ZA200301949B

ZA200301949B - Use of metal complexes containing perfluoroalkyl as contrast agents in MR-imaging for the representation of plaques, tumours and necroses.

Info

Publication number: ZA200301949B
Application number: ZA200301949A
Authority: ZA
Inventors: Johannes Platzek; Ulrich Niedballa; Hanns-Joachim Weinmann; Peter Mareski; Bernd Raduechel; Bernd Misselwitz
Original assignee: Schering Ag
Priority date: 2000-08-11
Filing date: 2003-03-10
Publication date: 2004-12-14
Also published as: CA2419223A1; PL365596A1; EE200300061A; AU2001277549B2; MXPA03001287A; HUP0300736A2; KR20030022387A; CN1469757A; EP1307236A2; BG107542A; NZ523932A; HRP20030173A2; DE10066210B4; CZ2003392A3; RU2290206C2; SK1572003A3; AU7754901A; WO2002013874A2; BR0113188A; AR034139A1

Description

° 9 02/13874 PCT/EP01/08498

Use of Perfluoroalkyl-Containing Metal Complexes as Contrast

Media in MR-Imaging for Visualization of Plaque, Tumors and

Necroses

Description

The invention relates to the use of perfluoroalkyl-containing metal complexes that have a critical micelle formation concentration of < 10” mol/l, a hydrodynamic micelle diameter (2 Rh) > 1 nm and a proton relaxivity in plasma RH > 10 I/mmol's as contrast media in MR-imaging both for visualization of plaque, lymph nodes, infarcted and necrotic tissue and for independent visualization of necrotic tissue and tumor tissue. It has been shown that perfluoroalkyl- containing metal complexes with the above-mentioned properties are extremely well suited for the independent visualization of plaque, tumors and necroses with the aid of MR-imaging and simultaneously can also cover the diagnostically important area of infarction and necrosis imaging.

Arteriosclerosis is the most important and most frequent pathological alteration of arteries with hardening, thickening, loss of elasticity and lumen constriction. It represents the most frequent cause of death in Western industrialized countries. Vascular wall alterations are produced by lipid retention, connective tissue reproduction and calcification with irregular dispersion for wall instability, vascular stenosis and for storage of clots. Causes of disease are numerous exogenic and endogenic noxae or diseases, €.g., hypertonia, hyperlipidemia, hyperfibrinogenemia, diabetes mellitus, toxins, nicotine, antigen-antibody complexes, inflammations, hypoxia, mental stress, age and family stress. The latter result in the disruption of the integrity of the vascular inside wall, in the disruption of growth control of smooth muscle cells of the vascular wall and in impairing the degradation of aged cell components. Treatment é MP teriosclerosis itself is not possible; the target of medical efforts is prevention by reducing risk factors, e.g.. using lipid reducing agents.

The diagnosis of arteriosclerosis in clinical practice is currently carried out mainly by angiography as a gold standard. The limitation in all processes that are based on the measurement of the reduction of the vascular lumen is, however, the early stage of the disease, which is characterized by a thickening of the vascular wall in the case of a normal vascular lumen (Glagov, S., Zarins, C. K. Quantitating Atherosclerosis. In: Bond, M. G.; Insull, W.;

Glagov, S.; Chandler, A. B.; Cornhill, J. F. (eds.). Clinical Diagnosis of Atherosclerosis.

Quantitative Methods of Evaluation. New York: Springer-Verlag, 1983, 11-35). Another method for diagnostic assessment of vascular wall and vascular lumen is the intravascular or percutaneous ultrasound.

Magnetic nuclear spin resonance tomography (MRT) is a modern, non-invasive radiological process, which makes possible the visualization of physiological and pathophysiological structures with a very good space and time resolution. The use of specific contrast media with selective concentration in certain tissues and organs can increase the diagnostic value considerably in this case. Contrast medium preparations with selective concentration in arteriosclerotic plaque were able to detect location and degree of the disease at an early time and thus to make possible a targeted therapy and prophylaxis, and therefore the search for suitable contrast media began early.

Thus, hematoporphyrin derivatives are claimed in U.S. Patent 4,577,636 as contrast media for the detection of atherosclerotic plaque. As methods, scintigraphy, radiography, - fluorescence and, for paramagnetic metalloporphyrins, even NMR-spectrometry, are mentioned.

As paramagnetic ions, Gd, Cr, Co, Ni, Ag and Eu are cited.

