgemeinen Formel VIII

in der R¹ die oben genannte Bedeutung hat,
und U² eine gegebenenfalls Imino-, Phenylen-, Phenylenoxy-, Phenylenimino-, Amid-, Hydrazid-, Carbonyl-, Estergruppen-, Sauerstoff-, Schwefel- und/oder Stickstoff-Atom(e)- enthaltende, gegebenenfalls durch Hydroxy-, Mercapto-, Oxo-, Thioxo-, Carboxy-, Carboxyalkyl, Ester-, und/oder Aminogruppe(n) substituierte geradkettige oder verzweigte, gesättigte oder ungesättigte C₁-C₂₀ Alkylengruppe darstellt,
oder der allgemeinen Formel VIII'

in der R¹ die oben genannte Bedeutung hat,
und im Rest K gegebenenfalls vorhandene freie Säuregruppen gegebenenfalls als Salze organischer und/oder anorganischer Basen oder Aminosäuren oder Aminosäureamide vorliegen können,
und
L einen Rest ausgewählt aus den nachfolgenden Resten IXa) bis IXg) darstellt:

wobei q' entweder 1, 2, 3 oder 4 ist, und
wobei α die Bindungsstelle von L an den Komplex K bedeutet, β die Bindungsstelle von L zum Rest Q ist und γ die Bindungsstelle von L zum N der Formel (I) darstellt,
und
A für eine geradlinige oder verzweigte, gesättigte oder ungesättigte C₁-C₁₅ Kohlenstoffkette steht, die von 1–4 O-Atomen, 1–3 -NHCO- Gruppen, 1–3 -CONH- Gruppen, 1–2 -SO₂-Gruppen, 1–2 Schwefelatomen, 1–3 -NH-Gruppen oder 1–2 Phenylengruppen, die gegebenenfalls mit 1–2 -OH Gruppen, 1–2 -NH₂ Gruppen, 1–2 -COOH Gruppen, oder 1–2 -SO₃H Gruppen substituiert sein können,
unterbrochen sein kann,
und die gegebenenfalls substituiert ist mit 1–10 -OH Gruppen, 1–5 -COOH Gruppen, 1–2 -SO₃H Gruppen, 1–5 -NH₂ Gruppen, 1–5 C₁-C₄-Alkoxygruppen,
darstellt.K stands for a metal complex of the general formula II,

in the
R ¹ is a hydrogen atom or a metal ion equivalent of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83 means
with the proviso that at least two R ^{1 are} metal ion equivalents
R ² and R ³ independently of one another represent hydrogen, C ₁ -C ₇ -alkyl, benzyl, phenyl, -CH ₂ OH or -CH ₂ OCH ₃ and
U -C ₆ H ₄ -O-CH ₂ -ω-, - (CH ₂ ) _1-5 -ω, a phenylene group, -CH ₂ -NHCO-CH ₂ -CH (CH ₂ COOH) -C ₆ H ₄ - ω-, -C ₆ H ₄ - (OCH ₂ CH ₂ ) _0-1 -N (CH ₂ COOH) -CH ₂ -ω or an optionally substituted by one or more oxygen atoms, 1 to 3 -NHCO-, 1 to 3 - CONH groups interrupted and / or with 1 to 3 (CH ₂ ) _0-5 COOH groups substituted C ₁ -C ₁₂ alkylene or - (CH ₂ ) _7-12 C ₆ H ₄ -O group represents .
where ω is -CO- for the binding site,
or
the general formula III

in which R ^{1 has} the abovementioned meaning, R ^{4 represents} hydrogen or a metal ion equivalent mentioned under R ¹ and U ¹ -C ₆ H _{4 represents} -O-CH ₂ -ω- or a group - (CH ₂ ) _{p '} -, where ω is the binding site to -CO- and p 'is an integer between 1 and 4,
or the general formula IV

in which R ¹ and R ^{2 have} the abovementioned meaning
or the general formula VA or VB

in which R ^{1 has} the abovementioned meaning,
or the general formula VI

in which R ^{1 has} the abovementioned meaning,
or the general formula VII

in which R ¹ and U ^{1 have} the abovementioned meaning, where ω is the binding site to -CO-
or the general formula VIII

in which R ^{1 has} the abovementioned meaning,
and U ^{2 is} an optionally imino, phenylene, phenyleneoxy, phenyleneimino, amide, hydrazide, carbonyl, ester group, oxygen, sulfur and / or nitrogen atom (s) -containing, optionally substituted by hydroxyl , mercapto, oxo, thioxo, carboxy, carboxyalkyl, ester and / or amino group (s) substituted straight or branched, saturated or unsaturated C ₁ -C ₂₀ alkylene group,
or the general formula VIII '

in which R ^{1 has} the abovementioned meaning,
and in the remainder K optionally present free acid groups may optionally be present as salts of organic and / or inorganic bases or amino acids or amino acid amides,
and
L represents a radical selected from the following radicals IXa) to IXg):

where q 'is either 1, 2, 3 or 4, and
where α is the binding site of L to the complex K, β is the binding site of L to the radical Q and γ represents the binding site of L to N of the formula (I),
and
A is a linear or branched, saturated or unsaturated C ₁ -C ₁₅ carbon chain which is of 1-4 O atoms, 1-3 -NHCO groups, 1-3 -CONH groups, 1-2 -SO ₂ - Groups, 1-2 sulfur atoms, 1-3 -NH groups or 1-2 phenylene groups optionally with 1-2 -OH groups, 1-2 -NH ₂ groups, 1-2 -COOH groups, or 1-2 SO ₃ H groups can be substituted,
can be interrupted
and which is optionally substituted with 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,
represents.

In a preferred embodiment, A is a radical - (CH ₂ ) _{s "} - (O) _{t '} - (CH ₂ ) _s''' - Z where s' represents an integer between 1 and 4,
s''' represents an integer between 0 and 4,
t 'is 0 or 1, and
Z is either -H, -OH, or -COOH.

In a preferred embodiment G is the group -O-.

In another preferred embodiment, Q has the meaning of a group δ-CO- (CH ₂ ) _{n "} -ε in which
n '' is an integer of 1 and 5, preferably n '' is 1, 2 or 3.

In a preferred embodiment, the radical R attached to the linker L via -CO-, -NR ⁷ - or a direct bond (Q is a direct bond) is a carbon chain having 1-30 C atoms and interrupted by from 1 to 10 oxygen atoms and / or substituted with 1-10 -OH groups. In a particularly preferred embodiment, R is a C ₁ -C ₁₅ carbon chain bonded via -CO-, -NR ⁷ - or a direct bond to L which is interrupted by 1 to 8 oxygen atoms and / or substituted by 1-8 OH groups ,

In a particularly preferred embodiment of the present invention, R is selected from one of the following radicals: -C (O) CH ₂ O [(CH ₂ ) ₂ O] _p R ' -C (O) CH ₂ OCH [CH ₂ OCH (CH ₂ OR ') ₂ ] ₂ -C (O) CH ₂ OCH ₂ CH [CH ₂ OCH (CH ₂ OR ') ₂ ] ₂ -R''N [(CH ₂ ) ₂ O] _p R ' -N {[(CH ₂ ) ₂ O] _p R '} ₂ -R''NCH ₂ CH (OH) CH ₂ OH -N [CH ₂ CH (OH) CH ₂ OH] ₂ -R''NCH (CH ₂ OH) CH (OH) CH ₂ OH -N [CH (CH ₂ OH) CH (OH) CH ₂ OH] ₂ -R''NCH [CH ₂ OCH (CH ₂ OR ') ₂ ] ₂ -R''NCH ₂ CH [CH ₂ OCH (CH ₂ OR ') ₂ ] ₂ -R''NCH ₂ CH ₂ OCH [CH ₂ OCH (CH ₂ OR ') ₂ ] ₂ -R''NCH ₂ CH ₂ OCH ₂ CH [CH ₂ OCH (CH ₂ OR ') ₂ ] ₂ -N {CH [CH ₂ OCH (CH ₂ OR ') ₂ ] ₂ } ₂ -N {CH ₂ CH [CH ₂ OCH (CH ₂ OR ') ₂ ] ₂ } ₂ -R''NCH ₂ CH (OH) CH (OH) CH (OH) CH (OH) CH ₂ OH -N [CH ₂ CH (OH) CH (OH) CH (OH) CH (OH) CH ₂ OH] ₂ and a complex of formula (II), with Q meaning direct bonding,
wherein R ¹ , R ² , R ³ and U are as defined above for formula (II),
p is either 1, 2, 3, 4, 5, 6, 7, 8 or 9
R 'is either H or CH ₃ and R "is either H or C ₁ to C ₄ alkyl.
Preferably, p is 1, 2, 3, or 4.

• Cassel 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
• Liu et al., Chem. Commun., 2002, 594
• Mitchell et al., Heterocyclic Chem, 1984, 697–699
• Bartsch et al., J. Org. Chem, 1984, 4076–4078
• Keana et al., J. Org. Chem, 1983, 2647–2654

The polar residues listed here are purchased goods or are presented according to methods described in the literature.

• Cassel 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
• Liu et al., Chem. Commun., 2002, 594
• Mitchell et al., Heterocyclic Chem, 1984, 697-699
• Bartsch et al., J. Org. Chem, 1984, 4076-4078
• Keana et al., J. Org. Chem., 1983, 2647-2654

In a very particularly preferred embodiment, R is a residue attached via -CO- to L of the formula: -C (O) CH ₂ O [(CH ₂ ) ₂ O] _p R '
with p and R 'in the meaning indicated above, particularly preferably R' is the group CH ₃ .

is the compound of the invention intended for use in NMR diagnosis, the metal ion must the signal-giving group be paramagnetic. These are in particular the divalent and trivalent ions of the elements of the atomic numbers 21-29, 42, 44 and 58-70. Suitable ions are, for example, the chromium (III) -, iron (II) -, Cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), Samarium (III) and Ytterbium (III) ions. Because of its strong magnetic Moments are particularly preferred gadolinium (III), terbium (III) -, Dysprosium (III), holmium (III), erbium (III), iron (III) and manganese (II) ions.

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

is the compound of the invention intended for use in X-ray diagnostics, Thus, the metal ion is preferably derived from an element of higher atomic number to obtain sufficient X-ray absorption. It has been found that for this purpose diagnostic means that a physiologically tolerable Complex salt with metal ions of elements of atomic numbers 25, 26 and 39 and 57-83 contain, are suitable.

Prefers are manganese (II), iron (II), iron (III), praseodymium (III), neodymium (III), Samarium (III), gadolinium (III), ytterbium (III) or bismuth (III) ions, especially dysprosium (III) ions and yttrium (III) ions.

Any azide hydrogen atoms present in R ¹ , that is to say those which have not been substituted by the central ion, may optionally be replaced in whole or in part by cations of inorganic and / or organic bases or amino acids or amino acid amides.

suitable inorganic cations are, for example, the lithium ion, the potassium ion, the calcium ion, and especially the sodium ion. Suitable cations Organic bases include those of primary, secondary or tertiary Amines, such as ethanolamine, diethanolamine, morpholine, Glucamine, N, N-dimethylglucamine and especially N-methylglucamine. Suitable cations of amino acids are for example those of lysine, arginine and ornithine as well as the amides of otherwise acidic or neutral amino acids.

Especially preferred compounds of the general formula I are those with the macrocycle K of the general formula II.

The radical U in the metal complex K is preferably -CH ₂ - or C ₆ H ₄ -O-CH ₂ -ω, where ω is the binding site on -CO-.

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

• – eine lineare Alkylengruppe mit 1 bis 6 C-Atomen, insbesondere 2, 3 oder 4 C-Atomen, oder
• – eine lineare Alkylengruppe mit 1 bis 6 C-Atomen, insbesondere 2, 3 oder 4 C-Atomen, die von 1 O-Atom unterbrochen ist, oder
• – eine lineare Alkylengruppe mit 1 bis 6 C-Atomen, insbesondere 2, 3 oder 4 C-Atomen, die eine -NHCO- Gruppe enthält.

The radical U ² in the metal complex K is preferably

• A linear alkylene group having 1 to 6 C atoms, in particular 2, 3 or 4 C atoms, or
• A linear alkylene group having 1 to 6 C atoms, in particular 2, 3 or 4 C atoms, which is interrupted by 1 O atom, or
• A linear alkylene group having 1 to 6 C atoms, in particular 2, 3 or 4 C atoms, which contains an -NHCO group.

In a particularly preferred embodiment, U ^{2 is} an ethylene group.

The alkyl groups R ² and R ³ in the macrocycle of the general formula II may be straight-chain or branched. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl. Preferably, R ² and R ³ independently of one another are hydrogen or C ₁ -C ₄ -alkyl.

In a very particularly preferred embodiment, R ^{2 is} methyl and R ^{3 is} hydrogen.

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

In a preferred embodiment of the invention R is a monosaccharide radical having 5 or 6 C atoms, preferably glucose, mannose, galactose, ribose, arabinose or Xylose or its deoxysugar such as 6-deoxygalactose (Fucose) or 6-deoxymannose (rhamnose) or their peralkylated Derivatives. Particularly preferred are glucose, mannose and galactose, and their peralkylated derivatives, especially mannose and peralkylated Mannose.

Peralkylated mono- or oligosaccharides may be alkylated with identical or different linear or branched C ₁ -C ₆ -alkyl groups, preferably they are per-methylated.

• • einer über -CO-, -NR⁶- oder eine direkte Bindung an den Linker L gebundene Kohlenstoffkette mit 1–15 C-Atomen, die geradlinig oder verzweigt, gesättigt oder ungesättigt sein kann, und die gegebenenfalls unterbrochen ist durch 1–10 Sauerstoffatome, und die gegebenenfalls substituiert ist mit 1–10 -OH-Gruppen, wobei R⁶ H oder C₁-C₄ Alkyl bedeutet,
• • und einem Komplex der Formel (II),

wobei R¹, R², R³ und U wie oben für Formel (II) definiert sind. Von den erfindungsgemäßen Verbindungen der allgemeinen Formel I sind weiterhin solche bevorzugt, in denen R_f -C_nF_2n+1 bedeutet; d.h. E in der Formel -C_nF_2nE bedeutet ein Fluoratom. n steht vorzugsweise für die Zahlen 4–15. Ganz besonders bevorzugt sind die Reste -C₄F₉, -C₆F₁₃, -C₈F₁₇, -C₁₂F₂₅ und -C₁₄F₂₉ sowie die Reste der in den Beispielen genannten Verbindungen.In another preferred embodiment of the present invention, R is selected from

• • a carbon chain linked to -CO-, -NR ⁶ - or a direct bond to the linker L of 1-15 C atoms, which may be linear or branched, saturated or unsaturated, and which is optionally interrupted by 1-10 oxygen atoms and which is optionally substituted with 1-10 -OH groups, where R ^{6 is} H or C ₁ -C ₄ alkyl,
• • and a complex of formula (II),

wherein R ¹ , R ² , R ³ and U are as defined above for formula (II). Of the compounds of general formula I according to the invention are further preferred those in which R _f -C _n F _{2n + 1} means; ie E in the formula -C _n F _2n E denotes a fluorine atom. n preferably represents the numbers 4-15. Very particularly preferred are the radicals -C ₄ F ₉ , -C ₆ F ₁₃ , -C ₈ F ₁₇ , -C ₁₂ F ₂₅ and -C ₁₄ F ₂₉ and the radicals of the compounds mentioned in the examples.

Of the Radical L in the general formula I, which represents the "skeleton", means in a preferred embodiment the invention an amino acid residue (IXa) or (IXb).

In another preferred embodiment the radical L in the general formula I is a radical of the formulas (IXc), (IXd), (IXe) or (IXf).

mit K in der Bedeutung eines Metallkomplexes einer der allgemeinen Formeln I bis IV, und A, L, Q, X, R, R_f, in der oben angegegebenen Bedeutung werden hergestellt, indem man in an sich bekannter Weise eine Carbonsäure der allgemeinen Formel IIa

worin R⁵ ein Metallionenäquivalent der Ordnungszahlen 21–29, 31–33, 37–39, 42–44, 49 oder 57–83 oder eine Carboxylschutzgruppe bedeutet, und R², R³ und U die genannte Bedeutung haben
oder eine Carbonsäure der allgemeinen Formel IIIa

worin R⁴, R⁵ und U¹ die genannte Bedeutung haben
oder eine Carbonsäure der allgemeinen Formel IVa

worin R⁵ und R² die genannte Bedeutung haben
oder eine Carbonsäure der allgemeinen Formel Va oder Vb

worin R⁵ die genannte Bedeutung hat
oder eine Carbonsäure der allgemeinen Formel VIa

worin R⁵ die genannte Bedeutung hat
oder eine Carbonsäure der allgemeinen Formel VIIa

worin R⁵ und U¹ die genannten Bedeutungen haben,

worin R⁵ die genannten Bedeutungen haben,
und U² wie in Anspruch 1 definiert ist,
in gegebenenfalls aktivierter Form mit einem Amin der allgemeinen Formel X

in der A, L, R, R_f, Q, und X, die oben angegebene Bedeutung haben, in einer Kupplungsreaktion und gegebenenfalls nachfolgender Abspaltung gegebenenfalls vorhandener Schutzgruppen zu einem Metallkomplex der allgemeinen Formel I umsetzt
oder
wenn R⁵ die Bedeutung einer Schutzgruppe hat, nach Abspaltung dieser Schutzgruppen in einem Folgeschritt in an sich bekannter Weise mit mindestens einem Metalloxid oder Metallsalz eines Elementes der Ordnungszahlen 21–29, 31–33, 37–39, 42–44, 49 oder 57–83 umsetzt, und anschließend, falls gewünscht, gegebenenfalls vorhandene azide Wasserstoffatome durch Kationen anorganischer und/oder organischer Basen, Aminosäuren oder Aminosäureamide substituiert.The perfluoroalkyl-containing metal complexes with N-alkyl group of the general formula I.

with K in the meaning of a metal complex of one of the general formulas I to IV, and A, L, Q, X, R, R _f , in the meaning given above are prepared by reacting in a conventional manner a carboxylic acid of general formula IIa

wherein R ^{5 is} a metal ion equivalent of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83 or a carboxyl protecting group, and R ² , R ³ and U have the meaning given
or a carboxylic acid of general formula IIIa

wherein R ⁴ , R ⁵ and U ^{1 have} the meaning given
or a carboxylic acid of general formula IVa

wherein R ⁵ and R ^{2 have} the meaning given
or a carboxylic acid of general formula Va or Vb

wherein R ^{5 has} the meaning given
or a carboxylic acid of general formula VIa

wherein R ^{5 has} the meaning given
or a carboxylic acid of general formula VIIa

wherein R ⁵ and U ^{1 have} the meanings mentioned,

wherein R ^{5 have} the meanings mentioned,
and U ^{2 is defined} as in claim 1,
in optionally activated form with an amine of general formula X.

in the A, L, R, R _f , Q, and X, which have the abovementioned meaning, in a coupling reaction and optionally subsequent cleavage of any protecting groups present to form a metal complex of general formula I.
or
when R ^{5 has} the meaning of a protective group, after removal of these protective groups in a subsequent step in a conventional manner with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57 -83, and then, if desired, optionally substituted azide hydrogen atoms substituted by cations of inorganic and / or organic bases, amino acids or amino acid amides.

