HK1120510A

HK1120510A - Perfluoroalkyl-containing complexes, process for their production as well as their use

Info

Publication number: HK1120510A
Application number: HK08113949.7A
Authority: HK
Inventors: H‧席尔默; H-J‧魏因曼; J‧普拉策克; L‧措恩; B‧米塞尔维茨; J‧梅丁; H‧施米特-维利希; T‧布伦比
Original assignee: 拜耳先灵医药股份有限公司
Priority date: 2005-07-15
Filing date: 2006-07-11
Publication date: 2009-04-03

Description

Perfluoroalkyl-containing complex, preparation method and application thereof

The invention relates to the subject matter characterized in the claims, namely perfluoroalkyl-containing metal complexes with nitrogen-containing groups of the general formula I, a method for the production thereof and the use thereof in NMR and X-ray diagnostics, radiodiagnostics and radiotherapy as well as in MRT lymphography and blood pool imaging. Perfluoroalkyl-containing metal complexes are used in nuclear spin resonance tomography (MRT) for visualizing (visualizing) different physiological and pathophysiological structures and thereby improving diagnostic information, i.e. disease localization and extent, the success of therapy for selection and monitoring purposes, and for prophylaxis.

The compounds of the invention are very particularly suitable for lymphography, for tumour diagnosis and for infarction and necrosis imaging.

In the field of nuclear magnetic resonance, some fluorine-containing compounds are known which can be used in the field of imaging. However, in most cases, these compounds are only proposed for use in fluorine-19 imaging and are only suitable for this application. These compounds are disclosed, for example, in U.S. Pat. No. 4,639,364(Mallinckrodt), DE 4203254(Max-Planck-Gesellschaft), WO 93/07907(Mallinckrodt), US4,586,511 (Children's Hospital Medical Center), EP 307863(Air Products), US4,588,279(University of Cincinnati, Children's Hospital research Foundation), and WO 94/22368(Molecular Biosystems).

Other fluorine-containing compounds useful for imaging are disclosed in US 5,362,478(VIVORX), US patent 4,586,511, DE 4008179(Schering), WO 94/05335 and WO 94/22368 (both molecular biological systems), EP 292306 (term o Kabushiki Kaisha), EP 628316 (term o KabushikiKaisha) and DE 4317588 (Schering).

Although no interaction between the two nuclei occurs in compounds containing elemental fluorine and iodine, strong interactions occur in compounds containing fluorine and paramagnetic centers (radicals, metal ions) and are expressed in terms of a reduction in the relaxation time of the fluorine nucleus. The extent of this effect depends on the number of unpaired electrons (Gd) of the metal ion³⁺＞Mn²⁺＞Fe³⁺＞Cu²⁺) And paramagnetic ions and¹⁹movement between F atoms.

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

The shortening of the relaxation time as a function of the spacing of the paramagnetic ions is evident in all nuclei with an odd number of spins and therefore also in the case of protons, so that gadolinium compounds are widely used as contrast agents in nuclear spin tomography (Magnevist)^®、Prohance^®、Omniscan^®And Dotarem^®)。

However, in¹H-MR imaging (¹H-MRI), the relaxation time T of protons, i.e. protons of mainly water, is measured¹Or T²Rather than the relaxation time of the fluorine nucleus, and is used for imaging. The quantitative measure for the shortening of the relaxation time is the relaxation [ L/mmol.s]. Complexes of paramagnetic ions have been successfully used to shorten the relaxation times. In the following table, the relaxivity of several commercial formulations is shown:

	t in water¹Relaxivity [ L/mmol. s, 39 ℃, 0.47T]	T in plasma¹Relaxivity [ L/mmol. s, 39 ℃, 0.47T]
	t in water¹Relaxivity [ L/mmol. s, 39 ℃, 0.47T]	T in plasma¹Relaxivity [ L/mmol. s, 39 ℃, 0.47T]	MAGNEVIST^®	3.8	4.8
DOTAREM^®	3.5	4.3	MAGNEVIST^®	3.8	4.8
DOTAREM^®	3.5	4.3	OMNISCAN^®	3.8	4.4
PRO HANCE^®	3.7	4.9	OMNISCAN^®	3.8	4.4

In these compounds, only the interaction between protons and gadolinium ions occurs. Thus, a relaxation of about 4[ L/mmol · s ] in water is observed for these contrast agents.

Thus, both fluorine compounds (where the shortened relaxation time of the fluorine nucleus is used) and fluorine-free compounds (where the relaxation time of the protons of water is measured) used for fluorine-19 imaging have been successfully used for MR imaging.

The relaxation properties associated with protons of water also increase rapidly in the case of the introduction of perfluorocarbon-containing groups into paramagnetic contrast agents, i.e. the combination of properties of compounds previously known to be suitable only for fluorine imaging with those of compounds used for proton imaging. Compared to the values between 3.5 and 3.8[ L/mmol.s ] as described above for some commercial products, values of 10-50[ L/mmol.s ] have now been reached.

Perfluoroalkyl-containing metal complexes are known from DE 19603033.1, WO 99/01161, DE 19914101, DE 10040381 and DE 10040858. However, for all applications, these compounds cannot be used satisfactorily, since in most cases the compatibility is not sufficient. Thus, there remains a need for MRT contrast agents that have both excellent imaging properties while being non-invasive in obtaining diagnostic methods and excellent compatibility. This is important, for example, if a tumour is to be diagnosed, including satellite metastases, and therefore the distribution of the contrast agent throughout the body is to be obtained.

Cluster metastasis of malignant tumors in regional lymph nodes, where several lymph node locations may be involved. Therefore, lymph node metastasis is found in approximately 50-69% of all patients with malignant tumors (Elke, Lymphophophie [ Lymphophographic ], in Frommhold, Stender, Thurn (ed.), Radiology diagnostic in Klinik und Praxis [ Radiology diagnostic in Clinical Studies and in Practice ], Vol.IV, Thieme Verlag Stuttgart, 7 th edition, 434. sup. 496, 1984). The diagnosis of metastatic invasion of lymph nodes is very important for the treatment and prognosis of malignant diseases. Lymphatic metastasis of malignant tumors has not been adequately detected with modern imaging methods (CT, US and MRI) because in most cases only the size of the lymph nodes can be used as a diagnostic criterion. Thus, small metastases (< 2cm) in non-swollen Lymph nodes cannot be distinguished from Lymph Node proliferation without malignant invasion (Steinkamp et al, Sonogrie und Kernspinographics: Differential Biopostive lymphoma-veragr ö. beta. erung und Lymph notentimestastasense amHals [ Sonogry and Nuclear Spin Tomography: Differential Diagnosis of Reactive lymphoma Node Enlargement and lymphoma Node metastasies on the nerve ], radio. Diagn.33: 158, 1992).

It would be desirable to be able to distinguish between a metastasically affected lymph node and a hyperplastic lymph node when using a particular contrast agent.

Direct x-ray lymphography (injection of an oily contrast agent suspension into prepared lymphatic vessels) is known as an invasive method that can reveal few lymphatic drainage sites, which is used only in rare cases.

Fluorescently labeled dextrans are also used experimentally in animal experiments to enable observation of lymphatic drainage after interstitial administration of them. After interstitial/intradermal administration, all markers commonly used to indicate lymphatic and lymph nodes share the fact that they are substances or large polymers with particulate properties ("particles", e.g. emulsions and nanocrystal suspensions) (see WO90/14846 above). However, the aforementioned formulations have proved to be less efficient in diagnosis due to their poor local and systemic compatibility and their small lymphatic channels and are therefore still not optimally suitable for indirect lymphography.

Since lymph nodes are shown to be crucial for the early detection of metastatic attacks in cancer patients, there is a great need for lymph specific contrast agent formulations featuring very good compatibility for diagnosing corresponding changes in the lymphatic system. According to the invention, the lymphatic system comprises lymph nodes and lymphatic vessels. The substances according to the invention are therefore suitable for the diagnosis of changes in the lymphatic system, preferably of changes in lymph nodes and/or lymph vessels, in particular of metastases in lymph nodes.

As the lymph concentration is as consistent as possible at several lymph sites diagnostically relevant, it is desirable that the contrast agent concentration and high stability are as high as possible. The burden on the entire body should be reduced by rapidly and completely excreting the contrast agent. For radiological procedures, the start is rapid, if possible, as early as within hours after administration of the contrast agent. Good compatibility is necessary.

Last but not least, it is desirable to have available lymph specific contrast agents that allow visualization of the primary tumor and possible lymph node metastases during diagnosis.

Another important medical field is the detection, localization and monitoring of necrosis or infarction. Therefore, myocardial infarction is not a static process, but a dynamic process that develops over a long period of time (weeks to months). The disease progression is in three stages, which are not strictly separated from each other but rather overlap. The first stage is as follows: myocardial infarction occurs, including 24 hours post-infarction, in which the destruction travels from subendocardial to myocardium as a shock wave (wave front phenomenon). And a second stage: there has been infarction, including area stabilization, in which fibrogenesis (fibrosis) occurs as the healing process. And a third stage: infarction healing, which begins after all damaged tissue is replaced by fibrous scar tissue. During this time, extensive reconstruction occurs.

To date, an accurate and reliable method capable of diagnosing the current stage of myocardial infarction in a surviving patient is unknown. To assess myocardial infarction, it is important to know how large the portion of tissue that is exactly lost in the infarction is and where the loss occurs, as the type of treatment depends on this knowledge.

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

While infarctions can heal to some extent, in the case of necrosis, localized limited tissue death, only deleterious consequences to the rest of the body can be prevented or at least mitigated. Necrosis can occur in a variety of ways: by trauma, chemicals, hypoxia or by radiation. As in the case of infarctions, knowledge of the extent and type of necrosis is important for further medical treatment.

Therefore, tests using contrast agents in non-invasive methods such as scintigraphy or nuclear spin tomography to improve the localization of infarcts and necrosis have been performed earlier. In the literature, tests using porphyrins for necrosis imaging occupy a large space. However, the results obtained are contradictory. In addition, porphyrins tend to deposit in the skin, which leads to photosensitization.

Contrast agents which are not derived from porphyrin scaffolds for necrosis and infarction imaging are described in DE19744003(Schering AG), DE 19744004(Schering AG) and WO99/17809 (EPIX). However, to date, there are no compounds that can be satisfactorily used as contrast agents in infarction and necrosis imaging while having excellent compatibility.

The same problem exists in the field of compounds that can be used for diagnosing thrombi or arteriosclerotic plaques: there is no compound that can be satisfactorily used as a contrast agent for exhibiting a thrombus or an arteriosclerotic plaque while having excellent compatibility.

It is therefore an object of the present invention to prepare contrast agents which are obtainable, on the one hand, with excellent imaging properties as MRT contrast agents and are particularly suitable for tumor and necrosis imaging and/or lymphography and/or blood pool imaging and/or for visualizing thrombi or arteriosclerotic plaques, and at the same time are characterized by excellent compatibility.

The object of the invention is achieved by perfluoroalkyl group-containing complexes having a nitrogen-containing linker structure of the general formula I,

wherein

R represents:

a monosaccharide or oligosaccharide group linked via 1-OH,

in which case Q has the meaning of a group selected from:

δ-CO-(CH₂)_n″-ε

δ-NH-(CH₂)_n″-ε

δ-(CH₂)_m-ε

wherein:

n' is an integer of 1 to 5, and

m is an integer of 1 to 6, and

wherein δ represents the attachment site to the linker L and ∈ represents the attachment site to the group R;

or

R has one of the following meanings, then Q has the meaning of a direct bond: r is a polar group selected from

Complexes K of the formulae II to V, where R¹Here a hydrogen atom or a metal ion equivalent of atomic number 20-29, 31-33, 37-39, 42-44, 49 or 57-83, and the radical R²、R³、R⁴U and U¹Has the meaning shown below and has the following meaning,

or

through-CO-, -NR-having 1 to 30C atoms⁷-or a carbon chain directly linked to a linker L,

it may be linear or branched, saturated or unsaturated, and

it is composed of

Optionally interrupted by 1 to 10 oxygen atoms, 1 to 5-NHCO groups, 1 to 5-CONH groups, 1 to 2 sulfur atoms, 1 to 5-NH groups or 1 to 2 phenylene groups, which may optionally be interrupted by 1 to 2-OH groups, 1 to 2-NH 2 groups, 1 to 2-COOH groups or 1 to 2-SO groups₃H is substituted by a group, and

optionally substituted by 1-10-OH groups, 1-5-COOH groups, 1-2-SO groups₃H group, 1-5-NH₂Radical or 1-5C₁-C₄-an alkoxy group substitution,

wherein R is⁷Is H or C₁-C₄An alkyl group, a carboxyl group,

R_fis of the formula-C_nF_2nA perfluorinated linear or branched carbon chain of E, wherein E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n represents a number from 4 to 30,

k represents a metal complex of the general formula II,

wherein

R¹Is a hydrogen atom or metal ion equivalent having an atomic number of 21-29, 31-33, 37-39, 42-44, 49 or 57-83,

with the proviso that at least two R¹It is meant to represent the equivalent of a metal ion,

R²and R³Independently of each other, hydrogen and C₁-C₇-alkyl, benzyl, phenyl, -CH₂OH or-CH₂OCH₃And is and

u represents optionally interrupted by one or more oxygen atoms, 1 to 3-NHCO groups or 1 to 3-CONH groups and/or interrupted by 1 to 3- (CH)₂)_0-5COOH group substituted-C₆H₄-O-CH₂-ω-、-(CH₂)_1-5-omega, phenylene, -CH₂-NHCO-CH₂-CH(CH₂COOH)-C₆H₄-ω、-C₆H₄-(OCH₂CH₂)_0-1-N(CH₂COOH)-CH₂- ω or C₁-C₁₂-alkylene or- (CH)₂)_7-12-C₆H₄-an O group, wherein ω represents a linking site to-CO-;

or metal complexes of the formula III

Wherein R is¹Having the above meaning, R⁴Represents hydrogen or at R¹Metal ion equivalents mentioned below, and U¹represents-C₆H₄-O-CH₂-omega-or a group- (CH)₂)_p-, where ω is the attachment site to the-CO-group and p¹Is an integer between 1 and 4;

or metal complexes of the formula IV

Wherein R is¹And R²Have the above-mentioned meanings;

or metal complexes of the general formula VA or VB

Wherein R is¹Have the above-mentioned meanings;

or metal complexes of the formula VI

Wherein R is¹Have the above-mentioned meanings;

or metal complexes of the formula VII

Wherein R is¹And U¹Has the above-mentioned meaning, wherein ω is the attachment site to the-CO-;

or metal complexes of the formula VIII

Wherein R is¹Have the above-mentioned meanings;

and U is²Represents a linear or branched, saturated or unsaturated C₁-C₂₀Alkylene which optionally contains imino, phenylene, phenoxy, phenylimino, amide, hydrazide, carbonyl, ester, oxygen, sulfur and/or nitrogen atoms and is optionally substituted by hydroxyl, mercapto, oxo, thio, carboxyl, carboxyalkyl, ester and/or amino,

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

and L represents a group selected from the following groups IXa) to IXc):

wherein n 'and m' independently of one another represent an integer between 0 and 4, and m '+ n' ≧ 1; preferably, m '+ n' is equal to 1, 2 or 3, and

R⁸and R^8′Independently of one another are-H or-OH, whichWhere m '+ n' > 1, each radical- (CR)⁸R^8′) May be different, and

w is a direct bond, -O-, or phenylene which may be optionally substituted with 1 to 4 hydroxyl groups,

and q' is 1, 2, 3 or 4;

wherein α is the attachment site of L to complex K and β is the attachment of L to group Q

A site, and γ represents the attachment site at which L is attached to the group X;

and is

X represents a group of formula (X);

ρ—Y—(CH₂)_s—(G)_t—(CH₂)_s’—ζ

(X)，

wherein Y is a direct bond, a radical-CO-or a radical NR⁶，

Wherein R is⁶represents-H or a linear or branched, saturated or unsaturated C₁-C₁₅The carbon chain is a carbon chain,

the carbon chain may be substituted with 1-4O atoms, 1-3-NHCO groups, 1-3-CONH groups, 1-2-SO groups₂A radical, 1-2 sulfur atoms, 1-3-NH groups or 1-2 phenylene groups,

which may optionally be substituted by 1-2-OH groups, 1-2-NH 2 groups, 1-2-COOH groups or 1-2-SO groups₃The substituent of the H group is replaced,

and the carbon chain is optionally substituted with 1-10 OH groups, 1-5-COOH groups, 1-2-SO groups₃H group, 1-5-NH₂Radical or 1-5C₁-C₄-alkoxy substitution;

and G is-O-or-SO₂-，

s and s' are each independently of the other 1 or 2, t is 0 or 1, and

ρ represents the attachment site of X to L, and ζ represents X and R_fThe ligation site of the ligation.