The disadvantage to these compounds is that the porphyrins are stored in the skin and cause discolorations that can last up to several weeks. Moreover, they result in a photosensitization. In addition, the danger exists that in a long retention time in vivo, the metalloporphyrin loses the metal.

In Application WO 95/09856, metalloporphyrins (deuteroporphyrins) are claimed for

® Mrosis and therapy of plaque. As a diagnostic method, MRI is mentioned. These porphyrins also cause discolorations of the skin.

In Application WO 93/09013, conjugates that consist of specifically binding polypeptides and metal complexes are claimed. These compounds are also to bind to plaque and thus make possible their diagnosis and therapy. As diagnostic methods, scintigraphy, computer tomography, and MRI are mentioned. While scintigraphy is confirmed by experiment, data is lacking for MRI.

Labeled phycocyanines are claimed as contrast media for the imaging of plaque in U.S.

Patent 5,807,536. As diagnostic methods, radiography, computer tomography, scintigraphy,

SPECT and MRI are mentioned here. Scintigraphy is confirmed by experiment.

Numerous contrast media for infarction and necrosis imaging are known from the literature. Tests were carried out early on to improve the localization of infarctions and necroses by use of contrast media in noninvasive processes such as scintigraphy or nuclear spin tomography. The literature devotes a great deal of space to attempts to use porphyrins for necrosis imaging. The results that are achieved paint a contradictory picture, however.

Winkelman and Hoyes thus describe in Nature, 200, 903 (1967) that manganese-5,10,15.20- tetrakis(4-sulfonatophenyl)-porphyrin (TPPS) selectively accumulates in the necrotic portion of a tumor.

Lyon et al. (Magn. Res. Med. 4, 24 (1987)) observed, however, that manganese-TPPS is dispersed into the body, specifically into the kidney, liver, tumor and only in a small portion to the muscles. It is advantageous in this case that the concentration in the tumor reach its maximum only on the fourth day and also only after the authors have increased the dose from 0.12 mmol/kg to 0.2 mmol/kg. The authors therefore also speak of a non-specific uptake of

TPPS in the tumor. Bockhurst et al. in turn report in Acta Neurochir 60, 347 (1994, Suppl.) that

MnTPPS binds selectively to tumor cells.

Foster et al. (J. Nucl. Med. 26, 756 (1985)) in turn found that '''In-5,10,15,20-tetrakis-(4-

N-methyl-pyridinium)-porphyrin (TMPyP) does not accumulate in the necrotic portion, but rather in the living edge areas. It follows from the above that a porphyrin-tissue interaction exists. is o @ ou but not necessary.

In Circulation Vol. 90, No. 4, part 2, page 1468, Abstract No. 2512 (1994), Ni et al. report that they can visualize infarction areas with a manganese-tetraphenyl-porphyrin (Mn-TPP) and a gadolinium-mesoporphyrin (Gd-MP). In International Patent Application WO 95/31219, both substances were used for infarction and necrosis imaging. The authors Marchal and Ni write (see Example 3) that for the compound Gd-MP, the metal content of the infarcted kidney was as high as that of the non-infarcted organ, but that for the myocardium in the infarcted tissue (Example 1), it was nine times as high. It was surprising that the ratio of the signal intensities during MRI for infarcted tissue in comparison to healthy tissue was comparatively high in both cases, at 2.10 or 2.19. Other metalloporphyrins were described in Application DE 19835082 (Schering AG).

Porphyrins tend to be stored in the skin, which results in photosensitization. The sensitization can last for days, and indeed even weeks. This is an undesirable side effect when using porphyrins as diagnostic agents. In addition, the therapeutic index for porphyrins is only very small, since, e.g., for Mn-TPPS, an action starts only at a dose of 0.2 mmol/kg, but the LDso is already approximately 0.5 mmol/kg.

Contrast media for necrosis and infarction imaging not derived from the porphyrin skeleton have been described in DE 19744003 (Schering AG), DE 19744004 (Schering AG) and

WO 99/17809 (EPIX).

In DE 19744003, oligomeric compounds, which consist of a nucleus and are bonded to the 1-3 metal complexes, are claimed.

In Application 19744004, lipophilic metal complexes for necrosis and infarction imaging are claimed. These compounds include metal complexes of polyaminopolycarboxylic acids, polvaminopolyphosphonic acids. porphyrins, texaphyrins, sapphyrins, and peptides.

In EPIX-Application WO 99/17809, the use of DTPA derivatives for necrosis imaging is claimed. The most prominent compound is the gadolinium complex of a phosphodiester of hydroxymethyl-DTPA (MS-325).