This process for the preparation of metal complex carboxamides is DE 196 52 386 known.

The mixture of metal complex carboxylic acid used in the coupling reaction which optionally contains carboxy and / or hydroxyl groups in protected form, and at least one solubilizing agent in an amount up to 5, preferably 0.5-2 molar equivalents based on the metal complex carboxylic acid can both in an upstream Reaction stage prepared and isolated (for example, by evaporation, freeze-drying or spray-drying of an aqueous or water-miscible solution of the ingredients or by precipitation with an organic solvent from such a solution) and then in DMSO with dehydrating reagent and optionally a Kupp lungs adjuvant can be implemented as well as in situ optionally by addition of solubilizing substance (s) to the DMSO suspension of metal complex carboxylic acid, dehydrating reagent and optionally a coupling excipient are formed.

The Be prepared by any of these methods reaction solution for pretreatment (acid activation) 1 to 24, preferably 3 to 12 hours at temperatures from 0 to 50 ° C, preferably at room temperature.

worin die Reste A, L, R, R_f, Q, und X die oben angegebenen Bedeutungen haben, ohne Lösungsmittel oder gelöst, zum Beispiel in Dimethylsulfoxid, Alkoholen wie z.B. Methanol, Ethanol, Isopropanol oder deren Gemischen, Formamid, Dimethylformamid, Wasser oder Mischungen der aufgeführten Lösungsmittel, vorzugsweise in Dimethylsulfoxid, in Wasser oder in mit Wasser gemischten Lösungsmitteln, zugesetzt. Zur Amidkupplung wird die so erhaltene Reaktionslösung bei Temperaturen von 0 bis 70°C, vorzugsweise 30 bis 60°C, 1 bis 48, vorzugsweise 8 bis 24 Stunden gehalten.Subsequently, an amine of the general formula X.

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

In some cases it has proven to be advantageous to use the amine in the form of its salts, e.g. as hydrobromide or hydrochloride in the reaction use. To release the amine, a base such as e.g. triethylamine, Diisopropylethylamine, N-methylmorpholine, pyridine, tripropylamine, Tributylamine, lithium hydroxide, lithium carbonate, sodium hydroxide or sodium carbonate added.

The Any remaining protective groups are subsequently split off.

The Isolation of the reaction product is carried out according to those known in the art Methods, preferably by precipitation with organic solvents, preferably acetone, 2-butanone, diethyl ether, ethyl acetate, methyl t-butyl ether, isopropanol or mixtures thereof. The further purification can, for example, by Chromatography, crystallization or ultrafiltration.

When solubilizing Substances are alkali, alkaline earth, trialkylammonium, tetraalkylammonium salts, ureas, N-hydroxyimides, hydroxyaryltriazoles, substituted phenols and salts of heterocyclic amines suitable. Examples include: Lithium chloride, lithium bromide, lithium iodide, sodium bromide, sodium iodide, Lithium methanesulfonate, sodium methanesulfonate, lithium 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, triethylammonium p-toluenesulfonate, 2-Morpholinoethylsulfonsäure, 4-nitrophenol, 3,5-dinitrophenol, 2,4-dichlorophenol, N-hydroxysuccinimide, N-hydroxyphthalimide, urea, tetramethylurea, N-methylpyrrolidone, Formamide and cyclic ureas, the first five preferred are.

When dehydrating reagents are all known in the art Medium. Examples include carbodiimides and onium reagents such as. Dicyclohexylcarbodiimide (DCCI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydroxychloride (EDC), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) and O- (benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), preferably DCCI.

• • Aktivierung von Carbonsäuren. Übersicht in Houben-Weyl, Methoden der Organischen Chemie, Band XV/2, Georg Thieme Verlag Stuttgart, 1974 (und J. Chem. Research (S) 1996, 302).
• • Aktivierung mit Carbodiimiden. R. Schwyzer u. H. Kappeler, Helv. 46: 1550 (1963).
• • E. Wünsch et al., B. 100: 173 (1967).
• • Aktivierung mit Carbodiimiden/Hydroxysuccinimid: J. Am. Chem. Soc. 86: 1839 (1964) sowie J. Org. Chem. 53: 3583 (1988). Synthesis 453 (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) und J. R. Voughn, Am. Soc. 73: 3547 (1951).
• • Imidazolid-Methode: B.F. Gisin, R.B. Menifield, D.C. Tosteon, Am. Soc. 91: 2691 (1969).
• • Säurechlorid-Methoden, Thionylchlorid: Helv., 42: 1653 (1959).
• • Oxalylchlorid: J. Org. Chem., 29: 843 (1964).

For example, the literature describes the following suitable methods:

• • Activation of carboxylic acids. Review in Houben-Weyl, Methods of Organic Chemistry, Volume XV / 2, Georg Thieme Verlag Stuttgart, 1974 (and J. Chem. Research (S) 1996, 302).
• Activation with carbodiimides. R. Schwyzer u. H. Kappeler, Helv. 46: 1550 (1963).
• E. Wünsch et al., B. 100: 173 (1967).
• Activation with carbodiimides / hydroxysuccinimide: J. Am. Chem. Soc. 86: 1839 (1964) and J. Org. Chem. 53: 3583 (1988). Synthesis 453 (1972).
• Anhydride method, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline: B. Belleau et al., J. Am. Chem. Soc., 90: 1651 (1986), H. Kunz et al., Int. J. Pept. Prot. Res., 26: 493 (1985) and JR Voughn, Am. Soc. 73: 3547 (1951).
• Imidazolide Method: BF Gisin, RB Menifield, DC Tosteon, Am. Soc. 91: 2691 (1969).
• • Acid chloride methods, thionyl chloride: Helv., 42: 1653 (1959).
• • Oxalyl chloride: J. Org. Chem., 29: 843 (1964).

When optionally used coupling auxiliaries are all the Expert known suitable (Houben-Weyl, methods of organic Chemie, Vol. XV / 2, Georg Thieme-Verlag, Stuttgart, 1974). exemplary 4-nitrophenol, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, 3,5-dinitrophenol and pentafluorophenol. Preference is given to 4-nitrophenol and N-hydroxysuccinimide, particularly preferred is the former Reagent.

The Cleavage of the protective groups is carried out according to those known to the skilled person Process, for example by hydrolysis, hydrogenolysis, alkaline Saponification of the esters with alkali in aqueous-alcoholic solution at Temperatures from 0 ° to 50 ° C, acidic Saponification with mineral acids or in the case of e.g. tert-butyl esters with the help of trifluoroacetic acid. [Protective Groups in Organic Synthesis, 2nd Edition, T.W. Greene and P.G.M. Wuts, John Wiley and Sons, Inc. New York, 1991], in the case of benzyl ethers with hydrogen / palladium / carbon.

mit K in der Bedeutung eines Metallkomplexes der allgemeinen Formel VIII', und A, L, Q, X, R, R_f, in der oben angegegebenen Bedeutung werden hergestellt indem man ein Amin der allgemeinen Formel VIII'a

worin R⁵ ein Metallionenäquivalent der Ordnungszahlen 21–29, 31–33, 37–39, 42–44, 49 oder 57–83 oder eine Carboxylschutzgruppe bedeutet,
mit einer, gegebenenfalls aktivierten, Carbonsäure der allgemeinen Formel X'

worin A, L, R, R_f, Q, X die oben angegebenen Bedeutungen haben,
in einer Kupplungsreaktion und gegebenenfalls nachfolgender Abspaltung gegebenenfalls vorhandener Schutzgruppen zu einem Metallkomplex der allgemeinen Formel I umsetzt
oder
wenn R⁵ die Bedeutung einer Schutzgruppe hat, nach Abspaltung dieser Schutzgruppen in einem Folgeschritt in an sich bekannter Weise mit mindestens einem Metalloxid oder Metallsalz eines Elementes der Ordnungszahlen 21–29, 31–33, 37–39, 42–44, 49 oder 57–83 umsetzt, und anschließend, falls gewünscht, gegebenenfalls vorhandene azide Wasserstoffatome durch Kationen anorganischer und/oder organischer Basen, Aminosäuren oder Aminosäureamide substituiert.The compounds of general formula I according to the invention

with K in the meaning of a metal complex of the general formula VIII ', and A, L, Q, X, R, R _f , in the meaning given above are prepared by reacting an amine of the general formula VIII'a

wherein R ^{5 represents} a metal ion equivalent of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83 or a carboxyl-protecting group,
with an optionally activated carboxylic acid of the general formula X '

wherein A, L, R, R _f , Q, X are as defined above,
in a coupling reaction and optionally subsequent removal of any protective groups present to form a metal complex of general formula I.
or
when R ^{5 has} the meaning of a protective group, after removal of these protective groups in a subsequent step in a conventional manner with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57 -83, and then, if desired, given if existing acidic hydrogen atoms substituted by cations of inorganic and / or organic bases, amino acids or amino acid amides.

The carboxylic acids of the general formulas IIa to VIIa used are either known compounds or are prepared by the processes described in the examples, see DE 10040381 and DE 10040858 , Thus, the preparation of the carboxylic acids of general formula IIa is made DE 196 52 386 known. The carboxylic acids of the general formulas VIIIa and XVIII'a used can be prepared as described in WO 95/17451.

The Amine of the general formula VIII'a is a known starting compound.

The perbenzylated sugar acids used as starting materials when R is a monosaccharide or oligosaccharide can be prepared analogously to Lockhoff, Angew. Chem. 1998, 110, No. 24, pp. 3634 et seq. Thus, for example, the preparation of 1-O-acetic acid of perbenzyl-glucose over 2 stages, via trichloroacetimidate and reaction with ethyl hydroxyacetate, BF ₃ catalysis in THF and subsequent saponification with NaOH in MeOH / THF.

In a more advantageous method, as in DE 10040381 described, the perbenzylated sugar acids used as starting materials are also prepared by the perbenzylated 1-OH-sugar dissolved in a water-immiscible organic solvent and with an alkylating reagent of general formula XII Nu-L-COO-Sg (XII), wherein Nu represents a nucleofuge, L - (CH ₂ ) - _n , (wherein n = 1-5), -CH ₂ -CHOH-, or -CH (CHOH-CH ₂ OH) -CHOH-CHOH-, and Sg represents a protective group,
in the presence of a base and optionally a phase transfer catalyst. As a nucleofuge in the alkylating reagent of general formula XII, for example, the radicals -Cl, -Br, -J, -OTs, -OMs, -OSO ₂ CF ₃ , -OSO ₂ C ₄ F ₉ or -OSO ₂ C ₈ F ₁₇ may be included ,

at the protecting group is a common acid protecting group. These protecting groups are well-known to those skilled in the art (Protective Groups in Organic Syntheses, second Edition, T.W. Greene and P.G.M. Wuts, John Wiley & Sons Inc., New York 1991).

The inventive reaction can at temperatures of 0-50 ° C, preferably from 0 ° C to room temperature. The reaction times are from 10 Minutes to 24 hours, preferably from 20 minutes to 12 hours.

The Base is either in solid form, preferably finely powdered, or as 10-70%, preferably 30-50%, added aqueous solution. Preferred bases are NaOH and KOH.

Examples of suitable organic, water-immiscible solvents in the alkylation process according to the invention include toluene, benzene, CF ₃ -benzene, hexane, cyclohexane, diethyl ether, tetrahydrofuran, dichloromethane, MTB or mixtures thereof.

As phase transfer catalysts used in the process according to the invention known for this purpose quaternary ammonium or phosphonium salts or crown ethers such. [15] Crown-5 or [18] Crown-6. Quaternary ammonium salts having four identical or different hydrocarbon groups on the cation, selected from methyl, ethyl, propyl, isopropyl, butyl or isobutyl, are preferably suitable. The hydrocarbon groups on the cation must be large enough to ensure good solubility of the alkylating reagent in the organic solvent. According to the invention particularly preferably N (butyl) ₄ ⁺ Cl ^-, N (butyl) ₄ ⁺ -HSO ₄ ^-, but also N (methyl) ₄ ⁺ Cl ^{- are} used.

In analogous way also the corresponding terminal protected Polyethylene glycolic acids produced become.

mit L in der Bedeutung von

werden hergestellt indem man die oben beschriebenen hydrophilen Carbonsäuren R nach dem Fachmann bekannten Methoden der Amidbildung mit Aminen der allgemeinen Formel (XIIIa)

oder im Falle der oben beschriebenen hydrophilen Amine R nach dem Fachmann bekannten Methoden der Amidbildung mit Carbonsäuren der allgemeinen Formel (XIIIb)

mit Sg in der Bedeutung einer Schutzgruppe und L, X, A und R_f in der oben angegebenen Bedeutung umsetzt.Compounds of the general formula (X)

with L in the meaning of

are prepared by reacting the abovedescribed hydrophilic carboxylic acids R by methods of amide formation known to the person skilled in the art with amines of the general formula (XIIIa)

or in the case of the hydrophilic amines R described above, methods of amide formation known to the person skilled in the art with carboxylic acids of the general formula (XIIIb)

with Sg in the meaning of a protective group and L, X, A and R _f in the meaning given above.

The Cleavage of the protective groups is carried out according to those known to the skilled person Process, for example by hydrolysis, hydrogenolysis, alkaline Saponification of the esters with alkali in aqueous-alcoholic solution at Temperatures from 0 ° to 50 ° C, acidic Saponification with mineral acids or in the case of e.g. tert-butyl esters with the help of trifluoroacetic acid. [Protective Groups in Organic Synthesis, 2nd Edition, T.W. Greene and P.G.M. Wuts, John Wiley and Sons, Inc. New York, 1991], in the case of benzyl ethers with hydrogen / palladium / carbon.

Sg und Sg' in der Bedeutung einer Schutzgruppe umsetzt, wobei Sg und Sg' unterschiedlich spaltbar sind und L, X, A und R_f in der oben angegebenen Bedeutung umsetzt.Compounds of general formula (XIII) are prepared by reacting doubly protected amino acids of general formula (XIV)

Sg and Sg 'in the meaning of a protective group, wherein Sg and Sg' are different cleavable and L, X, A and R _f in the meaning given above implements.

The Cleavage of the protective groups takes place after the above-described, known to those skilled in the process.

nach dem Fachmann bekannten Methoden der Amidbildung mit Aminen der allgemeinen Formel (XVI) umsetzt:

Compounds of the general formula (XIV) are prepared by reacting doubly protected amino acids of the general formula (XV)

according to methods known in the art of amide formation with amines of the general formula (XVI):

Such twice protected amino acids of the general formula (XV) are purchased goods (Bachem).

Amines of the general formula (XVI) can be obtained by the following processes: from perfluoro-containing amines of the general formula (XVIIa) by reaction with acylating agents of the general formula (XVIIb) cited in the art and subsequent reduction in a manner known per se with diborane or lithium aluminum hydride, the compounds of general formula (XVIIc)

• J. G. Riess, Journal of Drug Targeting, 1994, Vol. 2, pp. 455–468;
• J. B. Nivet et al., Eur. J. Med. Chem., 1991, Vol. 26, pp. 953–960;
• M.-P. Krafft et al., Angew. Chem., 1994, Vol. 106, No. 10, pp. 1146–1148;
• M. Lanier et al., Tetrahedron Letters, 1995, Vol. 36, No. 14, pp. 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, pp. 19–26;
• L. Clary et al., Tetrahedron, 1995, Vol. 51, No. 47, pp. 13073–13088;
• F. Szoni et al., Journal of Fluorine Chemistry, 1989, Vol. 42, pp. 59–68;
• H. Wu et al., Supramolecular Chemistry, 1994, Vol. 3, pp. 175–180;
• F. Guileri et al., Angew. Chem. 1994, Vol. 106, No. 14, pp. 1583–1585;
• M.-P. Krafft et al., Eur. J. Med. Chem., 1991, Vol. 26, pp. 545–550;
• J. Greiner et al., Journal of Fluorine Chemistry, 1992, Vol. 56, pp. 285–293;
• A. Milius et al., Carbohydrate Research, 1992, Vol. 229, pp. 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, pp. 4483–4488;
• V. Cirkva et al., Jounal of Fluorine Chemistry, 1997, Vol. 83, pp. 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;
• MM. Chaabouni et al., Journal of Fluorine Chemistry, 1990, Vol. 46, pp. 307–315;
• A. Milius et al., New J. Chem., 1991, Vol. 15, pp. 337–344;
• M.-P. Krafft et al., New J. Chem., 1990, Vol. 14, pp. 869–875;
• J.-B. Nivet et al., New J. Chem., 1994, Vol. 18, pp. 861–869;
• C. Santaella et al., New J. Chem., 1991, Vol. 15, pp. 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, pp. 771–773;
• F. Szönyi et al., Journal of Fluorine Chemistry, 1991, Vol. 55, pp. 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. 783–785;
• EP 0 548 096 B1 .