In a preferred embodiment, R⁶Is H or C which may be interrupted by 1 to 3O atoms and which may be substituted by 1 to 4-OH groups₁-C₆-an alkyl group.

In a particularly preferred embodiment, R⁶Is C₁-C₄An alkyl group.

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

In a particularly preferred embodiment, t is 0.

In a preferred embodiment, W is a direct bond.

In a preferred embodiment, by-CO-, -NR⁷The radical R which is bonded directly to the linking group L is a carbon chain having 1 to 30C atoms which is interrupted by 1 to 10 oxygen atoms and/or substituted by 1 to 10 OH groups.

In a particularly preferred embodiment, R is through-CO-, -NR⁷-or C which is directly linked to L, interrupted by 1 to 6 oxygen atoms and/or substituted by 1-6 OH groups₁-C₁₂A carbon chain.

If the compounds of the invention are intended for NMR diagnosis, the metal ions of the population must be paramagnetic. These are in particular the divalent and trivalent ions of the elements with atomic numbers 21 to 29, 42, 44 and 58 to 70. Suitable ions are, for example, chromium (III), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III) and ytterbium (III) ions. Gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III), iron (III) and manganese (II) ions are particularly preferred because of their strong magnetic moments.

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

If the compounds of the invention are intended for use in x-ray diagnostics, the metal ions are preferably from higher atomic number elements to achieve sufficient absorption of x-rays. For this purpose, diagnostic agents containing physiologically compatible complex salts of metal ions of the elements having atomic numbers 25, 26 and 39 and 57 to 83 have been found to be suitable.

Manganese (II), iron (III), praseodymium (III), neodymium (III), samarium (III), gadolinium (III), ytterbium (III)) or bismuth (III) ions are preferred, especially dysprosium (III) ions and yttrium (III) ions are preferred.

R¹The acidic hydrogen atoms optionally present in (a), i.e. the hydrogen atoms not substituted by the central ion, may optionally be replaced in whole or in part by inorganic and/or organic bases or by cations of amino acids or amino acid amides.

Suitable inorganic cations are, for example, lithium ions, potassium ions, calcium ions, in particular sodium ions. Suitable organic base cations are primary, secondary or tertiary amines, such as cations of ethanolamine, diethanolamine, morpholine, glucosamine, N-dimethylglucamine, in particular the cation of N-methylglucamine. Suitable amino acid cations are, for example, the cations of lysine, arginine and ornithine as well as the cations of amides of other acidic or neutral amino acids.

Particularly preferred compounds of the formula I are compounds of the formula II having a macrocyclic compound K.

The group U in the metal complex K is preferably-CH₂-or C₆H₄-O-CH₂- ω, wherein ω represents the attachment site to-CO-.

In a preferred embodiment, U²Is C₁-C₆An alkylene chain which is optionally interrupted by 1 to 2-NHCO groups and/or 1 to 2O atoms and which may be substituted by 1 to 3-OH groups.

Group U in Metal Complex K²Preference is given in particular to:

a linear alkylene radical having 1 to 6C atoms, in particular 2, 3 or 4C atoms, or

A linear alkylene radical having 1 to 6C atoms, in particular 2, 3 or 4C atoms, which is interrupted by 1O atom, or

-a linear alkylene group having 1 to 6C atoms, in particular 2, 3 or 4C atoms, said alkylene group containing a-NHCO group.

In a particularly preferred embodiment, U²Is an ethylene group.

Alkyl radicals R in macrocyclic compounds of the general formula II²And R³May be straight chain or branched. For example, methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl and 1, 2-dimethylpropyl groups may be mentioned. R²And R³Independently of one another, are preferably hydrogen or C₁-C₄An alkyl group.

In a particularly preferred embodiment, R²Represents a methyl group, and R³Represents hydrogen.

Benzyl or phenyl R in macrocyclic compounds of the general formula II²Or R³May also be substituted in the ring.

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

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

-C(O)CH₂O[(CH₂)₂O]_pR′

-C(O)CH₂OCH[CH₂OCH(CH₂OR′)₂]₂

-C(O)CH₂OCH₂CH[CH₂OCH(CH₂OR′)₂]₂

-R″N[(CH₂)₂O]_pR′

-N{[(CH₂)₂O]_pR′}₂

-R″NCH₂CH(OH)CH₂OH

-N[CH₂CH(OH)CH₂OH]₂

-R″NCH(CH₂OH)CH(OH)CH₂OH

-N[CH(CH₂OH)CH(OH)CH₂OH]₂

-R″NCH[CH₂OCH(CH₂OR′)₂]₂

-R″NCH₂CH[CH₂OCH(CH₂OR′)₂]₂

-R″NCH₂CH₂OCH[CH₂OCH(CH₂OR′)₂]₂

-R″NCH₂CH₂OCH₂CH[CH₂OCH(CH₂OR′)₂]₂

-N{CH[CH₂OCH(CH₂OR′)₂]₂}₂

-N(CH₂CH[CH₂OCH(CH₂OR′)₂]₂}₂

-R″NCH₂CH(OH)CH(OH)CH(OH)CH(OH)CH₂OH

-N[CH₂CH(OH)CH(OH)CH(OH)CH(OH)CH₂OH]₂

and Q has the meaning of a direct bond,

wherein R is¹、R²、R³And U is as defined above for formula (II),

p is 1, 2, 3, 4,5, 6, 7, 8 or 9,

R¹is H or CH₃And R' is H or C₁-C₄-an alkyl group.

p is preferably 1, 2, 3 or 4.

The polar groups shown here are commercially available products or are prepared according to methods described in the literature.

Cassel et al, Eur.J.org.chem., 2001, 5, 875-

Whitessides et al, JACS, 1994, 5057-

Voegtle et al, Liebigs Ann. chem., 1980, 858-862

Liu et al, chem

Mitchell et al, Heterocyclic Chem., 1984, 697-

Bartsch et al, J.org.chem., 1984, 4076-

Keana et al, J.org.chem., 1983, 2647-

In a particularly preferred embodiment, R is a group of formula-C (O) CH linked to L via-CO-)₂O[(CH₂)₂O]_PThe radical of R'.

When p and R 'have the abovementioned meanings, R' is particularly preferably a radical CH₃。

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

δ-CO-(CH₂)_n″-ε

wherein:

n' is an integer of 1 to 5, and

while L has the meaning of a radical of the formula IXa or IXb.

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

δ-NH-(CH₂)_n″-ε

wherein:

n' is an integer of 1 to 5, and

while L has the meaning of the group IXc.

Among the compounds of the general formula I according to the invention, furthermore, those are preferred in which R_fis-C_nF_2n+1A compound of (1); i.e. formula-C_nF_2nE in E is a fluorine atom. n preferably represents a number from 4 to 15. Very particular preference is given to the radical-C₄F₉、-C₆F₁₃、-C₈F₁₇、-C₁₂F₂₅and-C₁₄F₂₉And the radicals of the compounds mentioned in the examples.

In a preferred embodiment of the invention, the nitrogen-containing group L representing the "backbone" in formula I is an amino acid group (Vc).

In another preferred embodiment, the nitrogen-containing group L in formula I represents a diamine group of formula (IXb) or (IXa).

Perfluoroalkyl-containing metal complexes having nitrogen-containing linker structures of the general formula I are prepared in a manner known in the art by,

wherein K has the meaning of the metal complexes of the formulae II to IV, and L, Q, X, R and R_fHas the meaning of the above-mentioned formula,

by reacting carboxylic acids of the formula IIa

Wherein R is⁵Is an atomic number of 21-29, 31-33, 37-39, 42-44, 49 or 57-83

Or a carboxyl protecting group, and R²、R³And U has the abovementioned meaning, or a carboxylic acid of the formula IIIa

Wherein R is⁴、R⁵And U¹Has the meaning of the above-mentioned formula,

or carboxylic acids of the formula IVa

Wherein R is⁵And R²Has the meaning of the above-mentioned formula,

or carboxylic acids of the formulae Va or Vb

Wherein R is⁵Has the meaning of the above-mentioned formula,

or carboxylic acids of the formula VIa

Wherein R is⁵Has the meaning of the above-mentioned formula,

or a carboxylic acid of the formula VIIa,

wherein R is⁵And U¹Has the meaning of the above-mentioned formula,

wherein R is⁵And U²Has the meaning of the above-mentioned formula,

in optionally activated form with amines of the formula XI

L, R, R therein_fQ and X have the abovementioned meanings,

carrying out a coupling reaction and optionally subsequent cleavage of the optionally present protecting groups to form a metal complex of the general formula I,

or

If R is⁵Having the meaning of a protecting group, these protecting groups are cleavedAfter the protecting group is reacted in a subsequent step in a manner known in the art with at least one metal oxide or metal salt of an element having an atomic number of 21 to 29, 31 to 33, 37 to 39, 42 to 44, 49 or 57 to 83, and then, if desired, the optionally present acidic hydrogen atom is replaced by a cation of an inorganic and/or organic base, an amino acid or an amino acid amide.

This process for preparing metal complex carboxylic acid amides is known from DE 19652386.

The mixture used in the coupling reaction and consisting of the metal complex carboxylic acid IIIb optionally containing the carboxyl and/or hydroxyl groups in protected form and at least one solubilizing substance in an amount of at most 5 molar equivalents, preferably 0.5 to 2 molar equivalents, relative to the metal complex carboxylic acid, can be prepared and isolated in an upstream reaction stage (for example concentrated by evaporation, lyophilization or spray drying of aqueous or water-miscible solutions of these components or by precipitation from this solution with an organic solvent), can then be reacted with a dehydrating agent and optionally a coupling aid in DMSO, and can be formed in situ from the metal complex carboxylic acid, the dehydrating agent and optionally the coupling aid, optionally by adding the solubilizing substance to the DMSO suspension.

The reaction solution prepared according to one of these methods is kept at a temperature of 0 to 50 ℃, preferably room temperature for pretreatment (acid activation) for 1 to 24, preferably 3 to 12 hours.

Then, the group L, R, R therein is reacted_fAmines of the general formula XI in which Q and X have the abovementioned meanings

In the absence of a solvent or in dissolved form, for example in dimethyl sulfoxide, an alcohol such as methanol, ethanol, isopropanol or mixtures thereof, formamide, dimethylformamide, water or mixtures of said solvents, preferably in dimethyl sulfoxide, water or a solvent mixed with water. For the amide coupling, the reaction solution thus obtained is maintained at a temperature of 0 to 70 ℃, preferably 30 to 60 ℃, for 1 to 48 hours, preferably 8 to 24 hours.

In some cases, it has proven advantageous to use amines in the form of their salts in the reaction, for example as hydrobromide or hydrochloride. To liberate the amine, a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, tripropylamine, tributylamine, lithium hydroxide, lithium carbonate, sodium hydroxide or sodium carbonate is added.

The protecting groups optionally still present are then cleaved off.

The isolation of the reaction product is carried out according to methods known to the person skilled in the art, preferably by precipitation with an organic solvent, preferably acetone, 2-butanone, diethyl ether, ethyl acetate, methyl tert-butyl ether, isopropanol or mixtures thereof. Additional purification may be carried out by, for example, chromatography, crystallization or ultrafiltration.

As solubilizing substances, alkali metal salts, alkaline earth metal salts, trialkylammonium salts, tetraalkylammonium salts, urea, N-hydroxyimide, hydroxyaryltriazole, substituted phenols and salts of heterocyclic amines are suitable. For example, there may be mentioned 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-morpholinoethanesulfonic acid, 4-nitrophenol, 3, 5-dinitrophenol, 2, 4-dichlorophenol, N-hydroxysuccinimide, N-hydroxyphthalimide, urea, tetramethylurea, N-methylpyrrolidone, formamide and cyclic urea, of which the former five are preferred.

All reagents known to the person skilled in the art are used as dehydrating agents. For example, mention may be made of carbodiimide and onium reagents such as Dicyclohexylcarbodiimide (DCCI), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC), benzotriazole-1-oxytris (dimethylamino) -phosphonium hexafluorophosphate (benzodiamine) -1-yloxyhexafluorophosphate (BOP) and o- (benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium Hexafluorophosphate (HBTU), preferably DCCI.

Suitable methods are described in the literature, for example:

aktivierung von Kabon Karber.Ubersicht in Houben-Weyl, Methoden der Organischen Chemistry [ Activation of Carboxylic acids.Survein in Houben-Weyl, Methods of Organic Chemistry ], Vol.XV/2, Georg Thieme Verlag Stuttgart, 1974 (and J.Chem.Research (S)1996, 302).

Aktivierung mit Carbodiimides [ Activation with Carbodiimides ]. r.schwyzer and h.kappa, helv.46: 1550(1963).

E.W ü nsch et al, Vol 100: 173(1967).

Aktivierung mit Carbodiimides/Hydroxysucinamides [ Activationwith Carbodiimides/Hydroxy Succinimide ]: j.am.chem.soc.86: 1839(1964) and j.org.chem.53: 3583(1988) Synthesis 453 (1972).

◆Anhydridmethode，

2-Ethoxy-1-ethoxycarbonyl-1, 2-dihydrochinolin [ amide Method, 2-Ethoxy-1-ethoxycarbonyl-1, 2-dihydrochinoline ]: b.belleau et al, j.am.chem.soc., 90: 1651(1986), H.Kunz et al, int.J.Pept.prot.Res., 26: 493(1985) and J.R.Voughn, am.Soc.73: 3547(1951).

◆Imidazolid-Methode[Imidazolide Method]：B.F.Gisin，R.B.Menifield，D.C.Tosteon，Am.Soc.91：2691(1969)。

◆S*urechlorid-Methoden，Thionylchlorid[Acid Chloride Methods，Thionyl Chloride]：Helv.，42：1653(1959)。

◆Oxalylchlorid[Oxalyl Chloride]：J.Org.Chem.，29：843(1964)。

As coupling assistants which are optionally used, all coupling assistants known to the person skilled in the art are suitable (Houben-Weyl, Methoden der organischen Chemie, volume XV/2, Georg Thieme-Verlag, Stuttgart, 1974). For example, 4-nitrophenol, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 1-hydroxy-7-aza-benzotriazole, 3, 5-dinitrophenol and pentafluorophenol may be mentioned. Preferably 4-nitrophenol and N-hydroxysuccinimide; the first reagent is particularly preferred for this purpose.