Perfluoroalkyl-containing metal complexes are also known as contrast media for MR- i g ® ine. WO 97/26017 (Schering) and WO 99/01161 (Schering) thus disclose the use of perfluoroalkyl-containing metal complexes as lymphographic agents. In addition, WO 99/0116] also describes the suitability of these compounds for visualizing the vascular space (blood-pool agents).

Contrast media were also described for the individual visualization of tumors and necroses using MR-imaging.

In EP 417870 Al, compounds for tumor diagnosis and therapy are disclosed. It is stated that infarctions and ischemias can also be visualized. An experimental confirmation of this information cannot be derived from the application, however. The claimed compounds are chelates of complexes of N2S2 and N38 types with radioisotopes. Scintigraphy is used as a diagnostic method.

In DE 19646762, scintigraphy is also used as a diagnostic method. In the publication, metal chelates are claimed as radiosensitizers for therapy of hypoxic tumors and for diagnosis of hypoxic conditions and necroses. In the descriptive part, NMR-diagnosis, x-ray diagnosis and radiodiagnosis are mentioned as diagnostic processes.

In German Application DE 19824653, porphyrins are claimed as necrosis-affine substances for the therapy of tumors. In the application, it is explained that the compounds are concentrated in the necrotic and hypoxic areas of the tumors. The compounds can be used for diagnostic purposes in the form of their metal derivatives with paramagnetic ions or radioisotopes.

It is common to both applications -- DE 19646762 and DE 10824653 -- that the visualization of necroses and tumors does not take place independently of one another, but rather that the necrosis is part of the tumor.

The object of this invention was to make available contrast media for MR -imaging, which are suitable both for visualization of plaque, lymph nodes, infarcted and necrotic tissue and for independent visualization of necroses and tumors.

Surprisingly enough, it was now found that perfluoroalkyl-containing metal complexes, which have a critical micelle formation concentration of < 10° mol/l, a hydrodynamic micelle

® eter (2 Rh) > 1 nm and a proton relaxivity in plasma ®R' )> 10 l/mmols, are very well suited as contrast media in MR imaging for visualization of plaque. In addition, these compounds can be used both for visualization of lymph nodes, infarcted and necrotic tissue and for independent visualization of necrotic tissue and tumor tissue.

Amphiphilic compounds, which have a perfluoroalkyl side chain in the molecule as a nonpolar portion that is optionally connected to the total molecule via a lipophilic linker, are defined as perfluoroalkyl-containing metal complexes that are suitable for use according to the invention. The polar portion of the compounds according to the invention is formed by one or more metal complexes and optionally other existing polar groups.

In aqueous systems, these amphiphilic molecules show the properties that are characteristic of standard surfactants (such as, e.g., sodium dodecylsulfate, SDS). They thus reduce the surface tension of water. By tensiometry, the so-called CMC (critical micelle formation concentration in mol/l) can be determined. In this respect, the surface tension is determined based on the concentration of the substance to be measured. The CMC can be calculated from the plot of the surface tension function (¢) that is obtained. The critical micelle formation concentration of the compounds according to the invention must be < 10° mol/l, preferably < 10” mol/l.

The amphiphilic compounds according to the invention are combined in solution and are present as aggregates. The size (2 Rh) of such aggregates (e.g. micelles, rods, wafers, etc.) can be determined with the aid of photon-correction spectroscopy (PCS).

As a second criterion, the hydrodynamic micelle diameter 2 Rh, which must be > 1 nm, is therefore used. Those perfluoroalkyl-containing metal complexes according to the invention whose 2 RH is > 3, quite especially preferably > 4 nm, are especially suitable.

Both the determination of the CMC and the photon correlation spectroscopy are described in H.-D. Dérfler, "Grenzflichen- und Kolloidchemie [Interface and Colloid Chemistry],"

Weinheim, New York. Basel, Cambridge, Tokyo, VSH 1994.

As a third criterion, the proton-relaxivity in plasma (R') at 40°C and a field strength of 0.47 tesla is used. The relaxivity, which is indicated in [I/mmol’s], is the quantitative

¢® urement for the shortening of relaxation time T' of the protons. For the purpose according to the invention. the relaxivity must be as high as possible and > 10 I/mmol's, preferably > 13 /mmols, especially preferably > 15 I/mmol’s.