Perfluorinated amines of general formula (XVIIa) are either purchased (Fluorochem, ABCR), or their preparation is described in the following publications:

• JG Riess, Journal of Drug Targeting, 1994, Vol. 2, pp. 455-468;
• JB Nivet et al., Eur. J. Med. Chem., 1991, Vol. 26, pp. 953-960;
• M.-P. Krafft et al., Angew. Chem., 1994, Vol. 10, pp. 1146-1148;
• Lanier et al., Tetrahedron Letters, 1995, Vol. 14, pp. 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, pp. 19-26;
• L. Clary et al., Tetrahedron, 1995, Vol. 51, no. 47, pp. from 13,073 to 13,088;
• Szoni et al., Journal of Fluorine Chemistry, 1989, Vol. 42, pp. 59-68;
• Wu et al., Supramolecular Chemistry, 1994, Vol. 3, pp. 175-180;
• F. Guileri et al., Angew. Chem. 1994, Vol. 106, no. 14, pp. 1583-1585;
• M.-P. Krafft et al., Eur. J. Med. Chem., 1991, Vol. 26, pp. 545-550;
• J. Greiner et al., Journal of Fluorine Chemistry, 1992, Vol. 56, pp. 285-293;
• A. Milius et al., Carbohydrate Research, 1992, Vol. 229, pp. 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, pp. 4483-4488;
• V. Cirkva et al., Journal of Fluorine Chemistry, 1997, Vol. 83, pp. 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;
• Clary, et al., Tetrahedron Letters, 1995, Vol. 4, pp. 539-542;
• MM. Chaabouni et al., Journal of Fluorine Chemistry, 1990, Vol. 46, pp. 307-315;
• A. Milius et al., New J. Chem., 1991, Vol. 15, pp. 337-344;
• M.-P. Krafft et al., New J. Chem., 1990, Vol. 14, pp. 869-875;
• J.-B. Nivet et al., New J. Chem., 1994, Vol. 18, pp. 861-869;
• C. Santaella et al., New J. Chem., 1991, Vol. 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, pp. 771-773;
• Szonyi et al., Journal of Fluorine Chemistry, 1991, Vol. 55, pp. 85-92;
• C. Santaella et al., Angew. Chem., 1991, Vol. 5, pp. 584-586;
• M.-P. Krafft et al., Angew. Chem., 1993, Vol. 105, no. 5, pp. 783-785;
• EP 0 548 096 B1 ,

The Compounds of the invention are particularly suitable for the use in NMR and X-ray diagnostics, Radiodiagnostics and radiotherapy, as well as in MRI lymphography. The perfluoroalkyl-containing metal complexes are particularly suitable for use in magnetic resonance imaging (MRI) for imaging of different physiological and pathophysiological structures and thus to improve the diagnostic information, for example the localization and the degree of the disease, to the selection and success control a targeted therapy and for the prophylaxis of diseases and Disorders.

suitable Diseases and disorders include tumor diseases, especially detection and characterization of primary tumors, Distant metastases, lymph node metastases as well as necroses, cardiovascular diseases, especially changes the vessel diameter like stenoses and aneurysms, atherosclerosis by detection of atherosclerotic plaques, thromboembolic disorders, infarcts, Necrosis, inflammation, in particular arthritis, osteomyelitis, ulcerative colitis, as well as nerve damage.

In a particularly preferred embodiment become the substances according to the invention used for MRI lymphography.

In Another particularly preferred embodiment, the substances of the invention used for blood pool imaging.

In a particularly preferred embodiment become the substances according to the invention used for necrosis or tumor imaging.

object The invention also relates to pharmaceutical agents containing at least one physiologically compatible inventive compound possibly with those customary in galenics Additives.

The Compounds of the present invention are characterized by a excellent compatibility and at the same time excellent imaging properties. They are special good for the systemic application in MRI, especially in MRI lymphography and in tumor imaging. The connections are excellent systemic compatibility out.

The Preparation of the pharmaceutical according to the invention Agent is carried out in a conventional manner by reacting the complex compounds of the invention - optionally with the addition of the usual in galenics Additives - in watery Medium suspended or dissolved and subsequently the suspension or solution optionally sterilized. Suitable additives For example, physiologically acceptable buffers (such as Example tromethamine), additives complexing agents or weak complexes (such as diethylenetriaminepentaacetic acid or to the metal complexes of the invention corresponding Ca complexes) or, if necessary, electrolytes such as sodium chloride or, if necessary, antioxidants such as ascorbic acid.

If suspensions or solutions of the agents according to the invention in water or physiological saline solution are desired for enteral or parenteral administration or other purposes, they are combined with one or more auxiliaries customary in galenics) [for example methyl cellulose, lactose, mannitol] and / or surfactants) [for example, lecithins, Tween ^®, Myrj ^®] and / or flavoring substance (s) mixed for taste correction (eg, ethereal oils].

in principle it is also possible the pharmaceutical according to the invention To produce means without isolation of the complexes. In any case special care must be taken to ensure chelation make that the complexes of the invention practically free are of non-complexed toxic metal ions.

This For example, with the help of color indicators such as xylenol orange through control titrations during ensured the manufacturing process become. The invention therefore also relates to processes for the preparation the complex compounds and their salts. As last security remains a purification of the isolated complex.

at the in-vivo application of the agents according to the invention can this together with a suitable carrier such as serum or saline, and together with another protein such as human serum albumin (HSA).

The agents according to the invention become common parenteral, preferably i.v., applied. You can also use intravascular or interstitial / intracutaneous be applied, depending on whether examined body vessels or tissues should be.

The pharmaceutical according to the invention Means preferably contain 0.1 μmol-2 mol / l of the complex and are usually dosed in amounts of 0.0001-5 mmol / kg.

The agents according to the invention fulfill the diverse ones Requirements for the suitability as contrast agent for the magnetic resonance tomography. So they are perfect for after oral or parenteral administration by increasing the signal intensity the image obtained with the help of the magnetic resonance tomograph in its expressiveness to improve. Furthermore, they show the high effectiveness necessary is to the body with as possible to burden small amounts of foreign matter, and the outstanding Compatibility, which is necessary to the non-invasive nature of the investigations maintain.

The good water solubility and low osmolality the agents according to the invention allows highly concentrated solutions produce, so that the volume load of the circulation in justifiable To keep limits and dilution through the body fluid compensate. Furthermore, the agents according to the invention not only a high stability in vitro, but also a surprise high stability in vivo, allowing a release or an exchange of those in the complexes bound - on toxic - ions within the time in which the new contrast media completely recover are excreted, only extremely slowly he follows.

in the general agents of the invention for use as NMR-diagnostic agents in amounts of 0.0001-5 mmol / kg, preferably 0.005-0.5 mmol / kg, dosed.

Further can the complex compounds of the invention advantageous as susceptibility reagents and as shift reagents for the in vivo NMR spectroscopy be used.

The agents according to the invention are due to their cheap radioactive properties and good stability of in Complex compounds containing them also as radiodiagnostic agents suitable. Details of such application and dosage will e.g. in "Radiotracers for Medical Applications ", CRC-Press, Boca Raton, Florida.

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

histological Confirm investigations a regional microvascular Hyperpermeability.

you can therefore the contrast agent of the invention also use to depict abnormal capillary permeability.

The Compounds of the invention are characterized by the fact that they are completely from the body be eliminated and thus are extremely well tolerated. Thus, the excellent imaging and non-invasive Character of the diagnosis to be maintained.

Since the substances according to the invention accumulate in malignant tumors (no diffusion into healthy tissue, but high permeability of tumor vessels), they can also support the radiation therapy of malignant tumors. This differs from the corresponding diagnosis only by the amount and type of isotope used. The goal is the destruction of tumor cells by high-energy short-wave radiation with the shortest possible range. For this purpose, interactions of the metals contained in the complexes (such as iron or gadolinium) with ionizing radiation (eg X-rays) or with neutron beams are exploited. This effect significantly increases the local radiation dose at the site where the metal complex is located (eg in tumors). In order to produce the same radiation dose in the malignant tissue, the application of such metal complexes can significantly reduce the radiation burden on healthy tissue and thus avoid stressful side effects for the patients. The metal complex conjugates according to the invention are therefore also suitable as a radiosensitizing substance in the radiotherapy of malignant tumors (eg exploitation of Mössbauer effects or in neutron capture therapy). Suitable β-emitting ions are, for example, ⁴⁶ Sc, ⁴⁷ Sc, ⁴⁸ Sc, ⁷² Ga, ⁷³ Ga, and ⁹⁰ Y. Suitable low half-life α-emitting ions are, for example, ²¹¹ Bi, ²¹² Bi, ²¹³ Bi, and ²¹⁴ Bi ²¹² Bi is preferred. A suitable photon and electron emitting ion is ¹⁵⁸ Gd, which can be obtained from ¹⁵⁷ Gd by neutron capture.

If the agent according to the invention is for use in the method described by RL Mills et al. (Nature Vol. 336, (1988), p. 787], the central ion must be derived from a Mössbauer isotope such as ⁵⁷ Fe or ¹⁵¹ Eu.

at the in-vivo application of the agents according to the invention can this together with a suitable carrier such as serum or saline, and together with another protein such as Human Serum Albumin be administered. The dosage depends on the Type of cellular disorder the metal ion used and the type of imaging method.

The agents according to the invention become common parenteral, preferably i.v., applied. You can also - as already discussed - intravasal or interstitially / intracutaneously, depending on whether Body vessels or tissues are to be examined.

The agents according to the invention are excellent as X-ray contrast agents suitable, with particular emphasis being that with them no signs of the iodine-containing contrast agents known Anaphylactic reactions in biochemical pharmacological studies reveal. They are especially valuable because of the cheap Absorption properties in areas of higher tube voltages for digital Subtraction techniques.

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

The term "metal ion equivalent," as used in the present application a conventional and known in the art concept in the field of coordination chemistry. A metal ion equivalent is an equivalent of metal ions which instead of hydrogen can bind to a, for example, carboxylate group. For example, a Gd ³⁺ to 3 Bind carboxylate groups, ie 1/3 Gd ³⁺ corresponds to the metal ion equivalent R ¹ in formula (II), (III), (IV) or (V) when the metal is gadolinium.

embodiments

example 1

a) (1H, 1H, 2H, 2H-perfluorodecyl) -methylamine

To 18.9 ml (200 mmol) of acetic anhydride are added dropwise at 0 ° C 9.8 ml (260 mmol) of formic acid and heated to 60 ° C for 2 h. After cooling to room temperature, a solution of 27.78 g (60 mmol) of 1H, 1H, 2H, 2H-perfluorodecylamine (Cambon et al., J. Fluorine Chem., 1994, 115-118) in 150 ml of THF is added dropwise and 3 h at Room temperature stirred. The reaction solution is evaporated to dryness in vacuo, the residue dissolved in 100 ml of THF, treated with 20 ml of 10 M borane dimethyl sulfide (in THF) and heated under reflux for 5 h. It is cooled to 0 ° C, added dropwise 100 ml of methanol, stirred for 1 h at room temperature and then evaporated to dryness in vacuo. The residue is taken up in a mixture of 300 ml of ethanol / 50 ml of 1 M hydrochloric acid and stirred at 40 ° C. for 14 h. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).
Yield: 24.1 g (84% of theory) of a colorless oil

Elemental analysis:

• Re: C 27.69 H 1.69 N 2.94 F 67.69
• Found .: C 27.86 H 1.74 N 2.89 F 67.41

b) 6-N-Benzyloxycarbonyl-2-N-trifluoroacetyl-L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide

To 18.82 g (50 mmol) of 6-N-benzyloxycarbonyl-2-N-trifluoroacetyl-L-lysine (prepared according to EP 01/08498) and 23.86 g (50 mmol) of the title compound from Example 1a in 200 ml of THF are added at 0 ° C 24.7 g (100 mmol) of ethyl EEDQ (2-ethoxy-1,2-dihydro-quinoline-1-carboxylate) and stirred for 16 h at room temperature. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 38.0 g (91% of theory) of a colorless, viscous oil.

Elemental analysis:

• calc .: C 38.82 H 3.02 N 5.03 F 45.48
• Found: C 39.05 N 3.05 N 5.01 F 45.32

c) 6-N-Benzyloxycarbonyl-L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide

In a solution of 37.5 g (44.88 mmol) of the title compound from Example 1b in 250 ml of ethanol is introduced at 0 ° C for 1 h ammonia gas, and then stirred for 4 h at 0 ° C. It is evaporated to dryness in vacuo and the residue is stirred out of water. The solid is filtered off and dried in vacuo at 50 ° C.
Yield: 32.2 g (97% of theory) of an amorphous solid.

Elemental analysis:

• Re: C 40.61 H 3.54 N 5.68 F 43.68
• Found .: C 40.81 H 3.59 N 5.70 F 43.44

d) 6-N-Benzyloxycarbonyl-2-N- [1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -L-lysine - ((1H, 1H , 2H, 2H-perfluorodecyl) methyl] -amide

To a solution of 31.5 g (42.6 mmol) of the title compound of Example 1c and 25.5 g (42.6 mmol) of 1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose (prepared according to WO 99/01160 A1) and 4.9 g (42.6 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide are added at 0 ° C 10.99 g (53.25 mmol) dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea, the filtrate evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 48.5 g (86% of theory) of a colorless, viscous oil.

Elemental analysis:

• Calc .: C 55.50 H 4.73 N 3.18 F 24.46
• Found .: C 55.71 H 4.82 N 3.12 F 24.29

e) 2-N- (1-O-α-d-carbonylmethyl-1-mannranose) -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide

To a solution of 47.5 g (35.98 mmol) of the title compound from Example 1d in 600 ml of ethanol is added 4.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 29.6 g (quantitative) of a colorless solid.

Elemental analysis:

• comp .: C 36.37 H 3.91 N 5.09 F 39.12
• Found: C 37.00 H 3.99 N 5.01 F 38.87

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- (1-O-α-dodecarbonylmethyl-4-mannose) -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide, Gd-complex

25.0 g (30.28 mmol) of the title compound from Example 1e, 3.49 g (30.28 mmol) of N-hydroxysuccinimide, 2.57 g (60.56 mmol) of lithium chloride and 19.07 g (30.28 mmol) of 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)) dissolved in 200 ml of dimethyl sulfoxide with gentle warming. At 10 ° C., 7.81 g (37.85 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 16 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 35.7 g (77% of theory) of a colorless solid
Water content (Karl Fischer): 6.4%

Elemental analysis (related to the anhydrous substance):

• Re: C 36.77 H 4.21 N 7.80 F 22.47 Gd 10.94
• Found .: C 36.91 H 4.25 N 7.77 F 22.34 Gd 10.86

Example 2

a) (1H, 1H, 2H, 2H-perfluorododecyl) -methylamine

To 18.9 ml (200 mmol) of acetic anhydride are added dropwise at 0 ° C 9.8 ml (260 mmol) of formic acid and heated to 60 ° C for 2 h. After cooling to room temperature, a solution of 33.79 g (60 mmol) of 1H, 1H, 2H, 2H-perfluorododecylamine (Palomo et al., Org. Lett., 2001, 2361-2364) in 150 ml of THF is added dropwise and 3 h at room temperature touched. The reaction solution is evaporated to dryness in vacuo, the residue dissolved in 100 ml of THF, treated with 20 ml of 10 M borane dimethyl sulfide (in THF) and heated under reflux for 5 h. It is cooled to 0 ° C, added dropwise 100 ml of methanol, stirred for 1 h at room temperature and then evaporated to dryness in vacuo. The residue is taken up in a mixture of 300 ml of ethanol / 50 ml of 1 M hydrochloric acid and stirred at 40 ° C. for 14 h. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).
Yield: 26.7 g (77% of theory) of a colorless oil

Elemental analysis:

• Calculated: C 27.05 H 1.40 N 2.43 F 69.12
• Found .: C 27.23 H 1.43 N 2.37 F 66.97

b) 6-N-Benzyloxycarbonyl-2-N-trifluoroacetyl-L-lysine - [(1H, 1H, 2H, 2H-perfluorododecyl) -methyl] -amide

To 18.82 g (50 mmol) of 6-N-benzyloxycarbonyl-2-N-trifluoroacetyl-L-lysine (prepared according to EP 01/08498) and 28.86 g (50 mmol) of the title compound from Example 2a in 200 ml of THF are added at 0 ° C 24.7 g (100 mmol) of ethyl EEDQ (2-ethoxy-1,2-dihydro-quinoline-1-carboxylate) and stirred for 16 h at room temperature. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 44.1 g (94% of theory) of a colorless, viscous oil.

Elemental analysis:

• Re: C 37.23 H 2.69 N 4.49 F 48.74
• Found .: C 37.42 H 2.73 N 4.44 F 48.62

c) 6-N-Benzyloxycarbonyl-L-lysine - [(1H, 1H, 2H, 2H-perfluorododecyl) -methyl] -amide

In a solution of 43.0 g (45.96 mmol) of the title compound from Example 2b in 250 ml of ethanol is introduced at 0 ° C for 1 h ammonia gas, and then stirred for 4 h at 0 ° C. It is evaporated to dryness in vacuo and the residue is stirred out of water. The solid is filtered off and dried in vacuo at 50 ° C.
Yield: 36.5 g (95% of theory) of an amorphous solid.

Elemental analysis:

• calc .: C 38.63 H 3.21 N 5.01 F 47.52
• Found: C 38.69 H 3.28 N 4.97 F 47.36

d) 6-N-Benzyloxycarbonyl-2-N- [1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -L-lysine - [(1H, 1H , 2H, 2H-perfluorododecyl) -methyl] -amide

To a solution of 35.5 g (42.3 mmol) of the title compound of Example 2c and 25.3 g (42.3 mmol) of 1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose (prepared WO 99/01160 A1) and 4.9 g (42.3 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide are added at 0 ° C 10.69 g (52.8 mmol) dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea, the filtrate evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 53.2 g (89% of theory) of a colorless, viscous oil.

Elemental analysis:

• calc .: C 53.28 H 4.40 N 2.96 F 28.09
• Found .: C 53.47 H 4.45 N 2.89 F 27.88

e) 2-N- (1-O-α-d-carbonyl-methyl-mannopyranose) -L-lysine - [(1H, 1H, 2H, 2H-perfluorododecyl) -methyl] -amide

To a solution of 52.0 g (36.62 mmol) of the title compound of Example 2d in 600 ml of ethanol is added 5.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 33.4 g (quantitative) of a colorless solid.

Elemental analysis:

• calc .: C 35.04 H 3.49 N 4.54 F 43.11
• Found .: C 35.19 H 3.51 N 4.49 F 43.07

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- (1-O-α-dodecarbonylmethyl-4-mannose) -L-lysine - [(1H, 1H, 2H, 2H-perfluorododecyl) -methyl] -amide, Gd-complex

30.0 g (32.41 mmol) of the title compound of Example 2e, 3.73 g (32.41 mmol) of N-hydroxysuccinimide, 2.75 g (64.82 mmol) of lithium chloride and 20.41 g (32.41 mmol) of 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)) dissolved in 200 ml of dimethyl sulfoxide with gentle warming. At 10 ° C., 8.36 g (40.51 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 16 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 34.1 g (68% of theory) of a colorless solid
Water content (Karl Fischer): 6.9%

Elemental analysis (related to the anhydrous substance):

• Calc .: C 35.94 H 3.93 N 7.29 F 25.95 Gd 10.23
• Found .: C 35.88 H 3.96 N 7.21 F 25.73 Gd 10.17

Example 3

a) (1H, 1H, 2H, 2H-perfluorooctyl) -methylamine

To 18.9 ml (200 mmol) of acetic anhydride are added dropwise at 0 ° C 9.8 ml (260 mmol) of formic acid and heated to 60 ° C for 2 h. After cooling to room temperature, a solution of 21.79 g (60 mmol) of 1H, 1H, 2H, 2H-perfluorooctylamine (Cambon et al., J. Fluorine Chem., 1994, 115-118) in 150 ml of THF is added dropwise and 3 h at Room temperature stirred. The reaction solution is evaporated to dryness in vacuo, the residue dissolved in 100 ml of THF, treated with 20 ml of 10 M borane dimethyl sulfide (in THF) and heated under reflux for 5 h. It is cooled to 0 ° C, added dropwise 100 ml of methanol, stirred for 1 h at room temperature and then evaporated to dryness in vacuo. The residue is taken up in a mixture of 300 ml of ethanol / 50 ml of 1 M hydrochloric acid and stirred at 40 ° C. for 14 h. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).
Yield: 20.2 g (89% of theory) of a colorless oil

Elemental analysis:

• Calculated: C 28.66 H 2.14 N 3.71 F 65.49
• Found .: C 28.82 H 2.19 N 3.67 F 65.12

b) 6-N-Benzyloxycarbonyl-2-N-trifluoroacetyl-L-lysine - [(1H, 1H, 2H, 2H-perfluorooctyl) -methyl] -amide

To 18.82 g (50 mmol) of 6-N-benzyloxycarbonyl-2-N-trifluoroacetyl-L-lysine (prepared according to EP 01/08498) and 18.86 g (50 mmol) of the title compound from Example 3a in 200 ml of THF are added at 0 ° C 24.7 g (100 mmol) of ethyl EEDQ (2-ethoxy-1,2-dihydro-quinoline-1-carboxylate) and stirred for 16 h at room temperature. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 33.2 g (90% of theory) of a colorless, viscous oil.