The cleavage of the protecting Groups is carried out according to methods known to the person skilled in the art, for example by hydrolysis, hydrogenolysis, alkali saponification of the esters in aqueous-alcoholic solution at temperatures from 0 ℃ to 50 ℃ with bases, acid saponification with mineral acids or acid saponification with the aid of trifluoroacetic acid in the case of, for example, tert-butyl esters [ Protective Groups in Organic Synthesis, second edition, t.w.green and p.g.m.wuts, John Wiley and Sons, inc.new York, 1991], using hydrogen/palladium/carbon in the case of benzyl ethers.

The carboxylic acids of the formulae IIa to VIIa used are known compounds or are prepared according to the methods described in the examples, see DE 10040381 and DE 10040858. Thus, the preparation of carboxylic acids of the formula IIa is known from DE 19652386. The carboxylic acids of the formula VIIIa used are prepared as described in WO 95/17451.

Perbenzylated sugar acids (perbenzoylated sugar acids) used as starting materials when R is a monosaccharide or oligosaccharide may be similar to Lockhoff, Angew.]1998, 110, 24 th, p 3634. Thus, for example, the preparation of 1-O-acetic acid from perbenzylglucose proceeds via 2 stages: via trichloroethylimine and BF in THF₃Catalyzed reaction with ethyl glycolate followed by saponification with NaOH in MeOH/THF.

In a more advantageous process, as described in DE 10040381, the perbenzylated sugar acids used as starting materials can also be prepared by dissolving the perbenzylated 1-OH sugar in a water-immiscible organic solvent and reacting it with an alkylating agent of the formula XVIII in the presence of a base and optionally a phase transfer catalyst

Nu-L-COO-SG (XVIII)，

Wherein Nu is a nucleolytic reagent, L is- (CH)₂)-_n(wherein n is 1-5), -CH₂-CHOH-or-CH (CHOH-CH)₂OH) -CHOH-, and Sg represents a protecting group. As nucleofugic agents, the groups-Cl, -Br, -J, -OTs, -OMs, -OSO₂CF₃、-OSO₂C₄F₉or-OSO₂C₈F₁₇May be included in the alkylating agent of formula XVIII.

The protecting group is a typical 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 reaction of the present invention may be carried out at a temperature of 0 to 50 c, preferably 0c to room temperature. The reaction time is 10 minutes to 24 hours, preferably 20 minutes to 12 hours.

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

In the alkylation process of the invention, for example, toluene, benzene, CF₃Benzene, hexane, cyclohexane, diethyl ether, tetrahydrofuran, dichloromethane, MTB or mixtures thereof can be used as water-immiscible organic solvents.

In the process of the invention, quaternary ammonium salts or phosphonium salts or crown ethers known for this purpose, such as [15 ]]Crown-5 or [18 ]]Crown-6 is used as a phase transfer catalyst. Quaternary ammonium salts having four identical or different hydrocarbon groups selected from methyl, ethyl, propyl, isopropyl, butyl or isobutyl on the cation are preferably suitable. The hydrocarbon group on the cation must be large enough to ensure good solubility of the alkylating agent in the organic solvent. According to the invention, the use of N (butyl)₄ ⁺-Cl^-N (butyl)₄ ⁺-HSO₄ ^-And N (methyl)₄ ⁺-Cl^-。

The corresponding end-protected polyethylene glycol acids can also be prepared analogously.

Compounds of the general formula (XI) in which L has the following meanings,

by reacting the above-mentioned hydrophilic carboxylic acids R with those in which Sg has the meaning of a protecting group and L, X and R in accordance with amide formation methods known to the person skilled in the art_fAmines of the general formula (XII) having the abovementioned meanings,

A compound of the general formula (XII) wherein R⁸、R^8′N ', W and m' have the abovementioned meanings and Sg has the meaning of a protecting group

With perfluoronucleophiles of the general formula (XIV) in which Y, G, s' and ζ have the abovementioned meanings and in which Nu is a nucleofuge

Nu—Y—(CH₂)_s—(G)_t—(CH₂)_s’—ζ

(XIV)

In the presence of a base and optionally a phase transfer catalyst. As nucleofugic agents, the groups-Cl, -Br, -J, -OTs, -OMs, -OSO₂CF₃、-OSO₂C₄F₉or-OSO₂C₈F₁₇May be included in the alkylating agent of formula XVIII.

Known perfluoronucleophiles and other perfluoroalkyl-containing substances of the general formula (XIV) and their preparation are described in the following publications:

riess, Journal of Drug Targeting, 1994, volume 2, page 455-468;

nivet et al eur.j.med.chem., 1991, vol 26, page 953-;

p. krafft et al, angelw. chem., 1994, volume 106, phase 10, pages 1146-1148;

lanier et al Tetrahedron Letters, 1995, volume 36, phase 14, pages 2491-2492;

guillod et al, Carbohydrate Research, 1994, volume 261, pages 37-55;

achileffu et al, Journal of Fluorine Chemistry, 1995, volume 70, pages 19-26;

clary et al, Tetrahedron, 1995, Vol 51, No 47, p 13073-13088;

szoni et al, Journal of Fluorine Chemistry, 1989, Vol.42, pp.59-68;

wu et al, supra molecular Chemistry, 1994, volume 3, page 175-180;

guileri et al, Angew. chem.1994, volume 106, phase 14, pages 1583-1585;

p. krafft et al eur.j.med.chem., 1991, vol 26, p 545-550;

greiner et al, Journal of Fluorine Chemistry, 1992, Vol.56, pp.285-293;

milius et al, Carbohydrate Research, 1992, Vol.229, p.323-336;

riess et al, Colloids and Surfaces A, 1994, Vol.84, pp.33-48;

merh et al, J.Med.chem., 1996, vol.39, p. 4483-4488;

v. Cirkva et al, Journal of Fluorine Chemistry 1997, Vol.83, p.151-158;

ould Amanetoillah et al, Journal of Fluorine Chemistry 1997, vol.84, p.149-;

chen et al, Inorg. chem., 1996, vol.35, p.1590-161;

clary et al, Tetrahedron Letters, 1995, volume 36, phase 4, page 539-;

M.M. Chaaboundi et al, Journal of Fluorine Chemistry, 1990, Vol.46, p.307-315;

milius et al, New J.chem., 1991, Vol.15, pp.337-344;

p.krafft et al, New j.chem., 1990, volume 14, pages 869-;

J. nivet et al, New j.chem., 1994, volume 18, pages 861-869;

santaella et al, New j.chem., 1991, volume 15, pages 685-692;

santaella et al, New j.chem., 1992, volume 16, page 399-;

milius et al, New J.chem., 1992, Vol.16, pp.771-773;

sz ö nyi et al, Journal of Fluorine Chemistry, 1991, Vol.55, pp.85-92;

santaella et al, angelw. chem., 1991, volume 103, phase 5, page 584-;

P.Krafft et al, Angew.chem., 1993, Vol.105, No. 5, pp.783-785;

EP 0 548 096 B1。

compounds of the general formula (XI) in which L has the following meanings and q, alpha, beta and gamma have the abovementioned meanings

Wherein X and R are reacted by amide formation according to methods known to those skilled in the art_fThe perfluoro-containing carboxylic acids of the general formula (XV) having the above-mentioned meanings

HO—X—R_f

(XV)

With amines of the general formula (XVI) in which q, beta have the abovementioned meanings and Sg has the meaning of a protecting group,

the cleavage of the protecting Groups is carried out according to methods known to the person skilled in the art, for example by hydrolysis, hydrogenolysis, alkali saponification of the esters in aqueous-alcoholic solution at temperatures from 0 ℃ to 50 ℃ with bases, acid saponification with mineral acids or acid saponification with the aid of trifluoroacetic acid in the case of, for example, tert-butyl esters [ Protective Groups in Organic Synthesis, second edition, t.w.green and p.g.m.wuts, John Wiley and Sons, inc.new York, 1991], in the case of benzyl ethers using hydrogen/palladium/carbon.

The preparation of the compounds of the general formula (XV) is described in the abovementioned documents cited for the preparation of the compounds containing perfluoro groups.

Compounds of the general formula (XVI) in which q, beta have the abovementioned meanings and in which Sg has the meaning of a protecting group

Prepared by reacting the above-mentioned hydrophilic amines R with carboxylic acids of the general formula (XVII) in which q has the above-mentioned meaning and Sg 'have the meaning of a protecting group and in which Sg and Sg' can be cleaved in different ways according to amide-forming processes known to the person skilled in the art,

These 2X-protected amino acids of the general formula (XVII) are commercially available (Bachem).

The compounds according to the invention are particularly suitable for NMR and X-ray diagnostics, radiodiagnostics and radiotherapy, as well as MRT lymphography and blood pool imaging. Perfluoroalkyl-containing metal complexes are particularly suitable for use in nuclear spin resonance tomography (MRT) for displaying different physiological and pathophysiological structures and thereby improving diagnostic information such as disease localization and extent, success of therapy for selection and monitoring purposes, and for prevention of diseases and disorders.

In a particularly preferred embodiment, the substances according to the invention are used for MRT lymphography.

In another particularly preferred embodiment, the substances according to the invention are used for blood pool imaging.

Suitable diseases and conditions include detection and characterization of neoplastic diseases, particularly primary tumors, satellite metastases, lymph node metastases and necrosis, cardiovascular diseases, particularly changes in vessel diameter, such as stenosis and aneurysm, atherosclerosis by detecting atherosclerotic plaques, thromboembolic diseases, infarction, necrosis, inflammation, particularly arthritis, osteomyelitis, ulcerative colitis, and neurological damage.

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

The subject of the invention is also a medicament containing at least one physiologically compatible compound according to the invention and optionally additives customarily used in galenic formulations.

The compounds of the invention are characterized by excellent compatibility and at the same time excellent imaging properties. They are therefore particularly suitable for systemic use in MRT, in particular in MRT lymphography, and in tumor imaging.

The preparation of the medicaments according to the invention is carried out in a manner known in the art by suspending or dissolving the complexing compounds according to the invention, optionally with the addition of additives customarily used in galenic formulations, in an aqueous medium and then optionally sterilizing the suspension or solution. Suitable additives are, for example, physiologically harmless buffers (such as tromethamine), complexing agents or additives of weak complexes (such as diethylenetriaminepentaacetic acid or Ca complexes with the metal complexes corresponding to the invention), or, if necessary, electrolytes such as sodium chloride; or if necessary, an antioxidant such as ascorbic acid.

If it is desired to use the suspensions or solutions of the medicaments according to the invention in water or physiological saline solutions for enteral or parenteral administration or for other purposes, they are mixed with one or more of the auxiliaries customarily used in galenic formulations [ e.g. methylcellulose, lactose, mannitol]And/or surface agents [ e.g. lecithin, Tween^®、Myrj^®]And/or flavouring substances for flavouring purposes [ e.g. essential oils]And (4) mixing.

In principle, the medicaments according to the invention can also be prepared without isolation of the complex. In any case, great care must be taken to carry out the chelation so that the complexes according to the invention are substantially free of uncomplexed metal ions having a deleterious effect.

This can be ensured by controlling the titration during the preparation by means of a color indicator such as xylenol orange. The invention therefore also relates to a process for the preparation of the complex compounds and their salts. As a final precaution, the isolated complex is still purified.

In vivo administration of the medicament according to the present invention, the medicament may be administered together with an appropriate carrier such as serum or a physiologically common salt solution and with another protein such as Human Serum Albumin (HSA).

The medicaments according to the invention are generally administered parenterally, preferably intravenously. They may also be administered intravascularly or interstitially/intradermally, depending on whether the body is to be examined for vascular or tissue.

The medicament according to the invention preferably contains 0.1. mu. mol to 2mol/l of the complex and is generally administered in an amount of 0.001 to 5 mmol/kg.

The drugs according to the invention fulfill many requirements for being suitable as contrast agents for nuclear spin tomography. After oral or parenteral administration, it is therefore very well suited to enhance the information value of images obtained by means of nuclear spin tomography by increasing the signal intensity. They also show the remarkable effect required to load the body with as little foreign matter as possible and the good compatibility required to maintain the non-invasiveness of these studies.

The good water solubility and low osmolarity of the drug according to the invention make it possible to prepare highly concentrated solutions to keep the volumetric load of the circulatory system within reasonable limits and to compensate for the dilution of the body fluid. Furthermore, the medicaments according to the invention exhibit not only high stability in vitro but also surprisingly high stability in vivo, so that the ions which are inherently toxic and are bonded in complexes are released or exchanged only very slowly over the time the novel contrast agent is completely excreted again.

In general, the drug according to the present invention is administered in an amount of 0.0001 to 5mmol/kg, preferably 0.005 to 0.5mmol/kg, when used as an NMR diagnostic agent.

The complex compounds according to the invention can also be used advantageously as magnetization reagents (susceptibility reagents) and displacement reagents for in vivo NMR spectroscopy.

Due to the advantageous radioactive properties and the good stability of the complex compounds contained in the medicaments according to the invention, they are also suitable as radiodiagnostic agents. Details and dosages for this application are described, for example, in "Radiotracers for Medical Applications," CRC Press, BocaRaton, Florida.

The compounds and medicaments according to the invention may also be used in positron emission tomography using positron emitting isotopes, such as⁴³Sc、⁴⁴Sc、⁵²Fe、⁵⁵Co、⁶⁸Ga and⁸⁶Y(Heiss，W.D.；Phelps，M.E.；Positron EmissionTomography of Brain，Springer Verlag Berlin，Heidelberg，New York1983)。

histological studies confirmed local hyperpermeability of the microvessels.

Thus, the contrast agent according to the invention can also be used to show abnormal capillary permeability.

The compounds according to the invention are primarily characterized in that they are completely excreted from the body and are thus well tolerated. Thus, excellent imaging properties can be used and the non-invasive nature of the diagnosis is maintained.

Since the substances according to the invention accumulate in malignant tumors (which do not spread within healthy tissue but have a high permeability to tumor vessels), they can also assist in the radiotherapy of malignant tumors. Radiotherapy of malignant tumors differs from the corresponding diagnosis only in the amount and type of isotope used. The aim in this case is to destroy the tumor cells by high-energy short-wave radiation with the smallest possible range of action. For this purpose, the interaction of the metal contained in the complex, such as iron or gadolinium, with ionizing radiation (for example x-rays) or with neutron rays is used. By this effect, the local radiation dose at the site where the metal complex is present is significantly increased. In order to generate the same radiation dose in malignant tissue, the radiation exposure for healthy tissue can be greatly reduced when using these metal complexes and thus excessive side effects on the patient can be avoided. Therefore, the temperature of the molten metal is controlled,the metal complex conjugates (complex conjugates) according to the invention are also suitable as radiosensitizers in radiotherapy of malignant tumors, for example using the M ö ssbauer effect or in the case of neutron capture therapy. Suitable beta-emitting ions are, for example⁴⁶Sc、⁴⁷Sc、⁴⁸Sc、⁷²Ga、⁷³Ga and⁹⁰and Y. Alpha-emitting ions having a suitably low half-life are for example²¹¹Bi、²¹²Bi、²¹³Bi and²¹⁴bi, among them, preferred is²¹²And (4) Bi. Suitable photon and electron emitting ions are¹⁵⁸Gd, which can be captured from neutrons¹⁵⁷And obtaining Gd.

If the medicament according to the invention is intended for use in R.L. Mills et al Nature Vol.336, (1988), p.787]In a variant of the proposed radiotherapy, then the central ion must come from the M ö β bauer isotope, such as⁵⁷Fe or¹⁵¹Eu。

In the in vivo administration of the medicament according to the present invention, the medicament may be administered together with an appropriate carrier such as serum or a physiologically common salt solution and with another protein such as human serum albumin. The dose in this case depends on the type of cell division, the metal ions used and the type of imaging method.