Relaxivity R' [mmol 's] of the MR-contrast media according to the invention was determined with the Minispec P 20 device of the Bruker Company. The measurements were taken at 40°C and a field strength of 0.47 tesla. Eight measuring points were recorded by each

T1-sequence: 180°-TI-90°, inversion recovery. As a medium, bovine plasma of the Kraeber

Company was used. The contrast medium concentrations [mmol/l] in the batches were between 0.30 and 1.16.

In an embodiment of this invention, the compounds of general formula I according to claims 8 to 11 are used as preferred compounds. In this case, these are known compounds that are described in WO 97/26017. Their production can also be found in this WO publication.

Surprisingly enough, it has been shown that these compounds are also very well suited as MRI- contrast media for visualization of plaque. As quite especially preferred compounds, metal complexes I-[V, VI and XI-XIII (cf. also Table 1) are used.

In another embodiment of this invention, those compounds of general formula Ia according to claims 12 to 21 are used as preferred compounds. These compounds are known and are described in WO 99/01161. Their use as MRI contrast media for visualization of plaque still had not been described to date. Of these compounds, quite especially preferably metal complex

XIV (cf. Table 1) is used.

In another preferred embodiment of the invention, the macrocyclic perfluoroalkyl compounds of general formula Ib (A

K—N—L-R (Ib) in which

K means a complexing agent or a metal complex of general formula IIb

PY COOR’ ® ~~ Rr? R’ o ry ST

Ln oor (IIb) whereby

R' stands for a hydrogen atom or a metal ion equivalent of atomic numbers 23-29, 42-46 or 58-70,

R?and R® stand for a hydrogen atom, a C;-C7 alkyl group, a benzyl group, a phenyl group, -CH2OH or -CH.-OCH3, and

U? stands for radical L', whereby L' and U%, independently of one another, can be the same or different,

Al means a hydrogen atom, a straight-chain or branched Ci-Cso-alkyl group, which optionally is interrupted by 1-15 oxygen atoms, and/or optionally is substituted with 1-10 hydroxy groups, 1-2 COOH groups, a phenyl group, a benzyl group and/or 1-5 -OR’ groups, with R’ in the meaning of a hydrogen atom or a C1-Co- alkyl radical, or LR, . L' means a straight-chain or branched Ci-Cso-alkylene group, which optionally is interrupted by 1-10 oxygen atoms, 1-5 -NH-CO groups, 1-5 -CO-NH groups, by a phenylene group optionally substituted by a COOH group, 1-3 sulfur atoms, 1-2

N(B")-S02 groups and/or 1-2 -SO.-N(BY groups with B' in the meaning of Al an NHCO group, a CONH group, an N(B")-S0, group or an -S02-N(B') group and/or optionally is substituted with radical RF, and

RF means a straight-chain or branched perfluorinated alkyl radical of formula CaF2nE, whereby n stands for numbers 4-30, and

E stands for a terminal fluorine atom, chlorine atom, bromine atom, iodine atom or a hydrogen atom, and optionally present acid groups optionally can be present as salts of organic and/or inorganic

( @: or amino acids or amino acid amides, can be used.

Since the compounds according to the invention are intended for use in NMR diagnosis, the metal ion of the signaling group must be paramagnetic. These are in particular the divalent and trivalent ions of the elements of atomic numbers 23-29, 42-46 and 58-70. Suitable ions are, for example. the chromium(III), iron(II), cobalt(II), nickel(II), copper(II), praseodymium(IIl), neodymium(III), samarium(Ill) and ytterbium(lll) ions. Because of their strong magnetic moments, gadolinium(I11), terbium(11l), dysprosium(III). holmium(II), erbium(IID), iron(III) and manganese(I]) ions are especially preferred.

Preferred are manganese(11), iron(II), iron(IIl), praseodymium(1II), neodymium(III), samarium(III), gadolinium(IIl) and ytterbium(III) ions, especially dysprosium(IlI) ions.

Alkyl groups R?, R’, and R’ can be straight-chain or branched. By way of example, methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1- methylbutyl, 2-methylbutyl, 3-methylbutyl, and 1,2-dimethylpropyl can be mentioned.

Hydrogen and C;-Cs alkyl groups are preferred for rR’, R’.and Rr’ hydrogen and the methyl group are especially preferred.

The benzyl group and phenyl group R>, A' and B' can be substituted in the phenyl! ring.

The COOH group is suitable as a substituent.

If the compound of formula Ib contains radicals L' and U? at the same time, L' and U can be different from one another.