Elemental analysis:

• Re: C 40.83 H 3.43 N 5.71 F 41.33
• Found: C 41.03 H 3.45 N 5.67 F 41.21

c) 6-N-Benzyloxycarbonyl-L-lysine - [(1H, 1H, 2H, 2H-perfluorooctyl) -methyl] -amide

In a solution of 32.7 g (44.46 mmol) of the title compound from Example 3b in 250 ml of ethanol is introduced at 0 ° C for 1 h ammonia gas, and then stirred for 4 h at 0 ° C. It is evaporated to dryness in vacuo and the residue is stirred out of water. The solid is filtered off and dried in vacuo at 50 ° C.
Yield: 28.4 g (99% of theory) of an amorphous solid.

Elemental analysis:

• Re: C 43.20 H 4.10 N 6.57 F 38.62
• Found .: C 43.36 H 4.13 N 6.49 F 38.48

d) 6-N-Benzyloxycarbonyl-2-N- [1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -L-lysine - [(1H, 1H , 2H, 2H-perfluorooctyl) -methyl] -amide

To a solution of 28.0 g (43.79 mmol) of the title compound of Example 3c and 26.22 g (43.79 mmol) of 1-O-⎕-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose (prepared according to WO 99/01160 A1) and 5.04 g (43.79 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide are added at 0 ° C 11.29 g (54.74 mmol) of dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea, the filtrate is evaporated to dryness in vacuo and the residue is chromatographed stood on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 43.8 g (82% of theory) of a colorless, viscous oil.

Elemental analysis:

• Calc .: C 58.08 H 5.12 N 3.44 F 20.24
• Found: C 58.19 H 5.16 N 3.40 F 20.11

e) 2-N- (1-O-α-d-carbonylmethyl-3-mannranose) -L-lysine - [(1H, 1H, 2H, 2H-perfluorooctyl) -methyl] -amide

To a solution of 43.3 g (35.49 mmol) of the title compound from Example 3d in 600 ml of ethanol are added 4.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 25.9 g (quantitative) of a colorless solid.

Elemental analysis:

• Re: C 38.08 H 4.45 N 5.79 F 34.04
• Found .: C 38.29 H 4.61 N 5.62 F 33.88

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- (1-O-α-d-carbonylmethyl-4-mannose) -L-lysine - [(1H, 1H, 2H, 2H-perfluorooctyl) -methyl] -amide, Gd-complex

25.3 g (34.87 mmol) of the title compound from Example 3e, 4.01 g (34.87 mmol) of N-hydroxysuccinimide, 2.96 g (69.74 mmol) of lithium chloride and 21.96 g (34.87 mmol) of 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)) dissolved in 200 ml of dimethyl sulfoxide with gentle warming. At 10 ° C., 8.99 g (43.59 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 16 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 34.1 g (69% of theory) of a colorless solid
Water content (Karl Fischer): 5.9%

Elemental analysis (related to the anhydrous substance):

• Calc .: C 37.73 H 4.52 N 8.38 F 18.47 Gd 11.76
• Found .: C 37.88 H 4.55 N 8.29 F 18.42 Gd 11.68

Example 4

a) (1H, 1H, 2H, 2H-perfluoro-9-methyldecyl) amine

To a suspension of 100 g (160.25 mmol) of 1H, 1H, 2H, 2H-perfluoro-9-methyldecyl) iodide (fluorochemical) in 100 ml of water are added 20.84 g (320.5 mmol) of sodium azide and 4.04 g (10.0 mmol) of trioctylmethylammonium chloride and stirred for 16 h at 100 ° C. After cooling to room temperature, the organic phase is separated and the aqueous phase extracted twice with 50 ml dichloromethane. The combined organic phases are dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is suspended in a mixture of 500 ml of water and 100 ml of THF, mixed with 11.8 ml (240 mmol) of hydrazine monohydrate and 5 g of Raney nickel, and heated to 80 ° C for 48 h. After cooling to room temperature, the organic phase is separated and the aqueous phase extracted twice with 200 ml of diethyl ether. The combined organic phases are dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is distilled in vacuo at 15 mbar and 140 ° C bath temperature. At 95 ° C boiling temperature to obtain a colorless distillate, which cures waxy at room temperature.
Yield: 58.5 g (71% of theory) of a colorless wax

Elemental analysis:

• Calc .: C 27.75 H 1.18 N 2.73 F 70.34
• Found .: C 27.96 H 1.22 N 2.66 F 70.11

b) (1H, 1H, 2H, 2H-perfluoro-9-methyldecyl) -methylamine

To 18.9 ml (200 mmol) of acetic anhydride are added dropwise at 0 ° C 9.8 ml (260 mmol) of formic acid and heated to 60 ° C for 2 h. After cooling to room temperature, a solution of 30.79 g (60 mmol) of the title compound from Example 4a in 150 ml of THF is added dropwise and stirred for 3 h at room temperature. The reaction solution is evaporated to dryness in vacuo, the residue dissolved in 100 ml of THF, treated with 20 ml of 10 M borane dimethyl sulfide (in THF) and heated under reflux for 5 h. It is cooled to 0 ° C, added dropwise 100 ml of methanol, stirred for 1 h at room temperature and then evaporated to dryness in vacuo. The residue is taken up in a mixture of 300 ml of ethanol / 50 ml of 1 M hydrochloric acid and stirred at 40 ° C. for 14 h. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).
Yield: 25.6 g (81% of theory) of a colorless oil

Elemental analysis:

• Calculated: C 27.34 H 1.53 N 2.66 F 68.47
• Found .: C 27.45 H 1.57 N 2.62 F 68.33

c) 6-N-Benzyloxycarbonyl-2-N-trifluoroacetyl-L-lysine - [(1H, 1H, 2H, 2H-perfluoro-9-methyldecyl) -methyl] -amide

To 18.82 g (50 mmol) of 6-N-benzyloxycarbonyl-2-N-trifluoroacetyl-L-lysine (prepared according to EP 01/08498) and 26.36 g (50 mmol) of the title compound from Example 4b in 200 ml of THF are added at 0 ° C 24.7 g (100 mmol) of ethyl EEDQ (2-ethoxy-1,2-dihydro-quinoline-1-carboxylate) and stirred for 16 h at room temperature. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 37.3 g (84% of theory) of a colorless, viscous oil.

Elemental analysis:

• Re: C 37.98 H 2.85 N 4.75 F 47.20
• Found: C 38.09 H 2.88 N 4.70 F 47.04

d) 6-N-Benzyloxycarbonyl-L-lysine - [(1H, 1H, 2H, 2H-perfluoro-9-methyldecyl) -methyl] -amide

In a solution of 36.5 g (41.22 mmol) of the title compound from Example 4c in 250 ml of ethanol is introduced at 0 ° C for 1 h ammonia gas, and then stirred for 4 h at 0 ° C. It is evaporated to dryness in vacuo and the residue is stirred out of water. The solid is filtered off and dried in vacuo at 50 ° C.
Yield: 32.1 g (99% of theory) of an amorphous solid.

Elemental analysis:

• calc .: C 39.56 H 3.32 N 5.32 F 47.20
• Found .: C 39.50 H 3.41 N 5.29 F 47.31

e) 6-N-Benzyloxycarbonyl-2-N- [1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -L-lysine - [(1H, 1H , 2H, 2H-perfluoro-9-methyldecyl) -methyl] -amide

To a solution of 31.0 g (39.27 mmol) of the title compound of Example 4d and 23.51 g (39.27 mmol) of 1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose (prepared according to WO 99/01160 A1) and 4.52 g (39.27 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide are added at 0 ° C 10.13 g (49.09 mmol) dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea, the filtrate evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 47.5 g (88% of theory) of a colorless, viscous oil.

Elemental analysis:

• Calculated: C 54.35 H 4.56 N 3.07 F 26.34
• Found: C 54.52 H 4.64 N 3.00 F 26.17

f) 2-N- (1-O-α-d-carbonylmethyl-3-mannranose) -L-lysine - [(1H, 1H, 2H, 2H-perfluoro-9-methyl-decyl) -methyl] -amide

To a solution of 47.0 g (34.30 mmol) of the title compound of Example 4e in 600 ml of ethanol is added 4.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 30.2 g (quantitative) of a colorless solid.

Elemental analysis:

• calc .: C 35.67 H 3.68 N 4.80 F 41.23
• Found: C 35.99 H 3.75 N 4.76 F 41.01

g) 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- (1-O-α-d-carbonylmethylmannopyranose) -L-lysine - [(1H, 1H, 2H, 2H-perfluoro-9-methyldecyl) -methyl] -amide, Gd complex

(30.27 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 with gentle heating in 200 ml of dimethyl sulfoxide. At 10 ° C., 7.81 g (37.84 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 16 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 30.4 g (63% of theory) of a colorless solid
Water content (Karl Fischer): 6.7%

Elemental analysis (related to the anhydrous substance):

• Calculated: C 36.34 H 4.07 N 7.53 F 24.27 Gd 10.57
• Found .: C 36.49 H 4.11 N 7.48 F 24.36 Gd 10.40

Example 5

a) 3,5-Dinitrobenzoic acid - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide

To 23.86 g (50 mmol) of the title compound from Example 1a and 10.1 g (100 mmol) of triethylamine dissolved in 200 ml of dichloromethane is added dropwise at 0 ° C, a solution of 12.68 g (55 mmol) of dinitrobenzoyl chloride in 100 ml of dichloromethane and stirred for 3 h 0 ° C. It is mixed with 250 ml of 0.5 M hydrochloric acid, and then stirred for 10 min at room temperature. The organic phase is separated, dried over magnesium sulfate, evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: hexane / ethyl acetate 3: 1).
Yield: 29.6 g (88% of theory) of a colorless solid.

Elemental analysis:

• calc .: C 32.21 H 1.50 N 6.26 F 48.11
• Found .: C 32.49 H 1.56 N 6.13 F 48.23

b) 3,5-Diaminobenzoic acid - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide

To a solution of 28.0 g (41.71 mmol) of the title compound from Example 5a in 400 ml of ethanol is added 5.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 25.5 g (quantitative) of a yellowish solid.

Elemental analysis:

• comp .: C 35.37 H 2.31 N 6.87 F 52.83
• Found .: C 35.69 H 2.41 N 6.78 F 52.63

c) 5-Amino-3-N- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetyl) -benzoic acid - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl ] amide

To a solution of 15 g (24.54 mmol) of the title compound of Example 5b and 5.45 g (24.54 mmol) of {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) and 2.82 g (24.54 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide are added at 0 ° C 6.33 g (30.68 mmol) dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then for 24 h at room temperature , It is filtered from the precipitated urea, the filtrate evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).
Yield: 9.4 g (47% of theory) of a colorless solid.

Elemental analysis:

• Re: C 39.77 H 3.71 N 5.15 F 39.60
• Found .: C 39.86 H 3.75 N 5.11 F 39.48

d) 3-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 5-N- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetyl) benzoic acid - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] - amide, Gd complex

7.5 g (9.20 mmol) of the title compound from Example 5c, 1.06 g (9.2 mmol) of N-hydroxysuccinimide, 758 mg (18.4 mmol) of lithium chloride and 5.80 g (9.2 mmol) of 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)) dissolved in 200 ml of dimethyl sulfoxide with gentle warming. At 10.degree. C., 2.38 g (11.5 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 48 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 8.3 g (58% of theory) of a colorless solid
Water content (Karl Fischer): 8.5%

Elemental analysis (related to the anhydrous substance):

• Re: C 38.71 H 4.10 N 7.85 F 22.63 Gd 11.02
• Found .: C 38.94 H 4.06 N 7.79 F 22.57 Gd 10.96

Example 6

a) (1H, 1H, 2H, 2H, 3H, 3H-perfluorundecyl) -methylamine

To 18.9 ml (200 mmol) of acetic anhydride are added dropwise at 0 ° C 9.8 ml (260 mmol) of formic acid and heated to 60 ° C for 2 h. After cooling to room temperature, a solution of 28.63 g (60 mmol) of 1H, 1H, 2H, 2H, 3H, 3H-perfluoroundecylamine (Szlavik et al., J. Fluorine Chem., 2001, 7-14) in 150 ml of THF is added dropwise and stirred for 3 h at room temperature. The reaction solution is evaporated to dryness in vacuo, the residue dissolved in 100 ml of THF, treated with 20 ml of 10 M borane dimethyl sulfide (in THF) and heated under reflux for 5 h. It is cooled to 0 ° C, added dropwise 100 ml of methanol, stirred for 1 h at room temperature and then evaporated to dryness in vacuo. The residue is taken up in a mixture of 300 ml of ethanol / 50 ml of 1 M hydrochloric acid and stirred at 40 ° C. for 14 h. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).
Yield: 23.9 g (81% of theory) of a colorless oil

Elemental analysis:

• calc .: C 29.34 H 2.05 N 2.85 F 65.75
• Found: C 29.27 H 2.11 N 2.91 F 65.88

b) 6-N-Benzyloxycarbonyl-2-N-trifluoroacetyl-L-lysine - [(1H, 1H, 2H, 2H, 3H, 3H-perfluorundecyl) -methyl] -amide

To 18.82 g (50 mmol) of 6-N-benzyloxycarbonyl-2-N-trifluoroacetyl-L-lysine (prepared according to EP 01/08498) and 24.56 g (50 mmol) of the title compound from Example 6a in 200 ml of THF are added at 0 ° C 24.7 g (100 mmol) of ethyl EEDQ (2-ethoxy-1,2-dihydro-quinoline-1-carboxylate) and stirred for 16 h at room temperature. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 39.2 g (92% of theory) of a colorless, viscous oil.

Elemental analysis:

• calc .: C 39.59 H 3.20 N 4.95 F 44.73
• Found .: C 39.77 H 3.26 N 4.79 F 44.62

c) 6-N-benzyloxycarbonyl-L-lysine - [(1H, 1H, 2H, 2H, 3H, 3N-perfluorundecyl) -methyl] -amide

In a solution of 38.5 g (45.32 mmol) of the title compound from Example 6b in 250 ml of ethanol is introduced at 0 ° C for 1 h ammonia gas, and then stirred for 4 h at 0 ° C. It is evaporated to dryness in vacuo and the residue is stirred out of water. The solid is filtered off and dried in vacuo at 50 ° C.
Yield: 33.4 g (98% of theory) of an amorphous solid.

Elemental analysis:

• Calculated: C 41.45 H 3.75 N 5.58 F 42.86
• Found: C 41.88 H 3.79 N 5.60 F 42.52

d) 6-N-Benzyloxycarbonyl-2-N- [1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -L-lysine - [(1H, 1H , 2H, 2H, 3H, 3H-perfluoroundecyl) methyl] -amide

To a solution of 32.0 g (42.5 mmol) of the title compound of Example 6c and 25.4 g (42.5 mmol) of 1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose (prepared according to WO 99/01160 A1) and 4.9 g (42.5 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide are added at 0 ° C 10.79 g (53.1 mmol) dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea, the filtrate evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 48.7 g (86% of theory) of a colorless, viscous oil.

Elemental analysis:

• Re: C 55.82 H 4.84 N 3.15 F 24.21
• Found .: C 55.99 H 4.82 N 3.11 F 24.01

e) 2-N- (1-O-α-d-carbonyl-methyl-mannopyranose) -L-lysine - [(1H, 1H, 2H, 2H, 3H, 3H-perfluorundecyl) -methyl] -amide

To a solution of 48.0 g (35.98 mmol) of the title compound from Example 6d in 600 ml of ethanol is added 5.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 30.5 g (quantitative) of a colorless solid.

Elemental analysis:

• calc .: C 37.20 H 4.08 N 5.01 F 38.47
• Found .: C 37.44 H 4.16 N 4.95 F 38.24

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- (1-O-α-d-carbonylmethylmannopyranose) -L-lysine - [(1H, 1H, 2H, 2H, 3H, 3H-perfluoroundecyl) methyl] -amide, Gd complex

30.0 g (35.73 mmol) of the title compound of Example 6e, 4.11 g (35.73 mmol) of N-hydroxysuccinimide, 3.03 g (71.46 mmol) of lithium chloride and 22.50 g (35.73 mmol) of 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)) dissolved in 200 ml of dimethyl sulfoxide with gentle warming. At 10 ° C., 9.21 g (44.66 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 16 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 33.3 g (60% of theory) of a colorless solid
Water content (Karl Fischer): 6.3%

Elemental analysis (related to the anhydrous substance):

• Calc .: C 37.24 H 4.31 N 7.72 F 22.25 Gd 10.81
• Found .: C 37.50 H 4.42 N 7.59 F 22.01 Gd 10.66

Example 7

a) N-Benzyloxycarbonyl-3- {2- [2- (2-methoxyethoxy) -ethoxy] -ethyl} -L-serine methyl ester

To a solution of 11.76 g (50 mmol) of N-benzyloxycarbonyl-L-aziridinecarboxylic acid methyl ester (Aldrich) and 4.85 g (23.36 mmol) of 2- [2- (2-methoxyethoxy) -ethoxy] -ethanol (Aldrich) in 100 ml of dichloromethane is added dropwise at 0 ° C, 10 ml of a 10proz boron trifluoride etherate solution in chloroform and stirred for 6 h at room temperature. The reaction solution is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).
Yield: 15.4 g (77% of theory) of a colorless oil.