The medicaments according to the invention are generally administered parenterally, preferably intravenously. As discussed above, they may also be administered intravascularly or interstitially/intradermally, depending on whether the body's vasculature or tissue is being examined.

The medicaments according to the invention are very suitable for use as x-ray contrast agents, wherein it is particularly emphasized that the known symptoms of anaphylaxis in iodine-containing contrast agents may not be detected with the medicaments according to the invention in biochemical-pharmacological studies. They are particularly useful for digital subtraction techniques due to the favorable absorption characteristics in the higher tube pressure range.

In general, the medicaments according to the invention are administered in amounts of 0.1 to 5mmol/kg, preferably 0.25 to 1mmol/kg, when used as x-ray contrast agents similar to, for example, meglumine-diatrizoate.

The term "metal ion equivalent" as used in this application is a term commonly used in the art of complex chemistry known to those skilled in the art. Metal ion equivalents are equivalents of metal ions which may be linked, for example, to carboxylate groups rather than hydrogen. For example, if the metal is gadolinium, Gd³⁺May be linked to 3 carboxylate groups, i.e. 1/3Gd³⁺Corresponding to the metal ion equivalent R in the formula (II), (III), (IV) or (V)¹。

Examples

Example 1

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

23.31g (120mmol) of N-benzyloxycarbonyl-ethylenediamine (Atwell et al, Synthesis, 1984, 1032-propan 1033) and 10.2g (100mmol) of triethylamine were added to 54.22g (100mmol) of methanesulfonic acid- (1H, 1H, 2H, 2H-perfluorodecyl) -ester (Bartsch et al, Tetrahedron, 2000, 3291-propan 3302) in 500ml of acetonitrile and stirred at 60 ℃ for 48 hours. The insoluble components were filtered off from the reaction solution, evaporated to dryness in vacuo and the residue was chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C37.51H 2.68N 4.37F 50.44

Measured value: C37.82H 2.74N 4.29F 50.27

b) N- [2- (benzyloxycarbonyl) -aminoethyl-N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- [ 1-O-alpha-d- (2, 3, 4, 6-tetra-O-benzyl) mannopyranosyl ] -acetamide

8.05g (39.04mmol) dicyclohexylcarbodiimide were added at 0 ℃ to a solution of 20g (31.23mmol) of the title compound of example 1a with 18.70g (31.23mmol) of 1-O-. alpha. -d-carbonylmethyl- (2, 3, 4, 6-tetra-O-benzyl) mannopyranose (prepared according to WO 99/01160A 1) and 3.59g (31.23mmol) of N-hydroxysuccinimide in 200ml dimethylformamide, stirred at 0 ℃ for 3h and then at room temperature for 16 h. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C55.09H 4.38N 2.29F 26.45

Measured value: C55.27H 4.40N 2.24F 26.31

c) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- (1-O-alpha-d-mannopyranosyl) -acetamide, methanesulfonate

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

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

Elemental analysis:

calculated values: C30.67H 3.31N 3.41F 39.27

Measured value: C31.01H 3.29N 3.33F 39.04

d) N- { [1, 4, 7-tris (carboxymethyl) -1, 4, 7, 10-tetracyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) ] -2-aminoethyl } -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- (1-O-. alpha. -d-mannopyranosyl) -acetamide, Gd complex

18.7g (22.72mmol) of the title compound from example 1c, 2.61g (22.72mmol) of N-hydroxysuccinimide, 1.93g (45.44mmol) of lithium chloride and 14.31g (22.72mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (example 1)) are dissolved in 200ml of dimethyl sulfoxide with gentle heating. 5.86g (28.4mmol) dicyclohexylcarbodiimide and 2.30g (22.72mmol) triethylamine were added at 10 ℃ and stirred at room temperature for 16 hours. The solution was poured into 2000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

Yield: 22.3g (68% of theory) of a colorless solid

Water content (Karl-Fischer): 7.0 percent

Elemental analysis (versus anhydrous material):

calculated values: C35.01H 3.84N 7.33F 24.14 Gd 11.75

Measured value: C35.21H 3.89N 7.27F 24.09 Gd 11.61

Example 2

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

10.0g (15.62mmol) of the title compound of example 1a, 1.80g (15.62mmol) of N-hydroxysuccinimide, 1.33g (31.34mmol) of lithium chloride and 9.84g (15.62mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG, (example 1)) are dissolved in 150ml of dimethyl sulfoxide with gentle heating. 4.03g (19.52mmol) of dicyclohexylcarbodiimide were added at 10 ℃ and stirred at room temperature for 16 hours. The solution is poured into 2000ml of diethyl ether and stirred for a further 10 minutes. The precipitated solid is filtered off and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol/aqueous ammonia 10: 5: 1).

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

Water content (Karl-Fischer): 5.4 percent

Elemental analysis (versus anhydrous material):

calculated values: C37.41H 3.62N 7.83F 25.80 Gd 12.56

Measured value: C37.69H 3.56N 7.91F 25.64 Gd 12.37

b)1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-N- [1, 4, 7-tris- (carboxymethyl) -1, 4, 7, 10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) ] -perfluorotridecylamine, Gd complex, methanesulfonate

1.16g (12.08mmol) of methanesulfonic acid and 2.0g of palladium catalyst (10% Pd/C) are added to a solution of 16g (12.08mmol) of the title compound from example 2a in 300ml of ethanol and hydrogenated at room temperature for 24 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo.

Yield: 15.8g (quantitative) of a colorless solid.

Water content (Karl-Fischer): 7.0 percent

Elemental analysis (versus anhydrous material):

calculated values: C31.66H 3.57N 8.08F 26.60 Gd 12.95

Measured value: C31.88H 3.59N 8.14F 26.42 Gd 12.69

c)1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-N- [1, 4, 7-tris- (carboxymethyl) -1, 4, 7, 10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) ] -perfluorotridecyl-N-2- (1-O-alpha-d-mannopyranosyl) -acetamide, Gd complex

1.72g (8.33mmol) dicyclohexylcarbodiimide and 674mg (6.66mmol) triethylamine are added at 0 ℃ to a solution of 8.9g (6.66mmol) of the title compound of example 2b and 3.99g (6.66mmol) 1-O-. alpha. -d-carbonylmethyl- (2, 3, 4, 6-tetra-O-benzyl) mannopyranose (prepared according to WO 99/01160A 1) and 767mg (6.66mmol) N-hydroxysuccinimide in 100ml dimethylformamide, stirred at 0 ℃ for 3 hours and then at room temperature for 16 hours. The precipitated urea was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in 100ml of methanol, mixed with 2.0g of palladium catalyst (10% Pd/C) and hydrogenated at room temperature for 24 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. The residue is taken up in a small amount of water, the insoluble constituents are filtered off and the filtrate is purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

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

Water content (Karl-Fischer): 6.2 percent

Elemental analysis (versus anhydrous material):

calculated values: C35.01H 3.84N 7.33F 24.14 Gd 11.75

Measured value: C35.23H 3.88N 7.27F 24.01 Gd 11.59

Example 3

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

14.62g (75mmol) of tert-butyl bromoacetate are added at 0 ℃ to 30.02g (50mmol) of 1, 3-bis- (2-benzyloxy-1-benzyloxymethyl-ethoxy) -propan-2-ol (Cassel et al, Eur.J.Org.Chem., 2001, 5, 875-896) in 250 ml of toluene, with 5.6g (100mmol) of fine potassium hydroxide powder and a catalytic amount (1g) of tetra-n-butylammonium hydrogensulfate and stirred at this temperature for 2 hours and at room temperature for 12 hours. Reacting the reaction solution with 500ml of ethyl acetate and 300ml of water. The organic phase is separated and washed twice with 300ml of water each, then dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is suspended in a mixture of 400ml of methanol and 0.5M sodium hydroxide solution in a ratio of 2: 1 and then heated for 12 hours to 60 ℃. The reaction mixture was passed through a column with Amberlite IR 120 (H)⁺Type) cation exchange resin was mixed and neutralized for treatment, the exchanger was filtered off, evaporated to dryness and subjected to silica gel chromatography (mobile solvent: ethyl acetate/hexane 1: 3).

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

Elemental analysis:

calculated values: C71.10H 7.04

Measured value: C71.29H 7.21

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

8.05g (39.04mmol) dicyclohexylcarbodiimide were added at 0 ℃ to a solution of 20g (31.23mmol) of the title compound from example 1a and 20.57g (31.23mmol) of the title compound from example 3a and 3.59g (31.23mmol) of N-hydroxysuccinimide in 200ml dimethylformamide and stirred at 0 ℃ for 3h and then at room temperature for 16 h. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C55.32H 4.80N 2.19F 25.21

Measured value: C55.56H 4.87N 2.13F 26.07

c) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- [1, 3-bis- (2-hydroxy-1-hydroxymethyl-ethoxy) -propan-2-oxy ] -acetamide, methanesulfonate

1.96g (20.29mmol) of methanesulfonic acid and 4.0g of a palladium catalyst (10% Pd/C) are added to a solution of 26g (20.29mmol) of the title compound from example 3b in 500ml of ethanol and hydrogenated at room temperature for 24 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo.

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

Elemental analysis:

calculated values: C32.66H 4.00N 3.17F 36.59

Measured value: C32.89H 4.10N 3.11F 36.41

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

16.8g (19.07mmol) of the title compound of example 3c, 2.19g (19.07mmol) of N-hydroxysuccinimide, 1.62g (38.14mmol) of lithium chloride and 14.31g (19.07mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG (example 1)) are dissolved in 200ml of dimethyl sulfoxide with gentle heating. 4.92g (23.84mmol) dicyclohexylcarbodiimide and 1.93g (19.07mmol) triethylamine were added at 10 ℃ and stirred at room temperature for 16 hours. The solution was poured into 2000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

Yield: 20.6g (72% of theory) of a colorless solid

Water content (Karl-Fischer): 6.7 percent

Elemental analysis (versus anhydrous material):

calculated values: C36.06H 4.25N 7.01F 23.10 Gd 11.25

Measured value: C36.34H 4.32N 6.97F 22.88 Gd 11.17

Example 4

a)1, 4, 7- { tris (carboxymethyl) -10- [ (3-aza-4-oxo-hex-5-yl) acid-N-1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-N- [1, 4, 7-tris- (carboxymethyl) -1, 4, 7, 10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) ] -perfluorotridecylamide ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex

8.1g (6.31mmol) of the title compound from example 2b, 726mg (6.31mmol) of N-hydroxysuccinimide, 535mg (12.62mmol) of lithium chloride and 3.97g (6.31mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpent-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG (example 1)) are dissolved in 100ml of dimethyl sulfoxide with gentle heating. 1.63g (7.89mmol) of dicyclohexylcarbodiimide and 693mg (6.31mmol) of triethylamine were added at 10 ℃ and stirred at room temperature for 16 hours. The solution was poured into 2000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

Yield: 6.5g (56% of theory) of a colorless solid

Water content (Karl-Fischer): 5.8 percent

Elemental analysis (versus anhydrous material):

calculated values: C34.72H 3.90N 9.72F 18.67 Gd 18.18

Measured value: C34.94H 3.94N 9.67F 18.59 Gd 18.01

Example 5

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

8.05g (39.04mmol) dicyclohexylcarbodiimide were added to a solution of 20g (31.23mmol) of the title compound of example 1a and 5.57g (31.23mmol) [2- (2-methoxyethoxy) -ethoxy ] -acetic acid (Aldrich) and 3.59g (31.23mmol) N-hydroxysuccinimide in 200ml dimethylformamide at 0 ℃ and stirred for 3h at 0 ℃ and then for 16 h at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C40.51H 3.65N 3.50F 40.35

Measured value: C40.62H 3.68N 3.53F 40.09

b) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- [2- (2-methoxyethoxy) ethoxy ] -acetamide, methanesulfonate

2.28g (23.73mmol) of methanesulfonic acid and 4.0g of a palladium catalyst (10% Pd/C) are added to a solution of 19g (23.73mmol) of the title compound from example 5a in 500ml of ethanol and hydrogenated at room temperature for 24 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo.

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

Elemental analysis:

calculated values: C31.51H 3.57N 3.67F 42.36

Measured value: C31.77H 3.59N 3.54F 42.05

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

17.2g (22.51mmol) of the title compound of example 5b, 2.59g (22.51mmol) of N-hydroxysuccinimide, 1.91g (45.02mmol) of lithium chloride and 14.18g (22.51mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpent-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG (example 1)) are dissolved in 200ml of dimethyl sulfoxide with gentle heating. 5.81g (28.14mmol) dicyclohexylcarbodiimide and 2.28g (22.51mmol) triethylamine were added at 10 ℃ and stirred at room temperature for 16 hours. The solution was poured into 2000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP 18; mobile solvent: gradient consisting of water/acetonitrile).

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

Water content (Karl-Fischer): 6.4 percent

Elemental analysis (versus anhydrous material):

calculated values: C35.71H 4.02N 7.67F 25.72 Gd 12.30

Measured value: C35.79H 4.07N 7.59F 25.63 Gd 12.27

Example 6

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

17.8g (140mmol) of oxalyl chloride are added to 52.22g (100mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid (prepared according to EP 01/08498) in 500ml of dichloromethane and stirred at room temperature for 14 hours. Evaporation to dryness in vacuo was carried out, the residue was dissolved in 400ml of dichloromethane, mixed at 0 ℃ with 23.31g (120mmol) of N-benzyloxycarbonyl-ethylenediamine (Atwell et al, Synthesis, 1984, 1032-1033) and 10.2g (100mmol) of triethylamine, and stirred at room temperature for 24 hours. The reaction solution was mixed with 400ml of 1N hydrochloric acid and sufficiently stirred for 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane 1: 2).

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

Elemental analysis:

calculated values: C37.84H 2.74N 4.01F 46.25

Measured value: C38.02H 2.76N 3.97F 46.12

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

48.5g (69.45mmol) of the title compound of example 6a in 150ml of THF are mixed with 50ml of 10M borane dimethylsulfide in THF and refluxed for 5 hours. Cooled to 0 ℃, 100ml of methanol was added dropwise, stirred at room temperature for 1 hour, and then evaporated to dryness in vacuo. The residue is taken up in a mixture of 300ml of ethanol/50 ml of 1M hydrochloric acid and stirred at 40 ℃ for 14 hours. The evaporation to dryness is carried out in vacuo, the residue is taken up in 300ml of 5% sodium hydroxide solution and extracted three times with 300ml of each dichloromethane. The combined organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 10: 1).

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

Elemental analysis:

calculated values: C38.61H 3.09N 4.09F 47.19

Measured value: C38.88H 3.14N 4.06F 46.87

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

7.54g (36.53mmol) dicyclohexylcarbodiimide were added at 0 ℃ to a solution of 20g (29.22mmol) of the title compound of example 6b and 5.21g (29.22mmol) of [2- (2-methoxyethoxy) -ethoxy ] -acetic acid (Aldrich) and 3.36g (29.22mmol) of N-hydroxysuccinimide in 200ml of dimethylformamide and stirred at 0 ℃ for 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C41.24H 3.94N 3.32F 38.24

Measured value: C41.42H 3.98N 3.33F 38.21

d) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -2- [2- (2-methoxyethoxy) -ethoxy ] -acetamide, methanesulfonate

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

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

Elemental analysis:

calculated values: C32.76H 3.87N 3.47F 40.04

Measured value: C32.99H 3.98N 3.35F 39.84

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

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

Yield: 16.6g (64% of theory) of a colorless solid

Water content (Karl-Fischer): 6.9 percent

Elemental analysis (versus anhydrous material):

calculated values: C36.34H 4.19N 7.42F 24.43 Gd 11.89

Measured value: C36.49H 4.27N 7.36F 24.28 Gd 11.78

Example 7

a) 6-N-benzyloxycarbonyl-2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) -L-lysine

25g (31.31mmol) of 6-N-benzyloxycarbonyl-2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) -L-lysine methyl ester (prepared according to EP 03/07274) were dissolved in 200ml of methanol and 50ml of 2N potassium hydroxide solution and stirred at room temperature for 18 hours. It is acidified with 2N hydrochloric acid, evaporated to dryness and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 10: 1).