C,-C3o alkylene groups U? can be straight-chain or branched. By way of example, methylene, ethylene, propylene, isopropylene, n-butylene, 1-methylpropylene, 2- methylpropylene, n-pentylene, 1-methylbutylene, 2-methylbutylene, 3-methylbutylene, and 1,2- dimethylpropylene can be mentioned.

For U? in the meaning of alkylene, C1-Co alkylene groups are preferred; Ci-Cs alkylene groups are especially preferred.

Ci1-Cso alkyl groups A' can be straight-chain or branched. By way of example, methyl. ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-

C Aviburyl, 3-methylbutyl, 1.2-dimethylpropyl, and n-hexyl can be mentioned.

C1-Csp alkyl groups A! can be interrupted by 1-135 oxygen atoms and/or substituted with 1-10 hydroxy groups, 1-5 alkoxy groups or 1-2 COOH groups, such as, e.g..

C,H4-O-CH;, C3He-O-CHs,

CaHs-O-(C2Hs-O)-C2Hs-OH, C1H4-0O-(C2Ha-0)-CoH4-OCH; with t = 0 to 13

C>H4OH. C3HsOH, CsHsOH, CsHi0OH, C¢H120H, C;H,40H, as well as their branched isomers,

CH(OH)CH.OH,

CH(OH)CH(OH)CH:0H, CH:[CH(OH)]u' CH20H, with u' =1-10

CH[CH2(OH)]CH(OH)CH20H,

C,H4CH(OH)CH20H, (CH3)sCOOH with s = 1 to 15,

C,H4-0O-(C2Hs-0)-CH2COOH with t=0to 13,

CaHe-O~(C3Hu-O)-CaHe-CaF so with t = 010 13, 1 = 4 10 20 and

E = a fluorine, hydrogen, chlorine, bromine or iodine atom.

Preferred meanings of A! are hydrogen, C1-Cio-alkyl,

C2H4-O-CH3, C3He-O-CHs,

C2Hs-0-(C2Ha-0)x-C2Hs-OH, CaHa-0-(C2Ha-0)x-C2Ha-OCH3 with x =0to 5,

C,H4OH, C5HsOH,

CH,[CH(OH)]yCH:0H, with y = 1-6

CH[CH,(OH)]CH(OH)CH.0H, (CH2)wCOOH with w= 1 to 10,

C,H4-O-(C2Hs-0)x-CH2COOH with x = 0 to 5,

C2Hs-0-(CaHg-0)x-C2Ha-CoF2nE with x =0 to S,n=4 to 15, and

E = a fluorine atom.

If the compound of general formula Ib contains two radicals L'-RF, these radicals can be different from one another.

For radicals L', there can be mentioned by way of example, whereby a stands for the

11 22003/ 19 49 o fing to the nitrogen atom and f stands for the binding to radical RF:

a-(CHz)s-B with s = 1-15 a-CH,-CH,-(0-CH,-CHa-)y-B with y = 1-6 a-CHz-(0O-CH2-CHz-)y-B with y = 1-6 o-CH2-NH-CO-p a-CH2-CH2-NH-SO2-p a-CHz-NH-CO-CH2-N(CH2COOH)-S02- a-CH2-NH-CO-CH2-N(C2Hs)-SO2-B o-CH2-NH-CO-CH2-N(C10H21)-502-f o-CHa-NH-CO-CHa-N(CsH13)-SO2-B o-CHa-NH-CO-(CHz2)10-N(C2Hs)-SO2-B a-CHz-NH-CO-CH2-N(-CH2-CsHs)-SO2-8 o-CH2-NH-CO-CH2-N(-CH2-CH2-OH)S 02-3 o-CH2-NHCO-(CHa2)10-S-CH2CH2-f3 a-CH.NHCOCH:2-O-CH2CHa-B a-CHa-CH>NHCOCH:-O-CH.CH2-B a-CHa-(CHa-CH1-O)y-(CH2)sNHCO-CH,-O-CH2CHo-f with y = 1-6 a-CH,NHCO(CH2)10-0-CH2CH2-B a-CH,CH2NHCO(CHz)10-O-CH2CHa-

0-CHy-CgH4-O-CH2CHa-B, whereby the phenylene group 1,4 or 1,3 is linked a-CHp-0-CHy-C(CH;-OCH CH -CgF13)2-CH-OCH-CHp-B a-CHy-NHCOCH»CHCON-CH» CHHNHCOCH,N(CoH35)SO2CgF17B o-CH-CH2NHCOCH:N(C2Hs)-S02-B a-CH5-0-CH»-CH(OCgH21)-CH2-O-CHCH2-B a-(CHHNHCO)4-CHO0-CHpCHp-B a-(CHHONHCO)3-CH7O-CHpCHp-B a-CH)-OCHHC(CHoOH),-CH-O-CHyCH2-B