Elemental analysis:

• calc .: C 57.13 H 7.32 N 3.51
• Found: C 57.54 H 7.52 N 3.27

b) N-Benzyloxycarbonyl-3- {2- [2- (2-methoxyethoxy) -ethoxy] -ethyl} -L-serine

15.0 g (37.55 mmol) of the title compound from Example 7a are dissolved in 100 ml of methanol and 50 ml of 2N potassium hydroxide solution and stirred at room temperature for 16 h. It is acidified with 2N hydrochloric acid, concentrated in vacuo, and extruded three times with 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).
Yield: 12.9 g (89% of theory) of a colorless solid.

Elemental analysis:

• Re: C 56.10 H 7.06 N 3.63
• Found: C 56.31 H 7.11 N 3.59

c) N-Benzyloxycarbonyl-3- {2- [2- (2-methoxyethoxy) -ethoxy] -ethyl} -L-serine-1 - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide

To 12 g (31.13 mmol) of the title compound from Example 7b and 14.86 g (31.13 mmol) of the title compound from Example 1a in 100 ml of THF are added at 0 ° C 14.82 g (60 mmol) EEDQ (2-ethoxy-1,2- dihydroquinoline-1-carboxylic acid ethyl ester) and stirred for 16 h at room temperature. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 22.3 g (85% of theory) of a colorless, viscous oil.

Elemental analysis:

• calc .: C 41.24 H 3.94 N 3.32 F 38.24
• Found: C 41.42 H 3.97 N 3.29 F 39.11

d) 3- {2- [2- (2-methoxy-ethoxy) -ethoxy] -ethyl} -L-serine-1 - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide

2.0 g of palladium catalyst (10% Pd / C) are added to a solution of 20.0 g (23.68 mmol) of the title compound from Example 7c in 200 ml of ethanol and hydrogenated at room temperature for 24 h. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 16.8 g (quantitative) of a colorless solid.

Elemental analysis:

• Calculated: C 35.50 H 3.83 N 3.94 F 45.46
• Found .: C 35.74 H 3.88 N 3.89 F 45.36

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

10.0 g (14.08 mmol) of the title compound from Example 7c, 1.62 g (14.08 mmol) of N-hydroxysuccinimide, 1.18 g (28.16 mmol) of lithium chloride and 9.87 g (14.08 mmol) of 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)) dissolved in 200 ml of dimethyl sulfoxide with gentle warming. At 10.degree. C., 3.63 g (17.6 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 16 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 12.9 g (64% of theory) of a colorless solid
Water content (Karl Fischer): 7.4%

Elemental analysis (related to the anhydrous substance):

• comp .: C 36.34 H 4.19 N 7.42 F 24.43 Gd 11.89
• Found .: C 36.45 H 4.17 N 7.44 F 24.37 Gd 11.78

Example 8

a) (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -methylamine

To 18.9 ml (200 mmol) of acetic anhydride are added dropwise at 0 ° C 9.8 ml (260 mmol) of formic acid and heated to 60 ° C for 2 h. After cooling to room temperature, a solution of 30.43 g (60 mmol) (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) amine (prepared according to EP 01/08498) in 150 ml of THF added dropwise and stirred for 3 h at room temperature. The reaction solution is evaporated to dryness in vacuo, the residue dissolved in 100 ml of THF, treated with 20 ml of 10 M borane dimethyl sulfide (in THF) and heated under reflux for 5 h. It is cooled to 0 ° C, added dropwise 100 ml of methanol, stirred for 1 h at room temperature and then evaporated to dryness in vacuo. The residue is taken up in a mixture of 300 ml of ethanol / 50 ml of 1 M hydrochloric acid and stirred at 40 ° C. for 14 h. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of 5% sodium hydroxide solution and extracted three times with 300 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).
Yield: 26.7 g (85% of theory) of a colorless solid

Elemental analysis:

• calc .: C 29.96 H 2.32 N 2.69 F 61.96
• Found .: C 30.22 H 2.36 N 2.60 F 61.77

b) 6-N-Benzyloxycarbonyl-2-N-trifluoroacetyl-L-lysine - [(1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -methyl] -amide

To 18.82 g (50 mmol) of 6-N-benzyloxycarbonyl-2-N-trifluoroacetyl-L-lysine (prepared according to EP 01/08498) and 26.06 g (50 mmol) of the title compound from Example 8a in 200 ml of THF are added at 0 ° C 24.7 g (100 mmol) of ethyl EEDQ (2-ethoxy-1,2-dihydro-quinoline-1-carboxylate) and stirred for 16 h at room temperature. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 39.9 g (91% of theory) of a colorless, viscous oil.

Elemental analysis:

• Re: C 39.60 H 3.32 N 4.78 F 43.20
• Found .: C 39.79 H 3.36 N 4.74 F 43.00

c) 6-N-Benzyloxycarbonyl-L-lysine - [(1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -methyl] -amide

In a solution of 39.0 g (44.34 mmol) of the title compound from Example 8b in 250 ml of ethanol is introduced at 0 ° C for 1 h ammonia gas, and then stirred for 4 h at 0 ° C. It is evaporated to dryness in vacuo and the residue is stirred out of water. The solid is filtered off and dried in vacuo at 50 ° C.
Yield: 33.8 g (97% of theory) of an amorphous solid.

Elemental analysis:

• calc .: C 41.39 H 3.86 N 5.36 F 41.22
• Found: C 41.54 H 3.89 N 5.27 F 41.11
• calc .: C 41.39 H 3.86 N 5.36 F 41.22
• Found: C 41.54 H 3.89 N 5.27 F 41.11

d) 6-N-Benzyloxycarbonyl-2-N- [1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -L-lysine - [(1H, 1H , 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -methyl] -amide

To a solution of 33.0 g (42.12 mmol) of the title compound of Example 8c and 25.22 g (42.12 mmol) of 1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose (prepared WO 99/01160 A1) and 4.85 g (42.12 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide are added at 0 ° C 10.86 g (52.65 mmol) dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea, the filtrate evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 46.0 g (80% of theory) of a colorless, viscous oil.

Elemental analysis:

• Re: C 55.47 H 4.88 N 3.08 F 23.67
• Found: C 55.39 H 4.94 N 3.04 F 23.54

e) 2-N- (1-O-α-d-carbonyl-methyl-mannopyranose) -L-lysine - [(1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -methyl] - amide

To a solution of 45.0 g (32.99 mmol) of the title compound from Example 8d in 600 ml of ethanol is added 5.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 28.7 g (quantitative) of a colorless solid.

Elemental analysis:

• calc .: C 37.29 H 4.17 N 4.83 F 37.14
• Found .: C 37.44 H 4.21 N 4.79 F 36.98

pyranose) -L-lysine - [(1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -methyl] -amide, Gd-complex

28.0 g (32.20 mmol) of the title compound from Example 8e, 3.71 g (32.20 mmol) of N-hydroxysuccinimide, 2.73 g (64.40 mmol) of lithium chloride and 20.28 g (32.20 mmol) of 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)) dissolved in 200 ml of dimethyl sulfoxide with gentle warming. At 10 ° C., 8.30 g (40.25 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 16 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 31.5 g (61% of theory) of a colorless solid
Water content (Karl Fischer): 7.1%

Elemental analysis (related to the anhydrous substance):

• Calc .: C 37.30 H 4.35 N 7.56 F 21.80 Gd 10.62
• Found .: C 37.55 H 4.39 N 7.50 F 21.77 Gd 10.55

Example 9

a) N-tert-butyloxycarbonyl-L-glutamic acid 5-benzyl ester 1 - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide

To 16.87 g (50 mmol) of N-tert-butyloxycarbonyl-L-glutamic acid 5-benzyl ester (Bachem) and 23.86 g (50 mmol) of the title compound from Example 1a in 200 ml of THF are added at 0 ° C 24.7 g (100 mmol ) EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred for 16 h at room temperature. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 35.1 g (88% of theory) of a colorless, viscous oil.

Elemental analysis:

• calc .: C 42.22 H 3.67 N 3.52 F 40.55
• Found .: C 42.39 H 3.65 N 3.55 F 40.38

b) L-Glutamic acid 5-benzyl ester 1 - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide

To a solution of 20.0 g (25.11 mmol) of the title compound from Example 9a in 50 ml of dichloromethane is added at 0 ° C 25 ml of trifluoroacetic acid, and then stirred for 4 h at room temperature. It is evaporated to dryness in vacuo and the residue chromatographed on silica gel (mobile phase: dichloromethane / methanol 10: 1).
Yield: 15.3 g (87% of theory) of an amorphous solid.

Elemental analysis:

• calc .: C 39.67 H 3.04 N 4.02 F 46.38
• Found .: C 39.88 H 3.02 N 4.00 F 46.19

c) L-Glutamic acid 5-benzyl ester N- (2- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetyl) -1 - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] -amide

To a solution of 13.93 g (20.0 mmol) of the title compound of Example 9b and 4.88 g (22.0 mmol) of {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) and 2.54 g (22.0 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide are added at 0 ° C 5.68 g (27.5 mmol) dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature , It is filtered from the precipitated urea, the filtrate evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 16.6 g (92% of theory) of a colorless, viscous oil.

Elemental analysis:

• Re: C 42.68 H 4.14 N 3.11 F 35.86
• Found .: C 42.87 H 4.19 N 3.05 F 35.69

d) L-Glutamic acid N- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetyl) -1 - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] - amide

To a solution of 16.0 g (17.77 mmol) of the title compound of Example 9c in 200 ml of ethanol are added 2.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 14.4 g (quantitative) of a colorless solid.

Elemental analysis:

• Calc .: C 37.05 H 3.86 N 3.46 F 39.85
• Found .: C 37.25 H 3.88 N 3.42 F 39.77

e) L-Glutamic acid-5 - {[1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (2-hydroxy-3-yl)] - amido} - N- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetyl) -1 - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide, Gd complex

13.5 g (16.66 mmol) of the title compound of Example 9d, 1.92 g (16.66 mmol) of N-hydroxysuccinimide, 1.41 g (33.32 mmol) of lithium chloride and 9.56 g (16.66 mmol) of 1,4,7-tris (carboxylatomethyl) -10- [3-amino-2-hydroxypropyl] -1,4,7,10-tetraazacyclododecane, Gd complex (WO 95/17451, Schering AG) are dissolved in 200 ml of dimethylformamide with gentle heating. At 10.degree. C., 4.30 g (20.83 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 48 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 13.3 g (54% of theory) of a colorless solid
Water content (Karl Fischer): 7.1%

Elemental analysis (related to the anhydrous substance):

• Re: C 36.92 H 4.35 N 7.18 F 23.64 Gd 11.51
• Found .: C 37.11 H 4.42 N 7.09 F 23.48 Gd 11.44

Example 10

a) N-tert-butyloxycarbonyl-L-glutamic acid-1 - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide

2.0 g of palladium catalyst (10% Pd / C) are added to a solution of 20.0 g (25.11 mmol) of the title compound from Example 9a in 200 ml of ethanol and hydrogenated at room temperature for 24 h. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 17.8 g (quantitative) of a colorless solid.

Elemental analysis:

• calc .: C 35.71 H 3.28 N 3.97 F 45.72
• Found .: C 35.97 H 3.36 N 3.86 F 45.49

b) N-tert-butyloxycarbonyl-L-glutamic acid 5- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -ethyl) -amide-1 - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] -amide

To a solution of 16.5 g (23.36 mmol) of the title compound of Example 10a and 4.85 g (23.36 mmol) of (2- {2- (2- (2-methoxyethoxy) -ethoxy] -ethoxy} -ethyl) -amine (Whitessides et al., JACS, 1994, 5057-5062) and 2.69 g (23.36 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide are added at 0 ° C 6.02 g (29.20 mmol) dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h The mixture is filtered from the precipitated urea, the filtrate is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).
Yield: 16.4 g (78% of theory) of a colorless, viscous oil.

Elemental analysis:

• Re: C 40.23 H 4.73 N 4.69 F 36.06
• found: C 40.41 H 4.80 N 4.63 F 35.94

c) L-Glutamic acid 5- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -ethyl) -amide-1 - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl ] amide

To a solution of 16.0 g (17.86 mmol) of the title compound from Example 10b in 50 ml of dichloromethane is added at 0 ° C 25 ml of trifluoroacetic acid, and then stirred for 4 h at room temperature. It is evaporated to dryness in vacuo and the residue chromatographed on silica gel (mobile phase: dichloromethane / methanol 10: 1).
Yield: 12.9 g (91% of theory) of an amorphous solid.

Elemental analysis:

• Cons .: C 37.75 H 4.31 N 5.26 F 40.60
• Found .: C 37.94 H 4.36 N 5.22 F 40.41

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

12.0 g (15.08 mmol) of the title compound from Example 10c, 1.74 g (15.08 mmol) of N-hydroxysuccinimide, 1.28 g (30.16 mmol) of lithium chloride and 9.50 g (15.08 mmol) of 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)) dissolved in 200 ml of dimethyl sulfoxide with gentle warming. At 10 ° C., 3.89 g (18.85 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 16 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 15.4 g (68% of theory) of a colorless solid
Water content (Karl Fischer): 6.4%

Elemental analysis (related to the anhydrous substance):

• Calculated: C 37.55 H 4.44 N 7.96 F 22.95 Gd 11.17
• Found .: C 37.68 H 4.47 N 7.89 F 22.84 Gd 11.08

Example 11

a) 6-N-Benzyloxycarbonyl-2-N-trifluoroacetyl-L-lysine-N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl ) amide

To 18.82 g (50 mmol) of 6-N-benzyloxycarbonyl-2-N-trifluoroacetyl-L-lysine (prepared according to EP 01/08498) and 28.26 g (50 mmol) of N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) amine (prepared according to EP 01/08498) in 200 ml of THF are added at 0 ° C 24.7 g (100 mmol) EEDQ (2-ethoxy 1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred for 16 h at room temperature. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 41.3 g (89% of theory) of a colorless, viscous oil.

Elemental analysis:

• calc .: C 40.31 H 3.60 N 4.55 F 41.14
• found: C 40.54 H 3.72 N 4.47 F 40.96

b) 6-N-Benzyloxycarbonyl-L-lysine-N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -amide

Into a solution of 40.0 g (43.31 mmol) of the title compound from Example 11a in 250 ml of ethanol at 0 ° C for 1 h ammonia gas, and then stirred for 4 h at 0 ° C. It is evaporated to dryness in vacuo and the residue is stirred out of water. The solid is filtered off and dried in vacuo at 50 ° C.
Yield: 35.2 g (98% of theory) of an amorphous solid.

Elemental analysis:

• Re: C 42.09 H 4.14 N 5.08 F 39.03
• Found .: C 42.27 H 4.18 N 5.00 F 38.87

c) 6-N-benzyloxycarbonyl-2-N- [1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -L-lysine-N- (2 methoxyethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -amide

To a solution of 34.5 g (41.69 mmol) of the title compound of Example 11b and 24.96 g (41.69 mmol) of 1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose (prepared according to WO 99/01160 A1) and 4.80 g (41.69 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide are added at 0 ° C 10.75 g (52.11 mmol) dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea, the filtrate evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 44.6 g (76% of theory) of a colorless, viscous oil.

Elemental analysis:

• Re: C 55.44 H 5.01 N 2.98 F 22.93
• Found .: C 55.75 H 5.12 N 3.00 F 22.64

d) 2-N- (1-O-α-d-carbonylmethyl-mannopyranose) -L-lysine-N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3 oxa-perfluorotridecyl) amide

To a solution of 44.0 g (31.24 mmol) of the title compound from Example 11c in 600 ml of ethanol are added 5.0 g of palladium catalyst (10% Pd / C) and hydrogenated at room temperature for 24 h. It is filtered from the catalyst and the filtrate evaporated to dryness in vacuo.

• Found: C 38.47 H 4.62 N 4.54 F 35.13

e) 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- (1-O-α-d-carbonylmethylmannopyranose) -L-lysine N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H -3-oxa-perfluorotridecyl) amide, Gd complex

28.0 g (30.65 mmol) of the title compound from Example 11d, 3.53 g (30.65 mmol) of N-hydroxysuccinimide, 2.60 g (61.30 mmol) of lithium chloride and 19.30 g (30.65 mmol) of 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)) dissolved in 200 ml of dimethyl sulfoxide with gentle warming. At 10 ° C., 7.90 g (38.31 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 16 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 33.7 g (67% of theory) of a colorless solid
Water content (Karl Fischer): 7.0%

Elemental analysis (related to the anhydrous substance):

• Calc .: C 37.80 H 4.49 N 7.35 F 21.17 Gd 10.31
• Found .: C 37.99 H 4.54 N 7.37 F 21.07 Gd 10.27

Example 12

a) N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) amine

To 27.78 g (60 mmol) of 1H, 1H, 2H, 2H-perfluorodecylamine (Cambon et al., J. Fluorine Chem., 1994, 115-118) and 8.28 g (60 mmol) of potassium carbonate in 200 ml of acetonitrile are added 8.34 g (60 mmol) 2-methoxyethyl bromide and stirred for 18 h at 60 ° C. The reaction solution is filtered off from insoluble constituents, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 20.5 g (65% of theory) of a colorless oil

Elemental analysis:

• calc .: C 29.96 H 2.32 N 2.69 F 61.96
• Found .: C 30.12 H 2.41 N 2.71 F 61.66

b) 6-N-Benzyloxycarbonyl-2-N-trifluoroacetyl-L-lysine-N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -amide

To 18.82 g (50 mmol) of 6-N-benzyloxycarbonyl-2-N-trifluoroacetyl-L-lysine (prepared according to EP 01/08498) and 26.06 g (50 mmol) of the title compound from Example 12a in 200 ml of THF are added at 0 ° C 24.7 g (100 mmol) of ethyl EEDQ (2-ethoxy-1,2-dihydro-quinoline-1-carboxylate) and stirred for 16 h at room temperature. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 40.5 g (92% of theory) of a colorless, viscous oil.

Elemental analysis:

• Re: C 39.60 H 3.32 N 4.78 F 43.20
• Found .: C 39.82 H 3.37 N 4.75 F 43.01

c) 6-N-Benzyloxycarbonyl-L-lysine-N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -amide

In a solution of 39.5 g (40.36 mmol) of the title compound of Example 12b in 250 ml of ethanol is introduced at 0 ° C for 1 h ammonia gas, and then stirred for 4 h at 0 ° C. It is evaporated to dryness in vacuo and the residue is stirred out of water. The solid is filtered off and dried in vacuo at 50 ° C.
Yield: 30.3 g (96% of theory) of an amorphous solid.