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

Elemental analysis:

calculated values: C39.81H 3.21N 3.57F 41.17

Measured value: C40.07H 3.27N 3.49F 41.05

b) [ 1-O-alpha-d- (2, 3, 4, 6-tetra-O-benzyl) mannopyranosyl ] -acetamide

11.45g (90mmol) of oxalyl chloride are added to 40g (66.81mmol) of 1-O-. alpha. -d-carbonylmethyl- (2, 3, 4, 6-tetra-O-benzyl) mannopyranose (prepared according to WO 99/01160A 1) in 300ml of dichloromethane and stirred at room temperature for 14 hours. The evaporation to dryness in vacuo, the residue dissolved in 400ml of dichloromethane, ammonia gas introduced into the solution at 0 ℃ for about 2 hours and stirred at room temperature for 4 hours. The reaction solution was mixed with 400ml of 1N hydrochloric acid and sufficiently stirred for 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane 1: 2).

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

Elemental analysis:

calculated values: C72.34H 6.58N 2.34

Measured value: C72.69H 6.54N 2.39

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

33g (55.21mmol) of the title compound of example 7b in 100ml of THF are mixed with 30ml of 10M borane dimethylsulfide in THF and refluxed for 5 hours. Cooled to 0 ℃, 100ml of methanol was added dropwise, stirred at room temperature for 1 hour, and then evaporated to dryness in vacuo. The residue is taken up in a mixture of 200ml of ethanol/100 ml of ethanolamine and stirred at 60 ℃ for 14 hours. The evaporation to dryness is carried out in vacuo, the residue is taken up in 300ml of 5% sodium hydroxide solution and extracted three times with 300ml of each dichloromethane. The combined organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 10: 1).

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

Elemental analysis:

calculated values: C74.08H 7.08N 2.40

Measured value: C74.55H 7.19N 2.31

d) 6-N-benzyloxycarbonyl-2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) -L-lysine- {2- [1-O- α -d- (2, 3, 4, 6-tetra-O-benzyl) mannopyranosyl ] -ethyl } -amide

4.93g (23.90mmol) dicyclohexylcarbodiimide were added at 0 ℃ to a solution of 15g (19.12mmol) of the title compound from example 7a and 11.16g (19.12mmol) of the title compound from example 7c and 2.20g (19.12mmol) of N-hydroxysuccinimide in 200ml dimethylformamide and stirred at 0 ℃ for 3h and then at room temperature for 16 h. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C55.15H 4.78N 3.11F 23.92

Measured value: C55.32H 4.82N 3.09F 23.74

e)2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) -L-lysine- [2- { 1-O-alpha-d-mannopyranosyl } -ethyl } -amide

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

Yield: 11.8g (quantitative) of a colorless solid.

Elemental analysis:

calculated values: C36.50H 4.01N 4.91F 37.75

Measured value: C36.79H 3.98N 4.87F 37.84

f)6-N- [1, 4, 7-tris- (carboxymethyl) -1, 4, 7, 10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) ] -2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) -L-lysine- [2- { 1-O-alpha-d-mannopyranosyl } -ethyl } -amide, Gd complex

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

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

Water content (Karl-Fischer): 6.9 percent

Elemental analysis (versus anhydrous material):

calculated values: C36.84H 4.26N 7.64F 22.01 Gd 10.72

Measured value: C37.03H 4.31N 7.59F 21.95 Gd 10.62

Example 8

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

4.93g (23.90mmol) dicyclohexylcarbodiimide were added to a solution of 15g (19.12mmol) of the title compound from example 7a and 5.6g (28.68mmol) of N-methylglucamine (Aldrich) and 2.20g (19.12mmol) of N-hydroxysuccinimide in 200ml dimethylformamide at 0 ℃ and stirred for 3h at 0 ℃ and then for 16 h at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 5: 1).

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

Elemental analysis:

calculated values: C41.22H 4.19N 4.37F 33.58

Measured value: C41.47H 4.30N 4.29F 33.35

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

1.0g of palladium catalyst (10% Pd/C) are added to a solution of 9.0g (9.39mmol) of the title compound from example 8a in 100ml of ethanol and hydrogenated at room temperature for 24 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo.

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

Elemental analysis:

calculated values: C36.29H 4.14N 5.08F 39.03

Measured value: C36.44H 4.17N 4.98F 38.86

c)6-N- [1, 4, 7-tris- (carboxymethyl) -1, 4, 7, 10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) ] -2-N- (2H, 2H, 4H, 4H, 5H, 5H-3-oxaperfluorotridecyl) -L-lysine- { [ N- (2S, 3R, 4R, 5R) -2, 3, 4,5, 6-pentahydroxyhexyl ] -N-methyl } -amide, Gd complex

7.0g (8.46mmol) of the title compound of example 8b, 974mg (8.46mmol) of N-hydroxysuccinimide, 717mg (16.92mmol) of lithium chloride and 5.33g (8.46mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpent-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG (example 1)) are dissolved in 100ml of dimethyl sulfoxide with gentle heating. 2.18g (10.57mmol) dicyclohexylcarbodiimide were added at 10 ℃ and stirred at room temperature for 16 hours. The solution was poured into 2000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

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

Water content (Karl-Fischer): 6.1 percent

Elemental analysis (versus anhydrous material):

calculated values: C36.72H 4.34N 7.79F 22.44 Gd 10.93

Measured value: C36.87H 4.36N 7.72F 22.48 Gd 10.94

Example 9

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

4.93g (23.90mmol) dicyclohexylcarbodiimide were added at 0 ℃ to 15g (19.12mmol) of the title compound of example 7a and a solution of 3.97g (19.12mmol) of (2- {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -ethyl) -amine (Whitessides et al, JACS, 1994, 5057-5062) and 2.20g (19.12mmol) of N-hydroxysuccinimide in 200ml dimethylformamide and stirred at 0 ℃ for 3h and then at room temperature for 16 h. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 10: 1).

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

Elemental analysis:

calculated values: C43.17H 4.55N 4.32F 33.17

Measured value: C43.36H 4.61N 4.27F 33.00

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

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

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

Elemental analysis:

calculated values: C38.63H 4.56N 5.00F 38.47

Measured value: C38.75H 4.61N 4.93F 38.27

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

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

Yield: 10.1g (62% of theory) of a colorless solid

Water content (Karl-Fischer): 6.0 percent

Elemental analysis (versus anhydrous material):

calculated values: C36.21H 4.17N 6.87F 22.65 Gd 11.03

Measured value: C36.41H 4.22N 6.79F 22.58 Gd 10.92

Example 10

a)2H, 2H, 4H, 4H-3-oxa-perfluorododecanoic acid

64.96g (333.26mmol) of tert-butyl bromoacetate are added at 0 ℃ to 100g (222.17mmol) of 1H, 1H-perfluoro-1-nonanol (Apollo) and 24.9g (444mmol) of potassium hydroxide fine powder in 800ml of toluene and a catalytic amount (2g) of ammonium tetra-n-butylhydrogensulfate, and stirred at this temperature for 2 hours and at room temperature for 12 hours. The reaction solution was mixed with 1500ml of ethyl acetate and 800ml of water. The organic phase is separated and washed twice with 500ml of water each, then dried over magnesium sulfate and evaporated to dryness in vacuo.The residue is suspended in a mixture of 1200ml of methanol and 0.5M sodium hydroxide solution in a ratio of 2: 1 and then heated to 60 ℃ over 12 hours. The reaction mixture was passed through a column with Amberlite IR 120 (H)⁺Type) cation exchange resin was mixed for neutralization, the exchanger was filtered off, evaporated to dryness and subjected to silica gel chromatography (mobile solvent: ethyl acetate/hexane 1: 3).

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

Elemental analysis:

calculated values: C26.00H 0.99F 63.56

Measured value: C26.22H 1.01F 63.42

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

17.8g (140mmol) of oxalyl chloride are added to 50.81g (100mmol) of the title compound of example 10a in 500ml of dichloromethane and stirred at room temperature for 14 hours. Evaporation to dryness in vacuo was carried out, the residue was dissolved in 400ml of dichloromethane, mixed at 0 ℃ with 23.31g (120mmol) of N-benzyloxycarbonyl-ethylenediamine (Atwell et al, Synthesis, 1984, 1032-1033) and 10.2g (100mmol) of triethylamine, and stirred at room temperature for 24 hours. The reaction solution was mixed with 400ml of 1N hydrochloric acid and sufficiently stirred for 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane 1: 2).

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

Elemental analysis:

calculated values: C36.86H 2.50N 4.09F 47.19

Measured value: C37.00H 2.52N 4.11F 46.97

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

45.5g (66.40mmol) of the title compound of example 10b in 150ml of THF are mixed with 50ml of 10M borane dimethylsulfide in THF and refluxed for 5 hours. Cooled to 0 ℃, 100ml of methanol was added dropwise, stirred at room temperature for 1 hour, and then evaporated to dryness in vacuo. The residue is taken up in a mixture of 300ml of ethanol/50 ml of 1M hydrochloric acid and stirred at 40 ℃ for 14 hours. The evaporation to dryness is carried out in vacuo, the residue is taken up in 300ml of 5% sodium hydroxide solution and extracted three times with 300ml of each dichloromethane. The combined organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 10: 1).

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

Elemental analysis:

calculated values: C37.63H 2.86N 4.18F 48.18

Measured value: C37.87H 2.90N 4.17F 48.00

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

7.69g (37.29mmol) dicyclohexylcarbodiimide were added at 0 ℃ to a solution of 20g (29.83mmol) of the title compound of example 10c and 6.63g (29.83mmol) of {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -acetic acid (Voegtle et al, LiebigsAnn. chem., 1980, 858-862) and 3.43g (29.83mmol) of N-hydroxysuccinimide in 200ml dimethylformamide and stirred at 0 ℃ for 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C41.20H 4.03N 3.20F 36.93

Measured value: C41.44H 3.98N 3.11F 36.84

e) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H-3-oxa-perfluorododecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -acetamide, methanesulfonate

2.09g (21.72mmol) of methanesulfonic acid and 3.0g of palladium catalyst (10% Pd/C) are added to a solution of 19.0g (21.72mmol) of the title compound from example 10d in 300ml of ethanol and hydrogenated at room temperature for 24 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo.

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

Elemental analysis:

calculated values: C33.02H 3.98N 3.35F 38.61

Measured value: C33.41H 3.96N 3.25F 38.44

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

15.8g (18.9mmol) of the title compound of example 10e, 2.18g (18.9mmol) of N-hydroxysuccinimide, 1.60g (37.80mmol) of lithium chloride and 11.90g (18.30mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG (example 1)) are dissolved in 200ml of dimethyl sulfoxide with gentle heating. 4.87g (23.63mmol) dicyclohexylcarbodiimide and 1.91g (18.9mmol) triethylamine were added at 10 ℃ and stirred at room temperature for 16 hours. The solution was poured into 2000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

Yield: 16.7g (61% of theory) of a colorless solid

Water content (Karl-Fischer): 6.9 percent

Elemental analysis (versus anhydrous material):

calculated values: C36.42H 4.25N 7.25F 23.89 Gd 11.63

Measured value: C36.71H 4.32N 7.19F 23.67 Gd 11.51

Example 11

17.8g (140mmol) of oxalyl chloride are added to 52.21g (100mmol) of 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecanoic acid (example 39g of EP 01/08498) in 500ml of dichloromethane and stirred at room temperature for 14 hours. Evaporation to dryness in vacuo was carried out, the residue was dissolved in 400ml of dichloromethane, mixed at 0 ℃ with 23.31g (120mmol) of N-benzyloxycarbonyl-ethylenediamine (Atwell et al, Synthesis, 1984, 1032-1033) and 10.2g (100mmol) of triethylamine, and stirred at room temperature for 24 hours. The reaction solution was mixed with 400ml of 1N hydrochloric acid and sufficiently stirred for 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane 1: 2).

Yield: 49.6g (71% of theory) of colorless wax

Elemental analysis:

calculated values: C37.84H 2.74N 4.01F 46.25

Measured value: C37.99H 2.81N 4.05F 45.96

48.0g (68.73mmol) of the title compound of example 11a in 150ml of THF are mixed with 50ml of 10M borane dimethylsulfide in THF and refluxed for 5 hours. Cooled to 0 ℃, 100ml of methanol was added dropwise, stirred at room temperature for 1 hour, and then evaporated to dryness in vacuo. The residue is taken up in a mixture of 300ml of ethanol/50 ml of 1M hydrochloric acid and stirred at 40 ℃ for 14 hours. The evaporation to dryness is carried out in vacuo, the residue is taken up in 300ml of 5% sodium hydroxide solution and extracted three times with 300ml of each dichloromethane. The combined organic phases are dried over magnesium sulfate, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 10: 1).

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

Elemental analysis:

calculated values: C36.61H 3.09N 4.09F 47.19

Measured value: C36.77H 3.14N 4.02F 46.99

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

7.42g (36.59mmol) dicyclohexylcarbodiimide were added at 0 ℃ to a solution of 20g (29.22mmol) of the title compound of example 11b and 6.49g (29.22mmol) of {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -acetic acid (Voegtle et al, LiebigsAnn. chem., 1980, 858-862) and 3.29g (29.22mmol) of N-hydroxysuccinimide in 200ml dimethylformamide, stirred at 0 ℃ for 3 hours and then at room temperature for 16 hours. The precipitated urea was filtered off, the filtrate was evaporated to dryness in vacuo, and the residue was chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C41.90H 4.20N 3.15F 36.35

Measured value: C42.16H 4.28N 3.12F 36.21

d) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H, 5H, 5H-3-oxa-perfluorotridecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -acetamide, methanesulfonate

2.06g (21.38mmol) of methanesulfonic acid and 3.0g of palladium catalyst (10% Pd/C) are added to a solution of 19.0g (21.38mmol) of the title compound from example 11C in 300ml of ethanol and hydrogenated at room temperature for 24 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo.

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

Elemental analysis:

calculated values: C33.89H 4.15N 3.29F 37.97

Measured value: C34.11H 4.21N 3.10F 37.69

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

15.8g (18.55mmol) of the title compound of example 11d, 2.14g (18.55mmol) of N-hydroxysuccinimide, 1.57g (37.10mmol) of lithium chloride and 11.68g (18.55mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG (example 1)) are dissolved in 200ml of dimethyl sulfoxide with gentle heating. 4.78g (23.19mmol) dicyclohexylcarbodiimide and 1.88g (18.55mmol) triethylamine were added at 10 ℃ and stirred at room temperature for 16 h. The solution was poured into 2000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

Yield: 19.8g (73% of theory) of a colorless solid

Water content (Karl-Fischer): 6.5 percent

Elemental analysis (versus anhydrous material):

calculated values: C36.92H 4.35N 7.18F 23.64 Gd 11.51

Measured value: C37.15H 4.30N 7.07F 23.51 Gd 11.44

Example 12

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

8.05g (39.04mmol) dicyclohexylcarbodiimide were added to 20g (31.23mmol) of the title compound of example 1a at 0 ℃ with a solution of 8.32g (31.23mmol) (2- {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -ethoxy) -acetic acid (Voegtle et al, Liebigs Ann. chem., 1980, 858-862) and 3.59g (31.23mmol) N-hydroxysuccinimide in 200ml dimethylformamide, stirred at 0 ℃ for 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C41.90H 4.20N 3.15F 36.35

Measured value: C42.14H 4.26N 3.11F 36.12

b) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -acetamide, methanesulfonate

2.28g (23.63mmol) of methanesulfonic acid and 4.0g of palladium catalyst (10% Pd/C) are added to a solution of 21g (23.63mmol) of the title compound from example 12a in 500ml of ethanol and hydrogenated at room temperature for 24 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo.