COOH a-CHHNHCOCH,N(CgHs)-SO2-B «-NHCO-CH;-CHa-B @-NHCO-CH,-O-CHyCHo-B a-NH-CO-B a-NH-CO-CH»-N(CHCOOH)-SO2-f -NH-CO-CH;-N(C2Hs5)-502-p -NH-CO-CH,-N(C gH21)-SO2-B «-NH-CO-CH)-N(CgH]3)-SO02-B «-NH-CO-(CH»)1¢-N(C2Hs)-802-8 -NH-CO-CH)-N(-CH-CgHs)-S02-p -NH-CO-CHy-N(-CH-CH»-OH)SO2-B -NH-CO-CHp-B -CHn-0-CgHy-0-CHy-CHa-B a-CHy-CgHg-O-CHp-CHp-B a-N(CoHj5)-SO2-B a-N(CgH5)-SO2-B a-N(C10H21)-SO2-p a-N(CgH13)-SO2-B a-N(CoH4OH)-502-8 4-N(CH>COOH)-SO2-B -N(CH>CgHs)-S02-B «-N-[CH(CH,OH)5]-S02-8 -N-[CH(CHoOH)CH(OH)(CH2OH)]-S02-B

® . Preferred are: a-CH-O-CH2CH:-8 a-CH»-CHa-(O-CH2-CHaz-)y-B with y = 1-6 a-CH;-(0-CH2-CHa-)y-p with y = 1-6 a-CH;-CH>-NH-SO»- Example 10 a-CH.2NHCOCH2-O-CH2CHz-B a-CH2-CH2NHCOCH2-O-CH2CHz-$ a-CHa-(CH2-CH2-0)y-(CH2)sNHCO-CH2-O-CH>CHz-f with y = 1-6 a-CH2NHCO(CHz2)10-O-CH2CHz-f3 a-CH2CH2NHCO(CH2)10-O-CH2CH2-f a-CH2-O-CH;-CH(OCoHz21)-CH2-O-CH2CH»-B a-CHz-O-CsHs-O-CHz-CHz-f a-CH2-CsH4-O-CH2-CHz-f

According to the invention, radicals L' of the compounds mentioned in the examples of the description of this invention are quite especially preferred.

U? is considered to stand for the above-cited radicals for L' and the radicals that are characterized as preferred and especially preferred, and the above-cited and optionally preferred and especially preferred radicals are considered to stand for the meaning of alkylene, provided that no a-position nitrogen atom and no terminal (B-position) SOz or CO group must be present.

Preferred radicals B' are hydrogen, straight-chain or branched C;-C¢-alkyl radicals, which optionally are interrupted by 1-5 oxygen atoms and/or optionally are substituted with 1-5 hydroxy groups, 1-2 COOH groups, a phenyl group optionally substituted by a COOH group, a benzyl group and/or 1-3 OR’ groups, with R’ in the meaning of a hydrogen atom or a C;-C3 alkyl radical.

Preferred radicals R’ are straight-chain or branched perfluorinated alkyl radicals of formula CqF2,E, whereby n stands for numbers 4 to 15 and E stands for a terminal fluorine atom.

® ) The production of the compounds of general formula Ib according to the invention

K=N—L-R’ : (Ib) with

K in the meaning of a complexing agent or a metal complex of general formula IIb

COOR'

PN

Cl R 0

N< —N N 5

COOR' { iP 0 (

COOR (Ib) can be carried out according to the following process:

Process A.

The carboxylic acid of Formula Hb already contains metal ion equivalent : 3

For oF

N rR? Re o) a ROR og a “LL Aon Ar “rl Pa PN oN u +HN R — —N N u N R

CR’ a 0 A COR! {nl ° A

COR’ : " (IIb) (IVb) (Ib)

Carboxylic acid IIIb that is optionally activated in situ with R' in the meaning of a metal jon equivalent is reacted with an amine IVb in a coupling reaction to form an amide Ib.

This process for the production of metal complex carboxylic acid amides is known from

DE 196 52 386.