Elemental analysis:

• calc .: C 41.39 H 3.86 N 5.36 F 41.22
• Found: C 41.56 H 3.80 N 5.27 F 41.05

d) 6-N-benzyloxycarbonyl-2-N- [1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose] -L-lysine-N- (2- methoxyethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -amide

To a solution of 29.5 g (37.65 mmol) of the title compound of Example 12c and 22.54 g (37.65 mmol) of 1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose (prepared according to WO 99/01160 A1) and 4.33 g (37.65 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide are added at 0 ° C 9.71 g (47.06 mmol) dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea, the filtrate evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 43.5 g (82% of theory) of a colorless, viscous oil.

Elemental analysis:

• Re: C 55.47 H 4.88 N 3.08 F 23.67
• Found: C 55.69 H 5.00 N 3.04 F 23.48

e) 2-N- (1-O-α-d-carbonylmethyl-mannopyranose) -L-lysine-N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -amide

To a solution of 42.5 g (31.15 mmol) of the title compound of Example 12d in 600 ml of ethanol is added 5.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 27.3 g (quantitative) of a colorless solid.

Elemental analysis:

• calc .: C 37.29 H 4.17 N 4.83 F 37.14
• Found .: C 37.55 H 4.29 N 4.72 F 36.88

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- (1-O-α-d-carbonylmethylmannopyranose) -L-lysine N- (2-methoxyethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -amide, Gd complex

26.0 g (29.90 mmol) of the title compound of Example 12e, 3.42 g (29.90 mmol) of N-hydroxysuccinimide, 2.71 g (59.80 mmol) of lithium chloride and 18.82 g (29.90 mmol) of 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)) dissolved in 200 ml of dimethyl sulfoxide with gentle warming. At 10 ° C., 7.71 g (37.38 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 16 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 28.4 g (60% of theory) of a colorless solid
Water content (Karl Fischer): 6.2

Elemental analysis (related to the anhydrous substance):

• Calc .: C 37.30 H 4.35 N 7.56 F 21.80 Gd 10.62
• Found .: C 37.49 H 4.58 N 7.46 F 21.69 Gd 10.51

Example 13

a) (3-Benzyloxy-2,2-bisbenzyloxymethylpropoxy) acetic acid

To 50 g (123 mmol) of 3-benzyloxy-2,2-bisbenzyloxymethylpropan-1-ol (Liu et al., Chem. Commun., 2002, 594) and 10.35 g (184.5 mmol) of finely powdered potassium hydroxide and a catalytic amount ( 1 g) tetra-n-butylammoniumhydrogensulfat in 500 ml of toluene are added at 0 ° C 29.99 g (153.75 mmol) of bromoacetic acid tert-butyl ester and stirred for 2 h at this temperature and 12 h at room temperature. The reaction solution is mixed with 800 ml of ethyl acetate and 500 ml of water. The organic phase is separated and washed twice with 500 ml of water, then dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is suspended in a mixture consisting of 500 ml of methanol and 0.5 M sodium hydroxide solution in a ratio of 2: 1 and then heated to 60 ° C. for 12 hours. The reaction mixture is neutralized for work-up by addition of Amberlite IR 120 (H ⁺ form) cation exchange resin, filtered off from the exchanger, evaporated to dryness and chromatographed on silica gel (eluent: ethyl acetate / hexane 1: 3).
Yield: 35.3 g (62% of theory) of a colorless oil

Elemental analysis:

• Re: C 72.39 H 6.94
• Found: C 72.58 N 7.10

b) 6-N-Benzyloxycarbonyl-2-N - [(3-benzyloxy-2,2-bis-benzyloxymethylpropoxy) -acetyl] -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] - amide

To a solution of 31.83 g (43.05 mmol) of the title compound from Example 1c and 20 g (43.05 mmol). Title compound from Example 13a and 4.95 g (43.05 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide are added at 0 ° C 11.10 g (53.81 mmol) of dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea, the filtrate evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 43.0 g (84% of theory) of a colorless, viscous oil.

Elemental analysis:

• calc .: C 53.67 H 4.76 N 3.54 F 27.23
• Found .: C 53.89 H 4.85 N 3.47 F 27.12

c) 2-N - [(3-hydroxy-2,2-dihydroxymethylpropoxy) -acetyl] -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide

To a solution of 42.0 g (35.41 mmol) of the title compound from Example 13b in 600 ml of ethanol are added 4.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 27.6 g (quantitative) of a colorless solid.

Elemental analysis:

• Re: C 36.89 H 4.13 N 5.30 F 41.33
• Found: C 37.15 H 4.21 N 5.23 F 41.16

d) 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 - [(3-hydroxy-2,2-dihydroxymethylpropoxy) -acetyl] -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide, Gd complex

25.0 g (31.99 mmol) of the title compound from Example 13c, 3.68 g (31.99 mmol) of N-hydroxysuccinimide, 2.71 g (63.98 mmol) of lithium chloride and 20.15 g (31.99 mmol) of 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)) dissolved in 200 ml of dimethyl sulfoxide with gentle warming. At 10 ° C., 8.25 g (39.99 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 16 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 29.8 g (63% of theory) of a colorless solid
Water content (Karl Fischer): 5.9%

Elemental analysis (related to the anhydrous substance):

• Re: C 37.07 H 4.34 N 8.04 F 23.18 Gd 11.29
• Found .: C 37.23 H 4.39 N 7.99 F 22.98 Gd 11.21

Example 14

a) 1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-methyl) mannopyranose

To 24.1 g (101.94 mmol) of α- (2,3,4,6-tetra-O-methyl) mannopyranose (Ganguly et al., J. Chem. Soc., 1969, 1488) and 8.58 g (152.9 mmol) of fine powdered potassium hydroxide and a catalytic amount (1 g) of tetra-n-butylammoniumhydrogensulfat in 500 ml of toluene are added at 0 ° C 24.85 g (127.43 mmol) bromoacetic acid tert-butyl ester and stirred for 2 h at this temperature and 12 h at room temperature. The reaction solution is mixed with 800 ml of ethyl acetate and 500 ml of water. The organic phase is separated, the aqueous phase washed twice with 200 ml of ethyl acetate, the combined organic phases dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is suspended in a mixture consisting of 500 ml of methanol and 0.5 M sodium hydroxide solution in a ratio of 2: 1 and then heated to 60 ° C. for 12 hours. The reaction mixture is neutralized for work-up by addition of Amberlite IR 120 (H ⁺ form) cation exchange resin, filtered off from the exchanger, evaporated to dryness and chromatographed on silica gel (mobile phase: dichloromethane / methanol 10: 1).
Yield: 17.5 g (58% of theory) of a colorless oil

Elemental analysis:

• Re: C 48.97 H 7.53
• Found .: C 49.32 H 7.74

b) 6-N-Benzyloxycarbonyl-2-N- [1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-methyl) mannopyranose] -L-lysine - [(1H, 1H , 2H, 2H-perfluorodecyl) methyl] -amide

To a solution of 37.7 g (50.97 mmol) of the title compound of Example 1c and 15 g (50.97 mmol) of the title compound of Example 14a and 5.87 g (50.97 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide are added at 0 ° C 13.15 g ( 63.71 mmol) dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then for 16 h at room temperature. It is filtered from the precipitated urea, the filtrate evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 10: 1).
Yield: 42.1 g (81% of theory) of a colorless, viscous oil.

Elemental analysis:

• Calc .: C 43.75 H 4.56 N 4.14 F 31.80
• Found .: C 43.68 H 4.72 N 4.09 F 31.67

c) 2-N- [1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-methyl) mannopyranose] -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl ) -methyl] -amide

To a solution of 40 g (39.38 mmol) of the title compound from Example 14b in 600 ml of ethanol are added 4.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 34.5 g (quantitative) of a colorless solid.

Elemental analysis:

• calc .: C 39.51 H 4.57 N 4.77 F 36.63
• Found .: C 39.88 H 4.63 N 4.59 F 36.47

d) 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- [1-O-α-D-carbonylmethyl- (2,3,4,6-tetra-O-methyl) mannopyranose] -L-lysine - [(1H, 1H, 2H, 2H -perfluordecyl) -methyl] -amide, Gd complex

30.0 g (34.03 mmol) of the title compound from Example 14c, 3.92 g (34.03 mmol) of N-hydroxysuccinimide, 2.89 g (68.06 mmol) of lithium chloride and 21.43 g (34.03 mmol) of 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)) dissolved in 200 ml of dimethyl sulfoxide with gentle warming. At 10.degree. C., 8.78 g (42.54 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 16 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 31.4 g (58% of theory) of a colorless solid
Water content (Karl Fischer): 6.0

Elemental analysis (related to the anhydrous substance):

• Calc .: C 38.61 H 4.59 N 7.50 F 21.63 Gd 10.53
• Found: C 38.75 H 4.49 N 7.52 F 21.44 Gd 10.39

Example 15

a) L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide

2.0 g of palladium catalyst (10% Pd / C) are added to a solution of 20 g (27.05 mmol) of the title compound from Example 1c in 400 ml of ethanol and hydrogenated at room temperature for 24 h. It is filtered from the catalyst and the filtrate evaporated to dryness in vacuo.
Yield: 16.4 g (quantitative) of a colorless solid.

Elemental analysis:

• calc .: C 33.73 H 3.33 N 6.94 F 53.35
• Found: C 33.96 H 3.42 N 6.79 F 53.06

b) 2,6-N, N-bis [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo) 5-methyl-5-yl)] - L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] -amide, Gd complex

10.0 g (16.52 mmol) of the title compound of Example 15a, 3.80 g (33.04 mmol) of N-hydroxysuccinimide, 2.89 g (66.08 mmol) of lithium chloride and 20.81 g (33.04 mmol) of 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)) dissolved in 200 ml of dimethyl sulfoxide with gentle warming. At 10 ° C., 8.52 g (41.3 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 16 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 14.3 g (44% of theory) of a colorless solid
Water content (Karl Fischer): 7.2%

Elemental analysis (related to the anhydrous substance):

• Re: C 36.12 H 4.19 N 9.96 F 17.66 Gd 14.87
• Found .: C 36.27 H 4.12 N 9.88 F 17.52 Gd 14.68

Example 16

a) 2-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 6-N-benzyloxycarbonyl-L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] -amide, Gd complex

50.0 g (67.62 mmol) of the title compound from Example 1c, 7.78 g (67.62 mmol) of N-hydroxysuccinimide, 5.73 g (135.24 mmol) of lithium chloride and 42.58 g (67.62 mmol) of 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)) dissolved with gentle warming in 400 ml of dimethyl sulfoxide. At 10 ° C., 17.44 g (84.53 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 16 h. The solution is poured into 5000 ml of diethyl ether and stirred for 10 minutes. The precipitated solid is filtered off and then the residue is chromatographed on silica gel (mobile phase: dichloromethane / methanol / aqueous ammonia 10: 5: 1).
Yield 69.2 g (71% of theory) of a colorless solid
Water content (Karl Fischer): 6.0%

Elemental analysis (related to the anhydrous substance):

• Calculated: C 39.11 H 4.03 N 8.29 F 23.90 Gd 11.64
• Found .: C 39.44 H 4.11 N 8.21 F 23.75 Gd 11.57

b) 2-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide, Gd complex

To a solution of 65 g (45.2 mmol) of the title compound of Example 16b in 600 ml of methanol and 100 ml of water is added 5.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 57.9 g (quantitative) of a colorless solid.
Water content (Karl Fischer): 4.5%

Elemental analysis (related to the anhydrous substance):

• calc .: C 35.53 H 3.98 N 9.21 F 26.54 Gd 12.92
• Found .: C 35.76 H 4.02 N 9.15 F 26.37 Gd 12.81

c) 2-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 6-N- (1-O-α-dodecarbonylmethyl-3-mannranose) -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide, Gd-complex

To a solution of 15.7 g (12.32 mmol) of the title compound of Example 16b and 7.38 g (12.32 mmol) of 1-O-α-d-carbonylmethyl- (2,3,4,6-tetra-O-benzyl) mannopyranose (prepared according to WO 99101160 A1) and 1.42 g (12.32 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide are added at 0 ° C 3.18 g (15.4 mmol) dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 100 ml of methanol, treated with 2.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo. The residue is taken up in a little water, filtered off from insoluble constituents, and the filtrate is then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 13.2 g (69% of theory) of a colorless solid
Water content (Karl Fischer): 6.7%

Elemental analysis (related to the anhydrous substance):

• Re: C 36.77 H 4.21 N 7.80 F 22.47 Gd 10.94
• Found .: C 36.95 H 4.26 N 7.74 F 22.43 Gd 10.82

Example 17

a) 2-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 6-N- (2-hydroxyacetyl) -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] -amide, Gd complex

To a solution of 12.75 g (10.0 mmol) of the title compound of Example 16b and 1.83 g (11.0 mmol) of 2-Benzyioxyessigsäure (Aldrich) and 1.27 g (11.0 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide are added at 0 ° C 2.84 g (13.75 mmol) dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then for 16 h at room temperature. It is filtered from the precipitated urea and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 100 ml of methanol, treated with 2.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo. The residue is taken up in a little water, filtered off from insoluble constituents, and the filtrate is then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 10.6 g (78% of theory) of a colorless solid
Water content (Karl Fischer): 6.3%

Elemental analysis (related to the anhydrous substance):

• Calc .: C 35.80 H 3.95 N 8.79 F 25.33 Gd 12.33
• Found .: C 35.97 H 4.00 N 8.75 F 25.17 Gd 12.21

Example 18

a) 2-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 6-N- (2-methoxyacetyl) -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] -amide, Gd complex

To a solution of 12.75 g (10.0 mmol) of the title compound of Example 16b and 0.99 g (11.0 mmol) of 2-methoxyacetic acid (Aldrich) and 1.27 g (11.0 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide are added at 0 ° C 2.84 g (13.75 mmol) dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then for 16 h at room temperature. It is filtered from the precipitated urea and the filtrate is evaporated to dryness in vacuo. The residue is taken up in a little water, filtered off from insoluble constituents, and the fil subsequently purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 11.3 g (81% of theory) of a colorless solid
Water content (Karl Fischer): 6.9%

Elemental analysis (related to the anhydrous substance):

• Cons .: C 36.34 H 4.07 N 8.69 F 25.05 Gd 12.20
• Found .: C 26.47 H 4.11 N 8.62 F 24.89 Gd 12.05

Example 19

a) 2-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 6-N- [2- (2-methoxyethoxy) acetyl] -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] -amide, Gd complex

To a solution of 12.75 g (10.0 mmol) of the title compound of Example 16b and 1.48 g (11.0 mmol) of (2-methoxyethoxy) -acetic acid (Aldrich) and 1.27 g (11.0 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide are added at 0 ° C added 2.84 g (13.75 mmol) of dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then for 16 h at room temperature. It is filtered from the precipitated urea and the filtrate is evaporated to dryness in vacuo. The residue is taken up in a little water, filtered off from insoluble constituents, and the filtrate is then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 10.8 g (75% of theory) of a colorless solid
Water content (Karl Fischer): 7.2%

Elemental analysis (related to the anhydrous substance):

• Re: C 36.94 H 4.23 N 8.41 F 24.23 Gd 11.80
• Found .: C 37.05 H 4.28 N 8.37 F 24.09 Gd 11.68

Example 20

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

To a solution of 12.75 g (10.0 mmol) of the title compound of Example 16b and 1.96 g (11.0 mmol) of [2- (2-methoxyethoxy) ethoxy] acetic acid (Aldrich) and 1.27 g (11.0 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide are added at 0 ° C 2.84 g (13.75 mmol) of dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea and the filtrate is evaporated to dryness in vacuo. The residue is taken up in a little water, filtered off from insoluble constituents, and the filtrate is then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 11.6 g (78% of theory) of a colorless solid
Water content (Karl Fischer): 7.0%

Elemental analysis (related to the anhydrous substance):

• Calc .: C 37.50 H 4.39 N 8.14 F 23.45 Gd 11.42
• Found .: C 37.66 H 4.42 N 8.10 F 23.42 Gd 11.33

Example 21

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

To a solution of 12.75 g (10.0 mmol) of the title compound of Example 16b and 3.28 g (11.0 mmol) {2- [2- (2-Benzyloxyethoxy) -ethoxy] -ethoxy} -acetic acid (prepared according to WO 2000056723) and 1.27 g (11.0 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide are added at 0.degree. C. to 2.84 g (13.75 mmol ) Dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then for 16 h at room temperature. It is filtered from the precipitated urea and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 100 ml of methanol, treated with 2.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo. The residue is taken up in a little water, filtered off from insoluble constituents, and the filtrate is then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 10.9 g (72% of theory) of a colorless solid
Water content (Karl Fischer): 6.9%

Elemental analysis (related to the anhydrous substance):

• Calculated: C 37.55 H 4.44 N 7.96 F 22.95 Gd 11.17
• Found: C 37.69 H 4.51 N 8.00 F 22.77 Gd 11.04

Example 22

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

To a solution of 12.75 g (10.0 mmol) of the title compound of Example 16b and 2.44 g (11.0 mmol) of {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) and 1.27 g (11.0 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide are added at 0 ° C 2.84 g (13.75 mmol) of dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea and the filtrate is evaporated to dryness in vacuo. The residue is taken up in a little water, filtered off from insoluble constituents, and the filtrate is then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 11.2 g (74% of theory) of a colorless solid
Water content (Karl Fischer): 6.3%

Elemental analysis (related to the anhydrous substance):

• Re: C 38.03 H 4.54 N 7.88 F 22.72 Gd 11.06
• Found .: C 38.27 H 4.62 N 7.71 F 22.61 Gd 11.00

Example 23

a) 2-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 6-N- [2- (2-hydroxyethoxy) acetyl] -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] -amide, Gd complex

To a solution of 12.75 g (10.0 mmol) of the title compound of Example 16b and 2.31 g (11.0 mmol) of (2-benzyloxyethoxy) -acetic acid (Mitchell et al., Heterocyclic Chem., 1984, 697-699) and 1.27 g (11.0 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide are added at 0 ° C 2.84 g (13.75 mmol) of dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 100 ml of methanol, treated with 2.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo. The residue is taken up in a little water, filtered off from insoluble constituents, and the filtrate is then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 9.7 g (68% of theory) of a colorless solid
Water content (Karl Fischer): 7.1%

Elemental analysis (related to the anhydrous substance):

• Calc .: C 36.42 H 4.13 N 8.49 F 24.48 Gd 11.92
• Found .: C 36.61 H 4.17 N 8.44 F 24.39 Gd 11.87

Example 24

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

To a solution of 12.75 g (10.0 mmol) of the title compound of Example 16b and 2.31 g (11.0 mmol) of [2- (2-benzyloxyethoxy) ethoxy] acetic acid (Bartsch et al., J. Org. Chem., 1984, 4076-4078) and 1.27 g (11.0 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide are added at 0 ° C 2.84 g (13.75 mmol) of dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 100 ml of methanol, treated with 2.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo. The residue is taken up in a little water, filtered off from insoluble constituents, and the filtrate is then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 10.2 g (70% of theory) of a colorless solid
Water content (Karl Fischer): 6.5%