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

Elemental analysis:

calculated values: C33.89H 4.15N 3.29F 37.97

Measured value: C34.08H 4.19N 3.17F 37.65

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

16.9g (19.88mmol) of the title compound of example 12b, 2.29g (19.88mmol) of N-hydroxysuccinimide, 1.68g (39.76mmol) of lithium chloride and 12.52g (19.88mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG (example 1)) are dissolved in 200ml of dimethyl sulfoxide with gentle heating. 5.13g (24.85mmol) dicyclohexylcarbodiimide and 2.01g (19.88mmol) triethylamine were added at 10 ℃ and stirred at room temperature for 16 hours. The solution was poured into 2000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

Yield: 18.1g (62% of theory) of a colorless solid

Water content (Karl-Fischer): 6.8 percent

Elemental analysis (versus anhydrous material):

calculated values: C36.92H 4.35N 7.18F 23.64 Gd 11.51

Measured value: C37.11H 4.38N 7.09F 23.51 Gd 11.44

Example 13

a) N- [2- (benzyloxycarbonyl) -aminoethyl-N- (1H, 1H, 2H, 2H-perfluorodecyl) -2-methoxyacetamide

8.05g (39.04mmol) dicyclohexylcarbodiimide were added to a solution of 20g (31.23mmol) of the title compound of example 1a and 2.81g (31.23mmol) 2-methoxyacetic acid (Aldrich) and 3.59g (31.23mmol) N-hydroxysuccinimide in 200ml dimethylformamide at 0 ℃ and stirred for 3h at 0 ℃ and then for 16 h at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

Yield: 17.1g (77% of theory) of a colorless viscous oil.

Elemental analysis:

calculated values: C38.78H 2.97N 3.93F 45.34

Measured value: C38.94H 3.01N 3.88F 45.22

b) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2-methoxyacetamide, methanesulfonate

2.23g (23.16mmol) of methanesulfonic acid and 4.0g of palladium catalyst (10% Pd/C) are added to a solution of 16.5g (23.16mmol) of the title compound from example 13a in 500ml of ethanol and hydrogenated at room temperature for 24 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo.

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

Elemental analysis:

calculated values: C28.50H 2.84N 4.15F 47.89

Measured value: C28.79H 2.96N 4.09F 47.53

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

11.7g (17.29mmol) of the title compound of example 13b, 1.99g (17.29mmol) of N-hydroxysuccinimide, 1.46g (34.58mmol) of lithium chloride and 10.89g (17.29mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WOHH98/24775, Schering AG (example 1)) are dissolved in 200ml of dimethyl sulfoxide with gentle heating. 4.46g (21.6mmol) dicyclohexylcarbodiimide and 1.75g (17.29mmol) triethylamine were added at 10 ℃ and stirred at room temperature for 16 hours. The solution was poured into 2000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

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

Water content (Karl-Fischer): 6.0 percent

Elemental analysis (versus anhydrous material):

calculated values: C34.32H 3.64N 8.24F 27.14 Gd 13.21

Measured value: C34.59H 3.69N 8.18F 26.98 Gd 13.14

Example 14

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

8.05g (39.04mmol) dicyclohexylcarbodiimide were added at 0 ℃ to 20g (31.23mmol) of the title compound of example 1a with a solution of 6.94g (31.23mmol) {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -acetic acid (Voegtle et al, Liebigs Ann. chem., 1980, 858-862) and 3.59g (31.23mmol) N-hydroxysuccinimide in 200ml dimethylformamide, stirred at 0 ℃ for 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

Yield: 22.3g (85% of theory) of a colorless viscous oil.

Elemental analysis:

calculated values: C41.24H 3.94N 3.32F 38.24

Measured value: C41.37H 3.99N 3.27F 38.11

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

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

Elemental analysis:

calculated values: C32.76H 3.87N 3.47F 40.04

Measured value: C32.88H 3.91N 3.33F 39.89

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

11.4g (14.08mmol) of the title compound of example 14b, 1.62g (14.08mmol) of N-hydroxysuccinimide, 1.19g (28.12mmol) of lithium chloride and 8.87g (14.08mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG (example 1)) are dissolved in 200ml of dimethyl sulfoxide with gentle heating. 3.63g (17.6mmol) of dicyclohexylcarbodiimide and 1.43g (14.08mmol) of triethylamine were added at 10 ℃ and stirred at room temperature for 16 hours. The solution was poured into 2000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

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

Water content (Karl-Fischer): 5.7 percent

Elemental analysis (versus anhydrous material):

calculated values: C36.34H 4.19N 7.42F 24.43 Gd 11.89

Measured value: C36.57H 4.22N 7.44F 24.29 Gd 11.77

Example 15

a) N- [2- (benzyloxycarbonyl) -aminoethyl-N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- (2-methoxyethoxy) -acetamide

8.05g (39.04mmol) dicyclohexylcarbodiimide were added to a solution of 20g (31.23mmol) of the title compound of example 1a and 4.19g (31.23mmol) (2-methoxyethoxy) -acetic acid (Aldrich) and 3.59g (31.23mmol) N-hydroxysuccinimide in 200ml dimethylformamide at 0 ℃ and stirred for 3h at 0 ℃ and then for 16 h at room temperature. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C39.70H 3.33N 3.70F 42.70

Measured value: C40.01H 3.42N 3.66F 42.54

b) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- (2-methoxyethoxy) -acetamide, methanesulfonate

2.17g (22.47mmol) of methanesulfonic acid and 3.0g of palladium catalyst (10% Pd/C) are added to a solution of 17g (22.47mmol) of the title compound from example 15a in 500ml of ethanol and hydrogenated at room temperature for 24 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo.

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

Elemental analysis:

calculated values: C30.09H 3.23N 3.90F 44.96

Measured value: C30.33H 3.25N 3.84F 44.77

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

11.5g (16.07mmol) of the title compound from example 15b, 1.85g (16.07mmol) of N-hydroxysuccinimide, 1.36g (32.14mmol) of lithium chloride and 10.12g (16.07mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG (example 1)) are dissolved in 200ml of dimethyl sulfoxide with gentle heating. 4.14g (20.08mmol) dicyclohexylcarbodiimide and 1.63(16.07mmol) triethylamine were added at 10 ℃ and stirred at room temperature for 16 hours. The solution was poured into 2000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

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

Water content (Karl-Fischer): 6.0 percent

Elemental analysis (versus anhydrous material):

calculated values: C35.04H 3.84N 7.95F 26.17 Gd 12.74

Measured value: C35.38H 3.88N 7.91F 25.99 Gd 12.63

Example 16

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

25.0g (120mmol) of N-benzyloxycarbonyl-propanediamine (Atwell et al, Synthesis, 1984, 1032-propan 1033) and 10.2g (100mmol) of triethylamine were added to 54.22g (100mmol) of methanesulfonic acid- (1H, 1H, 2H, 2H-perfluorodecyl) -ester (Bartsch et al, Tetrahedron, 2000, 3291-propan 3302) in 500ml of acetonitrile and stirred at 60 ℃ for 48 hours. The insoluble components were filtered off from the reaction solution, evaporated to dryness in vacuo and the residue was chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C38.55H 2.93N 4.28F 49.36

Measured value: C38.73H 2.89N 4.17F 49.11

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

7.99g (38.74mmol) dicyclohexylcarbodiimide were added at 0 ℃ to a solution of 20g (30.99mmol) of the title compound of example 16a and 6.89g (30.99mmol) of {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -acetic acid (Voegtle et al, LiebigsAnn. chem., 1980, 858-862) and 3.56g (30.99mmol) of N-hydroxysuccinimide in 200ml dimethylformamide, stirred at 0 ℃ for 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C41.97H 4.11N 3.26F 37.62

Measured value: C42.24H 4.18N 3.15F 37.44

c) N- (3-aminopropyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -acetamide, methanesulfonate

2.25g (23.29mmol) of methanesulfonic acid and 4.0g of palladium catalyst (10% Pd/C) are added to a solution of 20g (23.29mmol) of the title compound from example 16b in 500ml of ethanol and hydrogenated at room temperature for 24 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo.

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

Elemental analysis:

calculated values: C33.67H 4.05N 3.41F 39.36

Measured value: C33.94H 4.09N 3.27F 39.11

d) N- { [1, 4, 7-tris- (carboxymethyl) -1, 4, 7, 10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) ] -3-aminopropyl } -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -acetamide, Gd complex

11.3g (13.80mmol) of the title compound of example 16c, 1.59g (13.80mmol) of N-hydroxysuccinimide, 1.17g (27.60mmol) of lithium chloride and 8.79g (13.80mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG (example 1)) are dissolved in 200ml of dimethyl sulfoxide with gentle heating. 3.59g (17.4mmol) dicyclohexylcarbodiimide and 1.40g (13.80mmol) triethylamine were added at 10 ℃ and stirred at room temperature for 16 hours. The solution was poured into 2000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

Yield: 12.9g (66% of theory) of a colorless solid

Water content (Karl-Fischer): 6.0 percent

Elemental analysis (versus anhydrous material):

calculated values: C36.86H 4.30N 7.34F 24.17 Gd 11.77

Measured value: C36.99H 4.37N 7.31F 24.01 Gd 11.69

Example 17

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

26.67g (120mmol) of N-benzyloxycarbonyl-butanediamine (Atwell et al, Synthesis, 1984, 1032-propan 1033) and 10.2g (100mmol) of triethylamine were added to 54.22g (100mmol) of methanesulfonic acid- (1H, 1H, 2H, 2H-perfluorodecyl) -ester (Bartsch et al, Tetrahedron, 2000, 3291-propan 3302) in 500ml of acetonitrile and stirred at 60 ℃ for 48 hours. The insoluble components were filtered off from the reaction solution, evaporated to dryness in vacuo and the residue was chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

Yield: 39.6g (59% of theory) of colorless wax

Elemental analysis:

calculated values: C39.53H 3.17N 4.19F 48.32

Measured value: C39.74H 3.21N 4.17F 48.17

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

7.71g (37.4mmol) dicyclohexylcarbodiimide were added at 0 ℃ to a solution of 20g (29.92mmol) of the title compound of example 17a and 6.65g (29.92mmol) of {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -acetic acid (Voegtle et al, LiebigsAnn. chem., 1980, 858-862) and 3.44g (29.92mmol) of N-hydroxysuccinimide in 200ml dimethylformamide, stirred at 0 ℃ for 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C42.67H 4.27N 3.21F 37.01

Measured value: C42.85H 4.30N 3.16F 36.87

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

4.0g of palladium catalyst (10% Pd/C) are added to a solution of 20g (22.92mmol) of the title compound of example 17b in 500ml of ethanol and hydrogenated at room temperature for 24 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo.

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

Elemental analysis:

calculated values: C37.41H 4.23N 3.79F 43.73

Measured value: C37.59H 4.29N 3.74F 43.61

d) N- { [1, 4, 7-tris- (carboxymethyl) -1, 4, 7, 10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl) ] -4-aminobutyl } -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -acetamide, Gd complex

10g (13.54mmol) of the title compound of example 17c, 1.56g (13.54mmol) of N-hydroxysuccinimide, 1.14g (26.08mmol) of lithium chloride and 8.69g (13.54mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpent-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG (example 1)) are dissolved in 200ml of dimethyl sulfoxide with gentle heating. At 10 ℃, 3.53g (17.07mmol) of dicyclohexylcarbodiimide was added and stirred at room temperature for 16 hours. The solution was poured into 2000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

Yield: 11.7g (60% of theory) of a colorless solid

Water content (Karl-Fischer): 6.5 percent

Elemental analysis (versus anhydrous material):

calculated values: C37.36H 4.40N 7.26F 23.92 Gd 11.65

Measured value: C37.51H 4.44N 7.22F 23.84 Gd 11.59

Example 18

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

7.69g (37.29mmol) dicyclohexylcarbodiimide were added at 0 ℃ to a solution of 20g (29.83mmol) of the title compound from example 10c and 5.32g (29.83mmol) of [2- (2-methoxyethoxy) -ethoxy ] -acetic acid (Aldrich) and 3.43g (29.83mmol) of N-hydroxysuccinimide in 200ml of dimethylformamide and stirred at 0 ℃ for 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C40.49H 3.76N 3.37F 38.89

Measured value: C40.62H 3.81N 3.38F 38.77

b) N- (2-aminoethyl) -N- (1H, 1H, 2H, 2H, 4H, 4H-3-oxa-perfluorododecyl) -2- [2- (2-methoxyethoxy) -ethoxy ] -acetamide, methanesulfonate

1.98g (20.50mmol) of methanesulfonic acid and 3.0g of palladium catalyst (10% Pd/C) are added to a solution of 17.0g (20.50mmol) of the title compound from example 18C in 300ml of ethanol and hydrogenated at room temperature for 24 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo.

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

Elemental analysis:

calculated values: C31.83H 3.69N 3.53F 40.75

Measured value: C31.57H 3.78N 3.44F 40.51

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

14.75g (18.30mmol) of the title compound of example 18d, 2.11g (18.30mmol) of N-hydroxysuccinimide, 1.55g (36.60mmol) of lithium chloride and 11.52g (18.30mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WO 98/24775, Schering AG (example 1)) are dissolved in 200ml of dimethyl sulfoxide with gentle heating. At 10 ℃ 4.72g (22.88mmol) dicyclohexylcarbodiimide and 1.85g (18.30mmol) triethylamine were added and stirred at room temperature for 16 h. The solution was poured into 2000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

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

Water content (Karl-Fischer): 6.1 percent

Elemental analysis (versus anhydrous material):

calculated values: C35.81H 4.06N 7.50F 24.69 Gd 12.02

Measured value: C36.04H 4.11N 7.49F 24.52 Gd 11.94

Example 19

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

6.13g (30mmol) N-tert-butoxycarbonyl-3-oxa-pentanediamine (Koenig et al, Eur. J. org. chem., 2002, 3004-propan 3014) and 2.55g (25mmol) triethylamine were added to 13.56g (25mmol) methanesulfonic acid- (1H, 1H, 2H, 2H-perfluorodecyl) -ester (Bartsch et al, Tetrahedron, 2000, 3291-propan 3302) in 150ml acetonitrile and stirred at 60 ℃ for 48 hours. The insoluble components were filtered off from the reaction solution, evaporated to dryness in vacuo and the residue was chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C35.09H 3.56N 4.31F 49.66

Measured value: C35.28H 3.64N 4.24F 49.53

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

3.97g (19.23mmol) dicyclohexylcarbodiimide were added at 0 ℃ to a solution of 10g (15.38mmol) of the title compound of example 19a and 3.42g (15.38mmol) of {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -acetic acid (Voegtle et al, LiebigsAnn. chem., 1980, 858-862) and 1.77g (15.38mmol) of N-hydroxysuccinimide in 200ml dimethylformamide, stirred at 0 ℃ for 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C39.35H 4.60N 3.28F 37.79

Measured value: C39.57H 4.66N 3.16F 36.55

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

50ml of trifluoroacetic acid are added at 0 ℃ to a solution of 9.5g (11.12mmol) of the title compound of example 19b in 100ml of dichloromethane and stirred at room temperature for 3 hours. Evaporation to dryness in vacuo and chromatography of the residue on silica gel (mobile solvent: dichloromethane/methanol 10: 1) were carried out.