C @ The mixture of metal complex carboxylic acid IIIb that is used in the coupling reaction and that contains optionally present carboxy and/or hydroxy groups in protected form and at least one solubilizing substance in an amount up to 3, preferably 0.5-2 molar equivalents relative to the metal complex carboxylic acid, can both be produced in an upstream reaction stage and isolated (e.g., by concentration by evaporation, freeze-drying or spray-drying of an aqueous or water-miscible solution of components or by precipitation with an organic solvent from such a solution) and then can be reacted in DMSO with dehydrating reagent and optionally a coupling adjuvant and can be formed in situ optionally by the addition of solubilizing substance(s) for

DMSO-suspension of metal complex carboxylic acid, dehydrating reagent and optionally a coupling adjuvant.

The reaction solution that is produced according to one of these processes is kept for pretreatment (acid activation) for 1 to 24 hours, preferably 3 to 12 hours at temperatures of 0 to 50°C, preferably at room temperature.

Then, an amine of general formula IVb

RL LaF

N R

A (IVb) in which radicals rR’ L RF and A have the above-indicated meanings, is added without solvent or dissolved in, for example, dimethyl sulfoxide, alcohols, such as, e.g., methanol, ethanol, isopropanol or mixtures thereof, formamide, dimethylformamide, water or mixtures of the cited solvents, preferably in dimethyl sulfoxide, in water or in solvents that are mixed with water. For amide coupling, the thus obtained reaction solution is kept at temperatures of 0 to 70°C, preferably 30 to 60°C, for 1 to 48 hours, preferably 8 to 24 hours.

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

® Oo:

The optionally still present protective groups are then cleaved off.

The isolation of the reaction product is carried out according to the methods that are known to one skilled in the art, preferably by precipitation with organic solvents, preferably acetone, 2-butanone, diethyl ether, ethyl acetate, methyl-t-butylether, isopropanol or mixtures thereof. Further purification can be carried out by, for example, chromatography, crystallization or ultrafiltration.

As solubilizing substances, alkali salts, alkaline-earth salts, trialkylammonium salts, tetraalkylammonium salts, ureas, N-hydroxyimides, hydroxyaryltriazoles, substituted phenols and salts of heterocyclic amines are suitable. By way of example, there can 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-morpholinoethylsulfonic acid, 4-nitrophenol, 3,5-dinitrophenol, 2,4- dichlorophenol, N-hydroxysuccinimide, N-hydroxyphthalimide, urea, tetramethylurea, N- methylpyrrolidone, formamide, as well as cyclic ureas, whereby the five first-mentioned are preferred.

As dehydrating reagents, all agents that are known to one skilled in the art are used. By way of example, carbodiimides and onium reagents, such as, e.g., dicyclohexylcarbodiimide (DCCI), 1-ethyl-3-(3-dimethylaminopropy!)-carbodiimide-hydroxychloride (EDC), benzotriazol- 1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP) and O-(benzotriazol-1- yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HBTU), preferably DCCL can be mentioned.

In the literature, for example, the following suitable processes are described: 4 Aktivierung von Carbonsduren. Ubersicht in Houben-Weyl, Methoden der

Organischen Chemie [Activation of Carboxylic Acids. Survey in Houben-Weyl,

@® ® Methods of Organic Chemistry], Volume XV/2, Georg Thieme Verlag Stuttgart, 1974 (and J. Chem. Research (S) 1996. 302). 4 Aktivierung mit Carbodiimiden [Activation with Carbodiimides]. R. Schwyzer and H. Kappeler, Helv. 46: 1550 (1963). 4 E. Wiinsch et al., Vol. 100: 173 (1967). + Aktivierung mit Carbodiimiden/Hydroxysuccinimid [Activation with

Carbodiimides/Hydroxysuccinimide]: J. Am. Chem. Soc. 8: 1839 (1964) and J.

Org. Chem. 53: 3583 (1988). Synthesis 453 (1972). ¢ Anhydridmethode, 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydrochinolin [Anhydride

Methods, 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline]: B. Belleau et al., J.

Am. Chem. Soc., 90: 1651 (1986), H. Kunz et al., Int. J. Pept. Prot. Res., 26: 493 (1985) and J. R. Voughn, Am. Soc. 73: 3547 (1951). 4 Imidazolid-Methode [Imidazolide Methods]: B. F. Gisin; R. B. Menifield; D. C.

Tosteon, Am. Soc. 21: 2691 (1969).

LZ Saurechlorid-Methoden, Thionylchlorid [Acid Chloride Methods, Thionyl

Chloride]: Helv., 42: 1653 (1959). + Oxalylchlorid [Oxalyl Chloride]: J. Org. Chem., 29: 843 (1964).