Elemental analysis (related to the anhydrous substance):

• Calc .: C 37.01 H 4.29 N 8.22 F 23.69 Gd 11.54
• Found .: C 37.09 H 4.35 N 8.17 F 23.41 Gd 11.29

Example 25

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

To a solution of 12.75 g (10.0 mmol) of the title compound of Example 16b and 2.93 g (11.0 mmol) of (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -ethoxy) -acetic acid (Vegtle et al., Liebigs Ann. Chem., 1980, 858-862) and 1.27 g (11.0 mmol) N-hydroxysuccinimide in 100 ml dimethylformamide are added at 0 ° C 2.84 g (13.75 mmol) dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea and the filtrate is evaporated to dryness in vacuo. The residue is taken up in a little water, filtered off from insoluble constituents, and the filtrate is then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 10.7 g (68% of theory) of a colorless solid
Water content (Karl Fischer): 6.7%

Elemental analysis (related to the anhydrous substance):

• Re: C 38.53 H 4.68 N 7.65 F 22.04 Gd 10.73
• Found .: C 38.49 H 4.80 N 7.75 F 21.98 Gd 10.69

Example 26

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

To a solution of 12.75 g (10.0 mmol) of the title compound of Example 16b and 3.77 g (11.0 mmol) of (2- {2- [2- (2-benzyloxyethoxy) -ethoxy] -ethoxy} -ethoxy) -acetic acid (Keana et al., J. Org. Chem., 1983, 2647-2654) and 1.27 g (11.0 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide are added at 0 ° C 2.84 g (13.75 mmol) of dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 100 ml of methanol, treated with 2.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo. Of the The residue is taken up in a little water, filtered off from insoluble constituents, and the filtrate is then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 12.2 g (79% of theory) of a colorless solid
Water content (Karl Fischer): 6.2%

Elemental analysis (related to the anhydrous substance):

• Re: C 38.07 H 4.58 N 7.72 F 22.25 Gd 10.84
• Found .: C 38.31 H 4.62 N 7.59 F 22.04 Gd 10.75

Example 27

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

To a solution of 12.75 g (10.0 mmol) of the title compound of Example 16b and 3.41 g (11.0 mmol) of [2- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -ethoxy) -ethoxy ] -acetic acid (prepared according to US 2769838 ) and 1.27 g (11.0 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide are added at 0 ° C 2.84 g (13.75 mmol) of dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea and the filtrate is evaporated to dryness in vacuo. The residue is taken up in a little water, filtered off from insoluble constituents, and the filtrate is then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 8.8 g (54% of theory) of a colorless solid
Water content (Karl Fischer): 7.1%

Elemental analysis (related to the anhydrous substance):

• Calc .: C 38.99 H 4.81 N 7.42 F 21.40 Gd 10.42
• Found .: C 39.22 H 4.94 N 7.36 F 21.27 Gd 10.32

Example 28

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

30.02 g (50 mmol) of 1,3-bis (2-benzyloxy-1-benzyloxymethylethoxy) -propan-2-ol (Cassel et al., Eur. J. Org. Chem., 2001, 5, 875- 896) and 5.6 g (100 mmol) of finely powdered potassium hydroxide and a catalytic amount (1 g) of tetra-n-butylammonium hydrogensulfate in 250 ml of toluene are added at 0 ° C 14.62 g (75 mmol) of bromoacetic acid tert-butyl ester and stirred h at this temperature and 12 h 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, then dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is suspended in a mixture consisting of 400 ml of methanol and 0.5 M sodium hydroxide solution in a ratio of 2: 1 and then heated to 60 ° C. for 12 hours. The reaction mixture is neutralized for work-up by addition of Amberlite IR 120 (H ⁺ form) cation exchange resin, filtered off from the exchanger, evaporated to dryness and chromatographed on silica gel (eluent: ethyl acetate / hexane 1: 3).
Yield: 23.5 g (71% of theory) of a colorless wax

Elemental analysis:

• Re: C 71.10 H 7.04
• Found .: C 71.29 H 7.21

b) 2-N- [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 6-N - {[1,3-bis- (2-benzyloxy-1-benzyloxymethyl-ethoxy) -prop-2-yl] acetyl} -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] -amide, Gd complex

To a solution of 12.75 g (10.0 mmol) of the title compound of Example 16b and 7.25 g (11.0 mmol) The title compound from Example 28a and 1.27 g (11.0 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide are added at 0 ° C 2.84 g (13.75 mmol) of dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature. It is filtered from the precipitated urea and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 100 ml of methanol, treated with 2.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h at room temperature. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo. The residue is taken up in a little water, filtered off from insoluble constituents, and the filtrate is then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 12.4 g (77% of theory) of a colorless solid
Water content (Karl Fischer): 6.7%

Elemental analysis (related to the anhydrous substance):

• Calc .: C 37.70 H 4.58 N 7.48 F 21.57 Gd 10.50
• Found .: C 37.86 H 4.61 N 7.47 F 21.49 Gd 10.44

Example 29

a) 3,5-N, N'-bis [1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo) 5-methyl-5-yl)] - benzoic acid - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] -amide, Gd complex

5.0 g (8.18 mmol) of the title compound from Example 5b, 1.88 g (16.36 mmol) of N-hydroxysuccinimide, 1.39 g (32.72 mmol) of lithium chloride and 10.30 g (16.36 mmol) of 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)) dissolved in 200 ml of dimethyl sulfoxide with gentle warming. At 10 ° C., 4.22 g (20.45 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 48 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 10.1 g (61% of theory) of a colorless solid
Water content (Karl Fischer): 8.9%

Elemental analysis (related to the anhydrous substance):

• Re: C 36.66 H 3.85 N 9.92 F 17.60 Gd 17.14
• Found .: C 36.87 H 3.88 N 9.86 F 17.55 Gd 16.98

Example 30

a) 6-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (butanoyl-4- (R) -carboxylato-4-yl)] - 2-N- (1-O-α-d-carbonylmethylmannopyranose) -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] -amide, Gd complex monosodium salt and 6-N - ({1,4,7-tris- (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (ethano- [2- (R) -carboxylatoethyl] - yl)} - 2-N- (1-O-α-d-carbonylmethyl-3-mannranose) -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide, Gd-complex Monosodium salt

2.5 g (3.03 mmol) of the title compound from Example 1e, 388 mg (3.79 mmol) of triethylamine and 3.02 g (3.79 mmol) of 2- (R) -2- [4,7,10-tris (carboxylatomethyl) -1,4 , 7,10-Tetraazacyclododecan-1-yl] pentanedicarboxylic acid monopentafluorophenyl ester, Gd complex (WO 2005/0014154, EPIX PHARMACEUTICALS, INC., (Example 9: EP-2104-15 Pfp)) are dissolved in 50 ml of dimethylsulfoxide and 16 h stirred at room temperature. The solution is poured into 1000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile). The fractions containing the product are evaporated, dissolved in water, neutralized with 0.1 N sodium hydroxide solution and then lyophilized
Yield: 1.43 g (29% of theory) of a colorless solid as a 3: 2 mixture of reagents.
Water content (Karl Fischer): 9.2%

Elemental analysis (related to the anhydrous substance):

• Re: C 38.07 H 4.58 N 7.72 F 22.25 Gd 10.84
• Found .: C 38.23 H 4.62 N 7.66 F 22.34 Gd 10.59

Example 31

a) 2-N-Benzyloxycarbonyl-6-N-tert-butyloxycarbonyl-L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide

To 19.02 g (50 mmol) of 2-N-benzyloxycarbonyl-6-N-tert-butyloxycarbonyl-L-lysine (Bachem) and 23.86 g (50 mmol) of the title compound of Example 1a in 200 ml of THF are added at 0 ° C 24.7 g (100 mmol) EEDQ (2-ethoxy-1,2-dihydro-quinoline-1-carboxylic acid ethyl ester) and stirred for 16 h at room temperature. It is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 36.5 g (87% of theory) of a colorless, viscous oil.

Elemental analysis:

• Calculated: C 42.92 H 4.08 N 5.00 F 38.47
• Found: C 43.15 H 4.12 N 4.96 F 38.22

b) 2-N-Benzyloxycarbonyl-L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide

To a solution of 35.0 g (41.69 mmol) of the title compound from Example 31a in 100 ml of dichloromethane is added at 0 ° C 50 ml of trifluoroacetic acid, and then stirred for 4 h at room temperature. It is evaporated to dryness in vacuo and the residue chromatographed on silica gel (mobile phase: dichloromethane / methanol 10: 1).
Yield: 28.9 g (94% of theory) of an amorphous solid.

Elemental analysis:

• Re: C 40.61 H 3.54 N 5.68 F 43.68
• found: C 40.84 H 3.62 N 5.63 F 43.51

c) 2-N-Benzyloxycarbonyl-6-N- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetyl) -L-lysine - [(1H, 1H, 2H, 2H- perfluorodecyl) methyl] -amide

To a solution of 10 g (13.52 mmol) of the title compound of Example 31b and 3.00 g (13.52 mmol) of {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetic acid (Voegtle et al., Liebigs Ann Chem., 1980, 858-862) and 1.56 g (13.52 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide are added at 0.degree. C. 3.49 g (16.9 mmol) of dicyclohexylcarbodiimide, stirred for 3 hours at 0.degree. C. and then for 16 hours room temperature. It is filtered from the precipitated urea, the filtrate evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 10.5 g (82% of theory) of a colorless, viscous oil.

Elemental analysis:

• calc .: C 43.27 H 4.49 N 4.45 F 34.22
• Found .: C 43.44 H 4.52 N 4.38 F 34.09

d) 6-N- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetyl) -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] - amide

2.0 g of palladium catalyst (10% Pd / C) are added to a solution of 10 g (10.60 mmol) of the title compound from Example 31c in 200 ml of ethanol and hydrogenated at room temperature for 24 h. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 8.6 g (quantitative) of a colorless solid.

Elemental analysis:

• Re: C 38.57 H 4.48 N 5.19 F 39.89
• Found: C 38.69 H 4.52 N 5.11 F 39.65

e) 2-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (butanoyl-4- (R) -carboxylato-4-yl)] - 6-N- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetyl) -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] -amide, Gd complex monosodium salt and 6-N - {[1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (ethano- [2- (R) -carboxylatoethyl] -yl} -6 -N- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetyl) -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide, Gd -Complex Monosodium salt

2.5 g (3.09 mmol) of the title compound of Example 31d, 400 mg (3.86 mmol) of triethylamine and 3.08 g (3.86 mmol) of 2- (R) -2- [4,7,10-tris (carboxylatomethyl) -1,4 , 7,10-Tetraazacyclododecan-1-yl] pentanedicarboxylic acid monopentafluorophenyl ester, Gd complex (WO 2005/0014154, EPIX PHARMACEUTICALS, INC., (Example 9: EP-2104-15 Pfp)) are dissolved in 50 ml of dimethylsulfoxide and 16 h stirred at room temperature. The solution is poured into 1000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile). The fractions containing the product are evaporated, dissolved in water, neutralized with 0.1 N sodium hydroxide solution and then lyophilized
Yield: 1.61 g (33% of theory) of a colorless solid as a 3: 2 mixture of reagents.
Water content (Karl Fischer): 8.8%

Elemental analysis (related to the anhydrous substance):

• Calc .: C 37.42 H 4.33 N 6.79 F 22.36 Gd 10.89
• Found .: C 37.58 H 4.36 N 6.72 F 22.44 Gd 10.68

Example 32

a) 2-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - 6-N- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetyl) -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl ] amide, trisodium salt

10 g (6.59 mmol) of the title compound from Example 22a are dissolved in a mixture of 100 ml of water and 30 ml of isopropanol, treated with 2.25 g (24.96 mmol) of oxalic acid and heated to 100 ° C for 5 h. After cooling to room temperature, the precipitated solid and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile). The fractions containing the product are evaporated, dissolved in water, adjusted to a pH of 10 with 0.1 N sodium hydroxide solution and then lyophilized
Yield 8.08 g (84% of theory) of a colorless solid
Water content (Karl Fischer): 8.6%

Elemental analysis (related to the anhydrous substance):

• calc .: C 40.55 H 4.84 N 8.41 F 24.23
• Found .: C 40.40 H 4.69 N 8.32 F 23.98

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

2.0 g (1.37 mmol) of the title compound from Example 25a are dissolved in 50 ml of water and 1 ml of acetic acid, treated with 405 mg (1.51 mmol) of dysprosium chloride and stirred at 80 ° C for 6 h. It is neutralized with ammonia, evaporated to dryness and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 1.86 g (89% of theory) of a colorless solid
Water content (Karl Fischer): 6.5%

Elemental analysis (related to the anhydrous substance):

• Calc .: C 37.89 H 4.52 N 7.85 F 22.64 Dy 11.39
• Found: C 38.04 H 4.55 N 7.80 F 22.46 Dy 11.21

Example 33

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

2.0 g (1.37 mmol) of the title compound from Example 25a are dissolved in 50 ml of water and 1 ml of acetic acid, treated with 421 mg (1.51 mmol) of ytterbium chloride and stirred at 80 ° C for 6 h. It is neutralized with ammonia, evaporated to dryness and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 1.67 g (79% of theory) of a colorless solid
Water content (Karl Fischer): 7.0%

Elemental analysis (related to the anhydrous substance):

• Calc .: C 37 61 H 4.49 N 7.80 F 22.47 Yb 12.04
• Found .: C 36.82 H 4.53 N 7.84 F 22.36 Yb 12.00

Example 34

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

2.0 g (1.37 mmol) of the title compound from Example 25a are dissolved in 50 ml of water and 1 ml of acetic acid, treated with 294 mg (1.51 mmol) of yttrium chloride and stirred at 80 ° C for 6 h. It is neutralized with ammonia, evaporated to dryness and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 1.61 g (81% of theory) of a colorless solid
Water content (Karl Fischer): 6.2%

Elemental analysis (related to the anhydrous substance):

• Re: C 39.95 H 4.77 N 8.28 F 23.87 Y 6.57
• Found .: C 40.11 H 4.80 N 8.26 F 23.77 Y 6.50

Example 35

a) L-2-Benzyloxycarbonylamino-4-amino-butyric acid - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide

To 17.62 g (50 mmol) of L-2-benzyloxycarbonylamino-4-tert-butyloxycarbonylamino-butyric acid (Bachem) and 23.86 g (50 mmol) of the title compound from Example 1a in 200 ml of THF are added at 0 ° C 24.7 g (100 mmol ) EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred for 16 h at room temperature. It is evaporated to dryness in vacuo, the residue is dissolved in 80 ml of dichloromethane, treated at 0 ° C with 40 ml of trifluoroacetic acid, and then stirred for 4 h at room temperature. It is evaporated to dryness in vacuo and the residue chromatographed on silica gel (mobile phase: dichloromethane / methanol 10: 1).
Yield: 23.8 g (67% of theory) of a colorless, viscous oil.

Elemental analysis:

• Re: C 38.83 H 3.12 N 5.91 F 45.40
• Found .: C 39.02 H 3.14 N 5.87 F 45.22

b) L-2-Benzyloxycarbonylamino-4- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetyl) -amino-butyric acid - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] -amide

To a solution of 20 g (28.11 mmol) of the title compound from Example 35a and 6.24 g (28.11 mmol) of {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) and 3.24 g (28.11 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide are added at 0 ° C 7.25 g (35.14 mmol) of dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature , It is filtered from the precipitated urea, the filtrate evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 20.8 g (81% of theory) of a colorless, viscous oil.

Elemental analysis:

• Re: C 41.98 H 4.18 N 4.59 F 35.27
• Found .: C 42.24 H 4.27 N 4.45 F 35.00

c) L-2-Amino-4- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetyl) -amino-butyric acid - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] -amide

2.0 g of palladium catalyst (10% Pd / C) are added to a solution of 20.0 g (21.84 mmol) of the title compound from Example 35b in 200 ml of ethanol and hydrogenated at room temperature for 24 h. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 17.2 g (quantitative) of a colorless solid.

Elemental analysis:

• Re: C 36.89 H 4.13 N 5.38 F 41.33
• Found: C 37.11 H 4.09 N 5.27 F 41.21

d) L-2- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - amino-4- (2- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetyl) amino-butyric acid - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl ] amide, Gd complex

15.0 g (19.19 mmol) of the title compound from Example 35c, 2.21 g (19.19 mmol) of N-hydroxysuccinimide, 1.63 g (38.38 mmol) of lithium chloride and 12.08 g (19.19 mmol) of 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)) Dissolved in 200 ml of dimethyl sulfoxide with gentle warming, 4.95 g (23.99 mmol) of dicyclohexylcarbodiimide are added at room temperature and stirred for 16 h at room temperature, the solution is poured into 2000 ml of acetone and the mixture is stirred for 10 more minutes subsequently purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 17.9 g (63% of theory) of a colorless solid
Water content (Karl Fischer): 6.0%

Elemental analysis (related to the anhydrous substance):

• Re: C 37.07 H 4.34 N 8.04 F 23.18 Gd 11.29
• Found .: C 37.22 H 4.31 N 7.99 F 23.01 Gd 11.21

Example 36

a) L-2-Benzyloxycarbonylamino-3-amino-propionic acid - [(1H, 1H, 2H, 2H-perfluorodecyl) -methyl] -amide

To 16.92 g (50 mmol) of L-2-benzyloxycarbonylamino-3-tert-butyloxycarbonylamino-propionic acid (Bachem) and 23.86 g (50 mmol) of the title compound from Example 1a in 200 ml of THF are added at 0 ° C 24.7 g (100 mmol ) EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) and stirred for 16 h at room temperature. It is evaporated to dryness in vacuo, the residue is dissolved in 80 ml of dichloromethane, treated at 0 ° C with 40 ml of trifluoroacetic acid, and then stirred for 4 h at room temperature. It is evaporated to dryness in vacuo and the residue chromatographed on silica gel (mobile phase: dichloromethane / methanol 10: 1).
Yield: 20.5 g (59% of theory) of a colorless, viscous oil.