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

Elemental analysis:

calculated values: C36.62H 4.14N 3.71F 42.81

Measured value: C36.88H 4.21N 3.55F 43.25

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

7g (9.28mmol) of the title compound of example 19c, 1.07g (9.28mmol) of N-hydroxysuccinimide, 787mg (18.56mmol) of lithium chloride and 5.84g (9.28mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpent-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WO 98/24775, ScheringAG (example 1)) are dissolved in 100ml of dimethyl sulfoxide with gentle heating. 2.39g (11.6mmol) of dicyclohexylcarbodiimide were added at 10 ℃ and stirred at room temperature for 16 hours. The solution was poured into 2000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

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

Water content (Karl-Fischer): 6.5 percent

Elemental analysis (versus anhydrous material):

calculated values: C36.92H 4.35N 7.18F 23.64 Gd 11.51

Measured value: C37.04H 4.39N 7.15F 23.57 Gd 11.47

Example 20

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

7.81g (30mmol) of N-tert-butoxycarbonyl- [2, 3- (2, 2-dimethyl- [1, 3] -dioxolanyl) ] butanediamine [ prepared from (5-aminoethyl-2, 2-dimethyl- [1, 3] -dioxolan-4-yl) -methylamine (ACROS) (Koenig et al, Eur.J.Org.Chem., 2002, 3004-propan 3014) ] and 2.55g (25mmol) of triethylamine in analogy to the preparation of N-tert-butoxycarbonyl-3-oxa-pentanediamine ] were added to 13.56g (25mmol) of methanesulfonic acid- (1H, 1H, 2H, 2H-perfluorodecyl) -ester (Bartsch et al, Tetrahedron, 2000, 3291-propan 3302) in 150ml of acetonitrile and stirred for 48H at 60 ℃. The insoluble components were filtered off from the reaction solution, evaporated to dryness in vacuo and the residue was chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C37.40H 3.85N 3.97F 45.72

Measured value: C37.66H 3.94N 3.88F 45.61

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

3.65g (17.7mmol) of dicyclohexylcarbodiimide are added at 0 ℃ to 10g (14.16mmol) of the title compound of example 20a with a solution of 3.15g (14.16mmol) of {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -acetic acid (Voegtle et al, LiebigsAnn. chem., 1980, 858-862) and 1.63g (14.16mmol) of N-hydroxysuccinimide in 200ml of dimethylformamide, stirred at 0 ℃ for 3 hours and then at room temperature for 16 hours. The precipitated urea is filtered off, the filtrate is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol 20: 1).

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

Elemental analysis:

calculated values: C40.89H 4.76N 3.08F 35.47

Measured value: C40.97H 4.85N 3.00F 35.37

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

50ml of trifluoroacetic acid are added at 0 ℃ to a solution of 8.2g (9.00mmol) of the title compound of example 20b in 100ml of dichloromethane and stirred at room temperature for 3 hours. Evaporation to dryness in vacuo and chromatography of the residue on silica gel (mobile solvent: dichloromethane/methanol 10: 1 to 2: 1) were carried out.

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

Elemental analysis:

calculated values: C35.85H 4.06N 3.64F 41.92

Measured value: C36.05H 4.11N 3.60F 41.77

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

6g (7.79mmol) of the title compound of example 20c, 897mg (7.79mmol) of N-hydroxysuccinimide, 660mg (15.58mmol) of lithium chloride and 4.90g (7.79mmol) of 1, 4, 7-tris- (carboxymethyl) -10- [ 1-carboxy-3-aza-4-oxo-5-methylpent-5-yl ] -1, 4, 7, 10-tetraazacyclododecane, Gd complex (WO 98/24775, ScheringAG (example 1)) are dissolved in 100ml of dimethyl sulfoxide with gentle heating. 2.01g (9.74mmol) of dicyclohexylcarbodiimide were added at 10 ℃ and stirred at room temperature for 16 hours. The solution was poured into 2000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

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

Water content (Karl-Fischer): 7.7 percent

Elemental analysis (versus anhydrous material):

calculated values: C36.50H 4.30N 7.09F 23.37 Gd 11.38

Measured value: C36.71H 4.35N 7.02F 23.41 Gd 11.29

Example 21

a) N- { [1, 4, 7-tris- (carboxymethyl) -1, 4, 7, 10-tetraazacyclododecane-10-N- (butyryl-4- (R) -carboxy-4-yl) ] -2-aminoethyl } -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -acetamide, Gd complex monosodium salt and N- ({1, 4, 7-tris- (carboxymethyl) -1, 4, 7, 10-tetraazacyclododecane-10-N- (ethano [2- (R) -carboxyethyl ] -yl) } -2-aminoethyl } -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- { -2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -acetamide, Gd Complex monosodium salt

2.84g (3.52mmol) of the title compound from example 14b, 448mg (4.4mmol) of triethylamine and 3.51g (4.4mmol) of 2- (R) -2- [4, 7, 10-tris- (carboxymethyl) -1, 4, 7, 10-tetraazacyclododecan-1-yl ] pentanedicarboxylic acid monopentafluorophenyl ester, the Gd complex (WO2005/0014154, EPIX PHARMACEUTICAL, INC., (example 9: EP-2104-15-Pfp)) were dissolved in 50ml of dimethyl sulfoxide, mixed with 356mg (3.52mmol) of triethylamine and stirred at room temperature for 16 hours. The solution was poured into 1000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile). The product-containing fractions were concentrated by evaporation, dissolved in water, neutralized with 0.1N sodium hydroxide solution and lyophilized.

Yield: 2.03g (39% of theory) of a colorless solid are a 3: 2 regioisomeric mixture.

Water content (Karl-Fischer): 9.2 percent of

Elemental analysis (versus anhydrous material):

calculated values: C35.72H 3.97N 6.25F 24.01 Gd 11.69

Measured value: C36.01H 4.06N 6.29F 23.89 Gd 11.46

Example 22

a) N- { [1, 4, 7-tris- (carboxymethyl) -1, 4, 7, 10-tetraazacyclododecane-10-N- (butyryl-4- (R) -carboxy-4-yl) ] -2-aminoethyl } -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- (1-O-. alpha. -d-mannopyranosyl) -acetamide, the monosodium salt of Gd complex and N- ({1, 4, 7-tris- (carboxymethyl) -1, 4, 7, 10-tetraazacyclododecane-10-N- (ethano [2- (R) -carboxyethyl ] -yl) } -2-aminoethyl) -N- (1H, 1H, 2H, 2H-perfluorodecyl) -2- (1-O-alpha-d-mannopyranosyl) -acetamide, the monosodium salt of the Gd complex

2.83g (3.44mmol) of the title compound from example 1c, 436mg (4.3mmol) of triethylamine and 3.43g (4.3mmol) of 2- (R) -2- [4, 7, 10-tris- (carboxymethyl) -1, 4, 7, 10-tetraazacyclododecan-1-yl ] pentanedicarboxylic acid monopentafluorophenyl ester, the Gd complex (WO2005/0014154, EPIX PHARMACEUTICAL, INC., (example 9: EP-2104-15Pfp)) were dissolved in 50ml of dimethyl sulfoxide, mixed with 348mg (3.44mmol) of triethylamine and stirred at room temperature for 16 hours. The solution is poured into 1000ml of acetone and stirred for a further 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile). The product-containing fractions were concentrated by evaporation, dissolved in water, neutralized with 0.1N sodium hydroxide solution and lyophilized.

Yield: 1.64g (32% of theory) of a colorless solid are a 3: 2 regioisomeric mixture.

Water content (Karl-Fischer): 8.8 percent

Elemental analysis (versus anhydrous material):

calculated values: C34.42H 3.63N 6.17F 23.73 Gd 11.55

Measured value: C34.66H 3.60N 6.09F 23.78 Gd 11.39

Example 23

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

10g (7.13mmol) of the title compound of example 14c are dissolved in a mixture of 100ml of water and 30ml of isopropanol, mixed with 2.25g (24.96mmol) of oxalic acid and heated to 100 ℃ over 5 hours. After cooling to room temperature, the precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile). The product-containing fractions were concentrated by evaporation, dissolved in water, adjusted to pH 10 with 0.1N sodium hydroxide solution and then lyophilized.

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

Water content (Karl-Fischer): 8.2 percent of

Elemental analysis (versus anhydrous material):

calculated values: C38.94H 4.49N 7.95F 26.18

Measured value: C39.03H 4.44N 7.98F 25.89

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

2.0g (1.49mmol) of the title compound of example 23a are dissolved in 50ml of water and 1ml of acetic acid, mixed with 441mg (1.64mmol) of dysprosium chloride and stirred at 80 ℃ for 6 hours. Neutralized with ammonia, evaporated to dryness and then purified by chromatography (RP-18; mobile solvent: gradient consisting of water/acetonitrile).

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

Water content (Karl-Fischer): 6.2 percent

Elemental analysis (versus anhydrous material):

calculated values: C36.19H 4.18N 7.39F 24.33 Dy 12.24

Measured value: C36.32H 4.24N 7.30F 24.19 Dy 12.16

Example 24

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

2.0g (1.49mmol) of the title compound from example 23a are dissolved in 50ml of water and 1ml of acetic acid, mixed with 458mg (1.64mmol) of ytterbium chloride and stirred at 80 ℃ for 6 hours. It was neutralized with ammonia, evaporated to dryness and then purified by chromatography (RP-18; mobile solvent: gradient consisting of water/acetonitrile).

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

Water content (Karl-Fischer): 6.9 percent

Elemental analysis (versus anhydrous material):

calculated values: C35.91H 4.14N 7.33F 24.14 Yb 12.93

Measured value: C36.05H 4.19N 7.31F 24.00 Yb 12.79

Example 25

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

2.0g (1.49mmol) of the title compound of example 23a are dissolved in 50ml of water and 1ml of acetic acid, mixed with 320mg (1.64mmol) of yttrium chloride and stirred at 80 ℃ for 6 hours. Neutralized with ammonia, evaporated to dryness and then purified by chromatography (RP-18; mobile solvent: gradient consisting of water/acetonitrile).

Yield: 1.56g (79% of theory) of a colorless solid

Water content (Karl-Fischer): 5.5 percent

Elemental analysis (versus anhydrous material):

calculated values: C38.32H 4.42N 7.82F 25.76Y 7.09

Measured value: C38.56H 4.51N 7.88F 25.65Y 6.98

Example 26

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

8.3g (207.6mmol) of sodium hydroxide are added to 12.0g (34.6mmol) of 1, 4, 7-tris (carboxymethyl) -1, 4, 7, 10-tetraazacyclododecane (D03A) in 50ml of water. A solution consisting of 5.02g (43.25mmol) of 3-oxiranylpropionic acid (Dakoji et al, J.Am.chem.Soc., 1996, 10971-10979) in 50ml of n-butanol/50 ml of 2-propanol was added dropwise thereto and the solution was heated to 80 ℃ over 24 hours. The reaction solution was evaporated to dryness in vacuo, the residue was mixed with 300ml of water, and the pH was adjusted to 3 with 3N hydrochloric acid. Then, three times with 200ml each of n-butanol, the combined butanol phases were evaporated to dryness in vacuo and the residue was purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

Yield: 13.6g (79% of theory) of a colorless solid

Water content (Karl-Fischer): 10.4 percent

Elemental analysis (versus anhydrous material):

calculated values: C51.34H 7.26N 12.60

Measured value: C51.63H 7.05N 12.44

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

12.0g (24.2mmol) of the title compound of example 26a are dissolved in 100ml of water and 1ml of acetic acid, mixed with 4.39g (12.1mmol) of gadolinium oxide and stirred at 80 ℃ for 6 hours. The solution was filtered, evaporated to dryness and then purified by chromatography (RP-18; mobile solvent: gradient consisting of water/acetonitrile).

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

Water content (Karl-Fischer): 6.5 percent

Elemental analysis (versus anhydrous material):

calculated values: C38.12H 4.88N 9.36 Gd 26.26

Measured value: C38.26H 4.89N 9.21 Gd 26.09

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

2.84g (3.52mmol) of the title compound of example 14b and 3.38g (5.28mmol) of the title compound of example 26b are dissolved in 50ml of methanol, mixed with 356mg (3.52mmol) of triethylamine and stirred at 50 ℃ for 48 hours. The evaporation to dryness is followed by purification by chromatography (RP-18; mobile solvent: gradient consisting of water/acetonitrile).

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

Water content (Karl-Fischer): 6.9 percent

Elemental analysis (versus anhydrous material):

calculated values: C36.70H 4.31N 6.42F 24.67 Gd 12.01

Measured value: C36.77H 4.38N 6.33F 24.59 Gd 11.96

Example 27

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

2.58g (12.5mmol) dicyclohexylcarbodiimide and 1.01g (10mmol) triethylamine are added at 0 ℃ to a solution of 12.14g (10mmol) of the title compound of example 2b and 2.22g (10mmol) of {2- [2- (2-methoxyethoxy) -ethoxy ] -ethoxy } -acetic acid (Voegtle et al, Liebigs ann. chem., 1980, 858-862) and 1.15g (10mmol) of N-hydroxysuccinimide in 100ml dimethylformamide, stirred at 0 ℃ for 3 hours and then at room temperature for 16 hours. The precipitated urea was filtered off and the filtrate was evaporated to dryness in vacuo. The residue is taken up in a small amount of water, the insoluble constituents are filtered off and the filtrate is purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile).

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

Water content (Karl-Fischer): 6.2 percent

Elemental analysis (versus anhydrous material):

calculated values: C36.34H 4.19N 7.42F 24.43 Gd 11.89

Measured value: C36.55H 4.27N 7.33F 24.21 Gd 11.70

Example 28

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

10g (7.11mmol) of the title compound of example 27a are dissolved in a mixture of 100ml of water and 30ml of isopropanol, mixed with 2.25g (24.96mmol) of oxalic acid and heated to 100 ℃ over 5 hours. After cooling to room temperature, the precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient composed of water/acetonitrile). The product-containing fractions were concentrated by evaporation, dissolved in water, adjusted to pH 8 with 0.1N sodium hydroxide solution and then lyophilized.

Yield: 8.64g (91% of theory) of a colorless solid

Water content (Karl-Fischer): 7.5 percent

Elemental analysis (versus anhydrous material):

calculated values: C38.94H 4.49N 7.95F 26.18

Measured value: C38.88H 4.40N 7.65F 25.77

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

2.0g (1.50mmol) of the title compound of example 28a are dissolved in 50ml of water and 1ml of acetic acid, mixed with 320mg (1.64mmol) of yttrium chloride and stirred at 80 ℃ for 6 hours. Neutralized with ammonia, evaporated to dryness and then purified by chromatography (RP-18; mobile solvent: gradient consisting of water/acetonitrile).

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

Water content (Karl-Fischer): 5.0 percent

Elemental analysis (versus anhydrous material):

calculated values: C38.32H 4.42N 7.82F 25.76Y 7.09

Measured value: C38.48H 4.55N 7.75F 25.66Y 6.96

Example 29: relaxation property

The relaxation times of T1 and T2 for water and plasma with increasing gadolinium complex concentration of the title substance of examples 1d, 5c, 14c, 15c contained therein were determined at 0.47T using an NMR pulse spectrometer (Minispec PC 20) at 40 ℃. The results are shown in table 1.