Elemental analysis:

• Re: C 37.89 H 2.89 N 6.03 F 46.31
• Found: C 38.11 H 2.95 N 5.98 F 46.24

b) L-2-Benzyloxycarbonylamino-3- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetyl) -amino-propionic acid - [(1H, 1H, 2H, 2N-perfluorodecyl) methyl] -amide

To a solution of 18 g (25.81 mmol) of the title compound of Example 50a and 5.73 g (25.81 mmol) of {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} acetic acid (Voegtle et al., Liebigs Ann. Chem., 1980, 858-862) and 2.97 g (25.81 mmol) of N-hydroxysuccinimide in 200 ml of dimethylformamide are added at 0 ° C 6.66 g (32.26 mmol) of dicyclohexylcarbodiimide, stirred for 3 h at 0 ° C and then 16 h at room temperature , It is filtered from the precipitated urea, the filtrate evaporated to dryness in vacuo and the residue chromatographed on silica gel (eluent: dichloromethane / methanol 20: 1).
Yield: 17.5 g (75% of theory) of a colorless, viscous oil.

Elemental analysis:

• Re: C 41.30 H 4.02 N 4.66 F 35.82
• Found: C 41.56 H 4.10 N 4.59 F 35.71

c) L-2-Amino-3- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetyl) -amino-propionic acid - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] -amide

2.0 g of palladium catalyst (10% Pd / C) are added to a solution of 17.0 g (18.85 mmol) of the title compound from Example 36b in 200 ml of ethanol and hydrogenated at room temperature for 24 h. The mixture is filtered off from the catalyst and the filtrate is evaporated to dryness in vacuo.
Yield: 14.5 g (quantitative) of a colorless solid.

Elemental analysis:

• comp .: C 36.00 H 3.94 N 5.48 F 42.08
• Found .: C 36.13 H 4.00 N 5.39 F 41.88

d) L-2- [1,4,7-Tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5- yl)] - amino-3- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetyl) -amino-propionic acid - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl ] amide, Gd complex

13.0 g (16.94 mmol) of the title compound of Example 36c, 1.95 g (16.94 mmol) of N-hydroxysuccinimide, 1.44 g (33.88 mmol) of lithium chloride and 10.67 g (16.94 mmol) of 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)) dissolved in 200 ml of dimethyl sulfoxide with gentle warming. At 10 ° C., 4.37 g (21.18 mmol) of dicyclohexylcarbodiimide are added and the mixture is stirred at room temperature for 16 h. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 16.4 g (66% of theory) of a colorless solid
Water content (Karl Fischer): 5.8%

Elemental analysis (related to the anhydrous substance):

• Calculated: C 36.58 H 4.24 N 8.12 F 23.42 Gd 11.40
• Found .: C 36.72 H 4.26 N 8.13 F 23.29 Gd 11.31

Example 37

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

To 12.0 g (34.6 mmol) of 1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane (DO3A) in 50 ml of water are added 8.3 g (207.6 mmol) of sodium hydroxide. To this is added dropwise 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 of n-butanol / 50 ml of 2-propanol and heated the solution is at 80 ° C. for 24 h. The reaction solution is evaporated to dryness in vacuo, the residue is combined with 300 ml of water and adjusted to pH 3 with 3 N hydrochloric acid. The mixture is then extracted three times with 200 ml of n-butanol, the combined butanol phases are evaporated to dryness in vacuo and the residue is purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 13.6 g (79% of theory) of a colorless solid
Water content (Karl Fischer): 10.4%

Elemental analysis (related to the anhydrous substance):

• calc .: C 51.34 H 7.26 N 12.60
• Found: 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 from Example 37a are dissolved in 100 ml of water and 1 ml of acetic acid, treated with 4.39 g (12.1 mmol) of gadolinium oxide and stirred at 80 ° C for 6 h. The solution is filtered, evaporated to dryness and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 13.8 g (89% of theory) of a colorless solid
Water content (Karl Fischer): 6.5%

Elemental analysis (related to the anhydrous substance):

• Re: C 38.12 H 4.88 N 9.36 Gd 26.26
• Found: C 38.26 H 4.89 N 9.21 Gd 26.09

c) 2-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-4-hydroxy-5-yl)] - 6-N- (2- {2- [2- (2-methoxyethoxy) -ethoxy] -ethoxy} -acetyl) -L-lysine - [(1H, 1H, 2H, 2H-perfluorodecyl) methyl] -amide, Gd complex

3.0 g (3.70 mmol) of the title compound from Example 31d and 3.32 g (5.55 mmol) of the title compound from Example 37b are dissolved in 50 ml of methanol and stirred at a temperature of 50 ° C. for 48 h. It is evaporated to dryness and then purified by chromatography (RP-18, mobile phase: gradient of water / acetonitrile).
Yield 3.94 g (71% of theory) of a colorless solid
Water content (Karl Fischer): 6.0%

Elemental analysis (related to the anhydrous substance):

• Calculated: C 38.38 H 4.65 N 6.96 F 22.93 Gd 11.17
• Found: C 38.52 H 4.71 N 6.88 F 22.81 Gd 11.08

Example 38: relaxivity

The T1 and T2 relaxation times of water and plasma (from bovine) with therein increasing concentrations of the gadolinium complexes (I-XIII) were at 40 ° C using an NMR Pulse Spectrometer (Minispec PC 20) 0.47 T and determines the relaxivity. The results are summarized in Table 1.

Example 39: acute toxicity after one-time intravenous Application in mice

After intravenous administration of the gadolinium complexes (I-X) in mice (n = 3, injection rate: 2 ml / min), the acute systemic tolerability (LD ₅₀ ) was determined as a guide. In each case several doses were examined with an observation period of 7 days. The expected acute toxicities are shown in Table 1.

Example 40: Excretion after intravenous Application in rats

To intravenous Application of 50 μmol Total gadolinium / kg bw of the gadolinium complexes (I-X) in rats (n = 3) was until 14 days after application of the metal content by means of Atomic emission spectrometry (ICP-AES) in the excretory media Urine and faeces, as well as in the body (Remainder of the body) fractionally determined. The results are summarized in Table 1.

Example 41: Plasma kinetics after intravenous Application in rats

To intravenous Application of 50 μmol Total gadolinium / kg bw of the gadolinium complexes (I-X) in rats (n = 3) was over a catheter in the common carotid artery to different Time points 8 to 24 h p.i.) blood samples taken, the metal content determined by atomic emission spectrometry (ICP-AES) and a Conversion factor (0.625) converted to plasma values. From the plasma concentrations became by means of special software (WinNonlin) the elimination half-life calculated. The results are summarized in Table 1.

Example 42: Presentation (MRI) of lymph node metastases and primary tumor after intravenous administration of the contrast agent in VX2 tumor carriers Rabbits

The pictures of the 1 show MR images of iliac lymph nodes pre-contrast and up to 24 h after intravenous administration of 50 .mu.mol Gd / kg body weight of gadolinium complex VIII (title substance from Example 16c) in rabbits with implanted VX2 tumor. The T ₁ -weighted turbo spin-echo images illustrate the strong signal increase in healthy lymph node tissue at early time points after contrast agent administration (15 to 60 min pi). Zones without signal increase within the lymph node were diagnosed as metastases and confirmed histologically (H / E staining of the lymph node sections).

Surprisingly could also immediately after application also a clear Enhancement in the primary tumor (especially in the periphery). At later times (24 h p.i.), this enhancement also spreads to the tumor center out.

Example 43: MRI presentation of arteriosclerotic plaques after intravenous administration of the contrast agent in rats

The pictures of the 2 show MR images of the aorta 6 or 24 h after intravenous administration of 50 or 100 .mu.mol Gd / kg body weight of the gadolinium complex I (title substance from Example 1f), the gadolinium complex IV (title substance from Example 11e) and the gadolinium Complex VIII (title substance from Example 16c) in Watanabe rabbits (WHHL rabbit, genetically induced arteriosclerosis) and in control animals without atherosclerosis (New Zealand white horses). The T ₁ -weighted inversion-recovery images (IR-TFL, TR / TE / TI = 300 / 4.0 / 120 ms, α 20 °) show a strong signal increase in the arteriosclerotic plaques of the WHHL rabbits, but not in the vessel wall of healthy control animals. The localization of the plaques, especially in the aortic arch and at the vascular branches, was confirmed by Sudan-3 staining. With this experiment, the suitability of the compounds according to the invention as markers for arteriosclerotic plaques could be demonstrated.

Example 44: MRI presentation of inflammatory lesions and necrotic areas after intravenous administration of the contrast agent in rats

The pictures of the 3 show exemplary MR images of inflammatory muscle lesions and necrotic areas at different times after intravenous administration of 50 .mu.mol Gd / kg body weight of the gadolinium complex XIV (title substance from Example 4g) in rats. Inflammation / necrosis was induced by intravenous administration of Rose Bengal (20 mg / kg, 24 h before contrast administration) followed by 20 minutes exposure to a xenon lamp. The T ₁ -weighted Turbo spin-echo images (1.5 T; sequence: T1-TSE; TR 451 ms, TE 8.7 ms) illustrate the strong signal rise in the flammable altered tissue at early time points (up to 60 min pi), as well as the delayed signal increase in central necrosis at 24 h pi.

Tab. 1: Physicochemical and experimental data on the example substances.

Claims (23)

Perfluoroalkyl-containing metal complexes with N-alkyl group of the general formula I.

where R is either represents a via the 1-OH bonded mono- or Oligosaccharidrest which is optionally peralkylated, in this case Q has the meaning of a group selected from δ-CO- (CH ₂ ) _{n "} -ε δ-NH- (CH ₂ ) _{n "} -ε δ- (CH ₂ ) _m -ε where n '' is an integer of 1 and 5, and m is an integer of 1 and 6, and wherein δ indicates the binding site to the linker L and ε the binding site to the radical R; or R has one of the following meanings, then Q has the meaning of a direct bond: R is a polar radical selected from • the complexes K of the general formulas II to VIII ', where R ¹ here is a hydrogen atom or a metal ion equivalent of atomic numbers 20-29 , 31-33, 37-39, 42-44, 49 or 57-83, and the radicals R ² , R ³ , R ⁴ , U, U ² and U ^{1 have} the meaning given below, or CO-, -NR ⁶ - or a direct bond to the linker L bonded carbon chain having 1-30 C atoms, - which may be straight or branched, saturated or unsaturated, - and which is optionally interrupted by 1-10 oxygen atoms, 1 -5 -NHCO groups, 1-5 -CONH groups, 1-2 sulfur atoms, 1-5 -NH groups or 1-2 phenylene groups optionally with 1-2 OH groups, 1-2 NH ₂ groups , 1-2 -COOH groups, or 1-2 -SO ₃ H groups may be substituted, - and which is optionally substituted with 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, wherein R ^{6 is} H or C ₁ -C ₄ alkyl, R _{f is} a perfluorinated, straight-chain or branched carbon chain with the formula -C _n F _2n E, in which E is a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n is the numbers 4-30, X represents a group of the formula (XI) ρ-Y- (CH ₂ ) _s - (G) _t - (CH ₂ ) _s' - (XI) and G is either -O- or -SO ₂ -, s and s', independently, either 1 or 2, t is either 0 or 1, and ρ represents the point of attachment of X to L and ξ the binding site of X to R _f is K is a metal complex of the general formula II,

wherein R ^{1 represents} a hydrogen atom or a metal ion equivalent of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83, with the proviso that at least two R ^{1 are} metal ion equivalents R ² and R ³ independently of one another represent hydrogen, C ₁ -C ₇ -alkyl, benzyl, phenyl, -CH ₂ OH or -CH ₂ OCH ₃ and U -C ₆ H ₄ -O-CH ₂ -ω-, - (CH ₂ ) _{1 -5-} ω, a phenylene group, -CH ₂ -NHCO-CH ₂ -CH (CH ₂ COOH) -C ₆ H ₄ -ω-, -C ₆ H ₄ - (OCH ₂ CH ₂ ) _0-1 -N (CH ₂ COOH) -CH ₂ -ω or an optionally substituted by one or more oxygen atoms, 1 to 3 -NHCO, 1 to 3 -CONH groups represents interrupted and / or with 1 to 3 (CH ₂ ) _0-5 COOH groups substituted C ₁ -C ₁₂ -alkylene or - (CH ₂ ) _7-12 -C ₆ H ₄ -O- group, wherein ω for the binding site to -CO-, or the general formula III

in which R ^{1 has} the abovementioned meaning, R ^{4 represents} hydrogen or a metal ion equivalent mentioned under R ¹ and U ¹ -C ₆ H _{4 represents} -O-CH ₂ -ω- or a group - (CH ₂ ) _{p '} -, where ω is the binding site to -CO- and p 'is an integer between 1 and 4, or the general formula IV

in which R ¹ and R ^{2 have} the abovementioned meaning or the general formula VA or VB

in which R ^{1 has} the abovementioned meaning, or the general formula VI

in which R ^{1 has} the abovementioned meaning, or the general formula VII

in which R ¹ and U ¹ have the abovementioned meaning, or of general formula VIII

in which R ^{1 has} the abovementioned meaning, and U ^{2 is} an optionally imino, phenylene, phenyleneoxy, phenyleneimino, amide, hydrazide, carbonyl, ester groups, oxygen, sulfur and / or nitrogen atom (e) -, optionally substituted by hydroxy, mercapto, oxo, thioxo, carboxy, carboxyalkyl, ester, and / or amino group (s) substituted straight-chain or branched, saturated or unsaturated C ₁ -C ₂₀ alkylene group , or the general formula VIII '

in which R ^{1 has} the abovementioned meaning, and optionally free acid groups present in the 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 selected from the following radicals IXa) to IXg):

where q 'is either 1, 2, 3 or 4, and wherein α is the binding site of L to the complex K, β is the binding site of L to the radical Q and γ represents the point of attachment of L to N of the formula (I), and A represents a linear or branched, saturated or unsaturated C ₁ -C ₁₅ carbon chain which is selected from 1-4 O atoms, 1-3 -NHCO groups, 1-3 -CONH groups, 1-2 -SO ₂ - groups, 1-2 sulfur atoms, 1-3 -NH- groups or 1-2 phenylene groups optionally with 1-2 -OH groups, 1-2 -NH ₂ groups, 1-2 -COOH groups, or 1-2 -SO ₃ H groups may be substituted, and which is optionally substituted with 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. Metal complexes according to claim 1, characterized in that the metal ion equivalent R ^{1 is} an element of atomic numbers 21-29, 39, 42, 44 or 57-83. Metal complexes according to claim 1, characterized in that the metal ion equivalent R ^{1 is} an element of atomic numbers 27, 29, 31-33, 37-39, 43, 49, 62, 64, 70, 75 and 77. Metal complexes according to one of claims 1 to 3, characterized in that R is a monosaccharide residue with 5 to 6 carbon atoms or its deoxy compound, preferably glucose, Mannose or galactose. Metal complexes according to one of claims 1 to 3, characterized in that A is a radical - (CH ₂ ) _{s "} - (O) _{t '} - (CH ₂ ) _s''' - Z where s '' is an integer between 1 and 4, s '''is an integer between 0 and 4, t' is 0 or 1, and Z is either -H, -OH, or -COOH. Metal complexes according to one of claims 1 to 5, characterized in that K is a metal complex of the general Formula II stands. Metal complexes according to Claim 6, characterized in that R ² and R ³ independently of one another are hydrogen or C ₁ -C ₄ -alkyl. Metal complexes according to one of claims 1 to 7, characterized in that E in the formula -C _n F _2n E represents a fluorine atom. Metal complexes according to one of claims 1 to 8, characterized in that L in the general formula I a amino acid residue (IXa) or (IXb). Metal complexes according to one of claims 1 to 8, characterized in that L in the general formula I a Radical of the formulas (IXc), (IXd), (IXe) or (IXf). Metal complexes according to one of claims 1 to 10, characterized in that U in the metal complex K represents -CH ₂ - or -C ₆ H ₄ -O-CH ₂ -ω, where ω stands for the point of attachment to -CO-. Use of metal complexes according to claim 2 to Production of contrast agents for use in NMR and X-ray diagnostics. Use of metal complexes according to claim 12 for the production of contrast agents for infarction and necrosis imaging. Use of metal complexes according to claim 3 Production of contrast agents for use in radiodiagnostics and radiotherapy. Use of metal complexes according to claim 2 for the preparation of contrast agents for the Lym phography for the diagnosis of changes in the lymphatic system. Use of metal complexes according to claim 2 to Production of contrast agents for the diagnosis of inflammatory Diseases. Use of metal complexes according to claim 2 to Preparation of contrast agents for the presentation of atherosclerotic Plaques. Use of metal complexes according to claim 2 to Production of contrast agents for the diagnosis of cardiovascular diseases. Use of metal complexes according to claim 2 to Production of contrast agents for tumor imaging. Use of metal complexes according to claim 2 to Production of contrast agents for the presentation of nerve damage. Pharmaceutical agents containing at least one physiologically compatible Connection according to the claims 1 to 11, optionally with the additives customary in galenicals. Process for the preparation of perfluoroalkyl-containing metal complexes with N-alkyl group of general formula I.

with K in the meaning of a metal complex of the general formulas II to VIII according to claim 1 and L, Q, X, R, R _f , as defined in claim 1, characterized in that a carboxylic acid of the general formula IIa

wherein R ^{5 is} a metal ion equivalent of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83 or a carboxyl protecting group, and R ² , R ³ and U have the meaning given or a carboxylic acid of the general Formula IIIa

wherein R ⁴ , R ⁵ and U ^{1 have} the meaning given or a carboxylic acid of the general formula IVa

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

wherein R ^{5 has} the meaning mentioned or a carboxylic acid of the general formula VIa

wherein R ^{5 has} the meaning mentioned or a carboxylic acid of the general formula VIIa

wherein R ⁵ and U ^{1 have} the meanings mentioned,

wherein R ^{5 have} the meanings mentioned, and U ^{2 is} as defined in claim 1, in optionally activated form with an amine of general formula X.

in the A, L, R, R _f , Q, and X, which have the meaning given above, in a coupling reaction and optionally subsequent cleavage of any protecting groups present to a metal complex of the general formula I or when R ^{5 is} the meaning of a protective group after cleavage of these protecting groups in a subsequent step in a conventional manner with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83, and then, if desired, optionally present azide hydrogen atoms substituted by cations of inorganic and / or organic bases, amino acids or amino acid amides. Process for the preparation of perfluoroalkyl-containing complexes with N-alkyl group of general formula I.

with K in the meaning of a metal complex of the general formula VIII 'according to claim 1, and L, Q, X, R, R _f , as defined in claim 1, characterized in that an amine of the general formula VIII'a

wherein R ^{5 represents} a metal ion equivalent of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83 or a carboxyl-protecting group, with an optionally activated carboxylic acid of the general formula X '

wherein A, L, R, R _f , Q, X have the meanings given above, in a coupling reaction and optionally subsequent cleavage of any protecting groups present to a metal complex of general formula I or when R ^{5 has} the meaning of a protective group, after Cleavage of these protecting groups in a subsequent step in a conventional manner with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83, and then, if desired, optionally present acidic azide atoms substituted by cations of inorganic and / or organic bases, amino acids or amino acid amides.