Example 30: acute toxic effects after one-time intravenous administration in mice

(initial test)

After intravenous administration of gadolinium complexes of the title substances of examples 1d, 5c, 14c, 15c to mice (n ═ 3; injection rate: 2ml/min), systemic acute compatibility (LD) was preliminarily determined₅₀). In each case, several doses were checked over a 7 day observation period. The expected acute toxic effects can be seen in table 1.

Example 31: excretion after intravenous administration in rats

After intravenous administration of 50 μmol total gadolinium/kg body weight to rats (n-3) of the gadolinium complexes of the title substances of examples 1d, 5c, 14c, 15c, the metal content in the excretion medium of urine and feces and in vivo (the rest of the body) up to 14 days after administration was determined by atomic emission spectrometry (ICP-AES). The results are shown in table 1.

Example 32: plasma kinetics in rats after intravenous administration

After intravenous administration of the gadolinium complexes of the title substances of examples 1d, 5c, 14c, 15c to rats (n 3) at 50 μmol total gadolinium per kg body weight, blood samples were taken at different time points (p.i.8 h to 24 h) via catheters in the common carotid artery, the metal content was determined by atomic emission spectroscopy (ICP-AES) and converted to plasma values by a conversion factor (0.625). Exclusion half-life was calculated from plasma concentrations by proprietary software (WinNonlin). The results are shown in table 1.

Example 33: intravenous contrast agent in rabbits harboring VX 2-tumor showing (MRT) lymph node metastasis and primary tumor

The pictures of fig. 1 and 2 show MR images up to 24 hours after the title substance of example 1d) was administered intravenously and before iliac lymph node visualization (precontrast) in rabbits with intramuscular implantation of VX2 tumor and 50 μmol Gd/kg body weight. T1-weighted fast spin echo images showed a strong signal rise in healthy lymph node tissue at earlier time points after administration of contrast agent (p.i.15 to 60 min). Regions with no signal rise within the lymph nodes were diagnosed as metastases and confirmed histologically (H/E staining of lymph node sections) (FIG. 1).

Quite surprisingly, a clear enhancement in the primary tumor (particularly in the periphery) immediately after administration was also observed (fig. 2). At the later time point (p.i.24 hours), the enhancement also expanded towards the tumor center.

Example 34: MRT post intravenous contrast agent administration in rats shows atherosclerotic plaques

FIG. 3 is a graph showing MR images of the aorta 6 or 24 hours after intravenous administration of 50. mu. mol Gd/kg body weight of example 1d) and the title substance of example 14c in Watanabe rabbits (WHHL rabbits; genetically induced atherosclerosis) and in control animals without atherosclerosis (New Zealand rabbits). T is₁The weighted inversion recovery image (IR-TFL, TR/TE/TI 300/4.0/120ms, α 20 °) indicates a strong signal rise in the arteriosclerotic plaque of WHHL rabbits, whereas there was no rise in the baseline image or in the vessel wall of healthy control animals. The localization of plaques, in particular in the aortic arch and in the vascular channels, was confirmed by sudan-3. By this test, it can be shown that the compounds according to the invention are suitable as markers for arteriosclerotic plaques.

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

By way of illustration, the picture of fig. 4 shows MR images of inflammatory muscle injury and necrotic areas at different time points after intravenous administration of 50 μmol Gd/kg body weight of the title substance of example 14c in rats. Inflammation/necrosis was induced by intravenous administration of rose bengal (20 mg/kg; 24 hours prior to administration of contrast agent) followed by xenon lamp irradiation for 20 minutes. T is₁Weighted fast spin echo images (1.5T; sequence: T1-TSE; TR 451ms, TE 8.7ms) show a strong signal rise in the primary (up to p.i.60 min) inflamed diseased tissue and a delayed signal rise in central necrosis at p.i.24 h.

Example 36: MRT lymph node display in rats after intravenous administration of contrast agent

By way of illustration, these pictures show that 50 μmo was administered intravenously in ratsMR images of lymph nodes at different time points after l Gd/kg body weight of the title substance from example 5c), the title substance from example 14c) and the title substance from example 15 c). T is₁Weighted fast spin echo imaging (1.5T; sequence: T1-TSE; TR 451ms, TE 8.7ms) shows a strong signal rise in functional lymph node tissue at the initial time point (up to p.i.60 min).

Table 1: physicochemical and experimental data on the materials of the examples

Numbering of examples from which Compounds were derived	Relaxation [ l/(mmol. s)]	The body stays for 14 days [% ]]	Elimination half-life of blood	Content of Gd in blood at p.i.24 hours [% ]]	Mouse LD50[ mmol/kg]
Numbering of examples from which Compounds were derived	Relaxation [ l/(mmol. s)]	The body stays for 14 days [% ]]	Elimination half-life of blood	Content of Gd in blood at p.i.24 hours [% ]]	Mouse LD50[ mmol/kg]	1	R1(w)：22.7R1(p)：25.8R2(w)：15.8R2(p)：29.8	0.0％	4.8 hours	0.7％	＞10
5	R1(w)：18.9R1(p)：24.8R2(w)：23.9	0.0％	0.8 hour	0.0％		1	R1(w)：22.7R1(p)：25.8R2(w)：15.8R2(p)：29.8	0.0％	4.8 hours	0.7％	＞10

Numbering of examples from which Compounds were derived	Relaxation [ l/(mmol. s)]	The body stays for 14 days [% ]]	Elimination half-life of blood	Content of Gd in blood at p.i.24 hours [% ]]	Mouse LD50[ mmol/kg]
Numbering of examples from which Compounds were derived	Relaxation [ l/(mmol. s)]	The body stays for 14 days [% ]]	Elimination half-life of blood	Content of Gd in blood at p.i.24 hours [% ]]	Mouse LD50[ mmol/kg]		R2(p)：32.8
14	R1(w)：18.6R1(p)：25.5R2(w)：21.6R2(p)：33.5	0.0％	1.1 hour	0.0％	7.5		R2(p)：32.8
14	R1(w)：18.6R1(p)：25.5R2(w)：21.6R2(p)：33.5	0.0％	1.1 hour	0.0％	7.5	15	R1(w)：17.2R1(p)：24.6R2(w)：15.1R2(p)：33.2	0.0％	4.8 hours	0.2％	＞10

R1(w) ═ R1-relaxation in water; r1(p) ═ R1(w) ═ R1-relaxivity in plasma; r2(w) ═ R2-relaxation in water; r2(p) ═ R1(w) ═ R2-relaxivity in plasma.

Claims

1. Perfluoroalkyl-containing complexes with nitrogen-containing linker structures of the general formula I

Wherein

R represents

A monosaccharide or oligosaccharide group linked via 1-OH,

in which case Q has the meaning of a group selected from:

δ-CO-(CH₂)_n″-ε

δ-NH-(CH₂)_n″-ε

δ-(CH₂)_m-ε

wherein:

n' is an integer of 1 to 5, and

m is an integer of 1 to 6, and

or

Complexes K of the formulae II to V, where R¹Here a hydrogen atom or metal ion equivalent of atomic number 20 to 29, 31 to 33, 37 to 39, 42 to 44, 49 or 57 to 83, and the radical R²、R³、R⁴U and U¹Has the meanings indicated below;

or

it may be linear or branched, saturated or unsaturated, and

it is composed of

wherein R is⁷Is H or C₁-C₄An alkyl group, a carboxyl group,

k represents a metal complex of the general formula II,

wherein

u represents optionally interrupted by one or more oxygen atoms, 1 to 3-NHCO groups or 1 to 3-CONH groups and/or interrupted by 1 to 3- (CH)₂)_0-5COOH group substituted-C₆H₄-O-CH₂-ω-、-(CH₂)_1-5-omega, phenylene, -CH₂-NHCO-CH₂-CH(CH₂COOH)-C₆H₄-ω-、-C₆H₄-(OCH₂CH₂)_0-1-N(CH₂COOH)-CH₂- ω or C₁-C₁₂-alkylene or- (CH)₂)_7-12-C₆H₄-an O group, wherein ω represents a linking site to-CO-;

or metal complexes of the formula III

or metal complexes of the formula IV

Wherein R is¹And R²Have the above-mentioned meanings;

or metal complexes of the general formula VA or VB

Wherein R is¹Have the above-mentioned meanings;

or metal complexes of the formula VI

Wherein R is¹Have the above-mentioned meanings;

or metal complexes of the formula VII

Wherein R is¹And U¹Having the above-mentioned meaning, where ω is the attachment site to the-CO-,

or metal complexes of the formula VIII

Wherein R is¹Has the meaning of the above-mentioned formula,

and U is²Represents a linear or branched, saturated or unsaturated C₁-C₂₀Alkylene group ofAlkylene optionally containing imino, phenylene, phenoxy, phenylimino, amide, hydrazide, carbonyl, ester, oxygen, sulfur and/or nitrogen atoms and optionally substituted by hydroxyl, mercapto, oxo, thio, carboxyl, carboxyalkyl, ester and/or amino groups,

and L represents a group selected from the following groups IXa) to IXc):

wherein n 'and m' independently of one another represent an integer between 0 and 4, and m '+ n' ≧ 1, and R⁸And R^8′Independently of one another, is-H or-OH, where m '+ n' > 1, each radical- (CR)⁸R^8′)-

May be the same or different, and

w is a direct bond, -O-, or phenylene which may be optionally substituted with 1 to 4 hydroxyl groups, and q' is 1, 2, 3, or 4,

wherein α is the attachment site for L to the complex K, β is the attachment site for L to the group Q, and γ represents the attachment site for L to the group X,

and is

X represents a group of formula (VI);

ρ—Y—(CH₂)_s—(G)_t—(CH₂)_s’—ζ

(X)

wherein Y is a direct bond, a radical-CO-or a radical NR⁶，

and which are optionally substituted by 1 to 10 OH groups, 1 to 5-COOH groups, 1 to 2-SO groups₃H group, 1-5-NH₂Radical or 1-5C₁-C₄Alkoxy substitution;

and G is-O-or-SO₂-，

s and s' are each independently of the other 1 or 2, t is 0 or 1, and

ρ represents the attachment site of X to L and ξ represents X and R_fThe ligation site of the ligation.

2. Metal complex according to claim 1, characterized in that the metal ion equivalent R¹Are elements having an atomic number of 21-29, 39, 42, 44, or 57-83.

3. The metal complex according to claim 1, wherein the metal ion equivalent R¹Are elements of atomic numbers 27, 29, 31-33, 37-39, 43, 49, 62, 64, 70, 75 and 77.

4. Metal complexes according to one of claims 1 to 3, wherein R represents a monosaccharide radical having 5 to 6C atoms or a deoxy compound thereof, preferably glucose, mannose or galactose.

5. The metal complex according to one of claims 1 to 3, wherein R is a group selected from:

-C(O)CH₂O[(CH₂)₂O]_pR′

-C(O)CH₂OCH[CH₂OCH(CH₂OR′)₂]₂

-C(O)CH₂OCH₂CH[CH₂OCH(CH₂OR′)₂]₂

-R″N[(CH₂)₂O]_pR′

-N{[(CH₂)₂O]_pR′}₂

-R″NCH₂CH(OH)CH₂OH

-N[CH₂CH(OH)CH₂OH]₂

-R″NCH(CH₂OH)CH(OH)CH₂OH

-N[CH(CH₂OH)CH(OH)CH₂OH]₂

-R″NCH[CH₂OCH(CH₂OR′)₂]₂

-R″NCH₂CH[CH₂OCH(CH₂OR′)₂]₂

-R″NCH₂CH₂OCH[CH₂OCH(CH₂OR′)₂]₂

-R″NCH₂CH₂OCH₂CH[CH₂OCH(CH₂OR′)₂]₂

-N{CH[CH₂OCH(CH₂OR′)₂]₂}₂

-N{CH₂CH[CH₂OCH(CH₂OR′)₂]₂}₂

-R″NCH₂CH(OH)CH(OH)CH(OH)CH(OH)CH₂OH

-N[CH₂CH(OH)CH(OH)CH(OH)CH(OH)CH₂OH]₂

and complexes of formula (II) wherein R¹、R²、R³And U is as defined in claim 1, and p is 1, 2, 3, 4,5, 6, 7, 8 or 9.

6. The metal complex according to one of claims 1 to 5, wherein K represents a metal complex of the general formula II.

7. The metal complex according to claim 6, wherein R²And R³Independently of one another, hydrogen or C₁-C₄-an alkyl group.

8. Metal complex according to one of claims 1 to 7, wherein in the formula-C_nF_2nE in E is a fluorine atom.

9. Metal complexes according to one of claims 1 to 8, wherein L in the general formula I represents a lysine group (Vc).

10. Metal complexes according to one of claims 1 to 8, wherein L in the general formula I represents a diamine group (Va) or (Vb).

11. Metal complex according to one of claims 1 to 10, wherein in the metal complex K U represents-CH₂-or-C₆H₄-O-CH₂- ω, wherein ω represents the attachment site to-CO-.

12. Use of the metal complexes according to claim 2 for the preparation of contrast agents for NMR and x-ray diagnostics.

13. Use of a metal complex according to claim 12 for the preparation of a contrast agent for the imaging of infarcts and necrosis.

14. Use of a metal complex according to claim 3 for the preparation of a contrast agent for radiodiagnosis and radiotherapy.

15. Use of a metal complex according to claim 2 for the preparation of a contrast agent for the diagnosis of changes in the lymphatic system.

16. Use of a metal complex according to claim 2 for the preparation of a contrast agent for the diagnosis of inflammatory diseases.

17. Use of a metal complex according to claim 2 for the preparation of a contrast agent for displaying arteriosclerotic plaques.

18. Use of a metal complex according to claim 2 for the preparation of a contrast agent for the diagnosis of cardiovascular diseases.

19. Use of a metal complex according to claim 2 for the preparation of a contrast agent for the imaging of tumors.

20. Use of the metal complexes of claim 2 for the preparation of contrast agents for the imaging of blood vessels.

21. A medicament containing at least one physiologically compatible compound according to claims 1 to 11 and optionally additives customarily used in galenic formulations.

22. A process for preparing perfluoroalkyl-containing complexes having nitrogen-containing linker structures of the general formula I,

wherein K has the meaning of the metal complexes of the formulae II to IV in claim 1, and L, Q, X, R and R_fHas the meaning as defined in claim 1,

wherein:

reacting a carboxylic acid of the formula IIa

Wherein R is⁵Is of atomic number 21-29, 31-33, 37-39, 42-44, 49 or 57-83

A metal ion equivalent or a carboxyl protecting group, and R²、R³And U has the abovementioned meaning, or a carboxylic acid of the formula IIIa

Wherein R is⁴、R⁵And U¹Has the meaning of the above-mentioned formula,

or carboxylic acids of the formula IVa

Wherein R is⁵And R²Has the meaning of the above-mentioned formula,

or carboxylic acids of the formulae Va or Vb

Wherein R is⁵Has the meaning of the above-mentioned formula,

or carboxylic acids of the formula VIa

Wherein R is⁵Has the meaning of the above-mentioned formula,

or carboxylic acids of the formula VIIa

Wherein R is⁵And U¹Has the meaning of the above-mentioned formula,

wherein R is⁵Has the meaning of the above-mentioned formula,

and U is²As defined in claim 1, wherein the first and second groups are,

in optionally activated form with amines of the formula XI

L, R, R therein_fQ and X have the meanings indicated above in the claims,

or

If R is⁵Having the meaning of protecting groups, these protecting groups are then, after cleavage, reacted in a subsequent step in a manner known in the art with a metal oxide or metal salt of at least one element having an atomic number of 21 to 29, 31 to 33, 37 to 39, 42 to 44, 49 or 57 to 83 and the acidic hydrogen atoms optionally present are then reacted, if desired, with inorganic and/or organic bases, amino acids or amino groupsCationic substitution of acid amides.