As coupling adjuvants that are optionally to be used, all that are known to one skilled in the art are suitable (Houben-Weyl, Methoden der organischen Chemie, Volume XV/2, Georg

Thieme-Verlag, Stuttgart, 1974). By way of example, 4-nitrophenol, N-hydroxysuccinimide, 1- hydroxybenzotriazole, 1-hydroxy-7-aza-benzotriazole, 3,5-dinitrophenol and pentafluorophenol can be mentioned. Preferred are 4-nitrophenol and N-hydroxysuccinimide; especially preferred in this case is the first-mentioned reagent.

The cleavage of the protective groups is carried out according to the processes that are known to one skilled in the art, for example by hydrolysis, hydrogenolysis, alkaline saponification of esters with alkali in aqueous-alcoholic solution at temperatures of 0°to 50°C, acid saponification with mineral acids or in the case of. e.g., tert-butylesters with the aid of . trifluoroacetic acid [Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P.

@ @: us John Wiley and Sons, Inc. New York, 1991]. in the case of benzyl ethers with hydrogen/palladium/carbon.

The production of the starting material, the compounds of Formula IIIb, oor a SN.

COR’ {AN ©

Coos oo (IIb), is known from DE 196 52 386.

The amines of general formula IVb 3

R Lo “N RF

A (IVb) are commercially available products (Fluorochem, ABCR) or can be obtained according to the following process from compounds of general formula Vb by reaction with an amine of general formula VIb and subsequent reduction of the compounds of general formula VIIb: 0 o}

H 3 F 3 £ 3

A ASR _— A — ete SR

A A TA

(Vb) (VIb) (VIIb) (IVb) in which :

RF, Al L! and R’ have the above-mentioned meaning, and L' has the meaning of group

L' in which the a-CHa-group is still missing, and

R’ stands for hydrogen or a methyl group.

9 [ According to the process described in the literature that was already disclosed above for the activation of carboxylic acid IIIb, acid Vb is activated with amine VIb before the reaction.

For R’ in the meaning of a methyl group, an aminolysis is performed.

The compounds of general formula Vb are commercially available products (Fluorochem,

ABCR) or are produced as disclosed in DE 196 05 053.

The compounds of general formula VIb are commercially available products (Fluorochem, ABCR) or can be produced as described in Houben- Weyl, Methoden der organischen Chemie, XI/2 Stickstoffverbindungen [XI/2 Nitrogen Compounds], Georg Thieme

Verlag Stuttgart, 1957, p. 680; J. E. Rickman and T. Atkins, Am. Chem. Soc., 96:2268, 1974, 96: 2268: F. Chavez and A. D. Sherry. J. Org. Chem. 1989, 34: 2990. }

The compounds of general formula IVb are obtained in a way that is known in the art [Helv. Chim. Acta. 77: 23 (1994)] by reduction of the compounds of general formula VII, for example, with diborane or lithium aluminum hydride and cleavage of the protective groups.

Process B.

As starting material, the carboxylic acid of formula IIIx is used with R' in the meaning of hydrogen -- it still does not contain any metal ion equivalent R'. The carboxyl groups are protected according to the processes that are known to one skilled in the art, and a compound of

Formula Illy is obtained, whereby R’ stands for any protective group and R’ stands for its precursor. cof cog’

So " oo 7 Re i 2 + RS a 7 i il © no onrMuen ——— nN on

COM . COR’ (IIx) (IlLy)

As carboxyl protective groups, e.g., straight-chain or branched C;-Cs alkyl, aryl and ® [ groups, for example, the methyl, ethyl, propyl, butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis(p-nitrophenyl)-methyl group and trialkylsilyl groups are suitable. The t- butyl group is preferred.

COR? CoH nN Nr yon +R —= oN NN a oo COR? oo CO,H (Illy) (IVb) (Ix)

The reaction of the protected carboxylic acid Illy with the amine of formula IVb and the cleavage of the protective groups is carried out as described under process A and in a subsequent step, the obtained carboxylic acid Ix is reacted with at least one metal oxide or metal salt of an element of the desired atomic number as is disclosed in, e.g., DE 195 25 924.

If the metal complex that is obtained from process A or B still contains free COOH groups, these groups can also be present as salts of physiologically compatible inorganic or organic bases.

The neutralization of optionally still present free carboxy groups is then carried out with the aid of inorganic bases (for example, hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium, lithium, magnesium, or calcium and/or organic bases such as, i.a., primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N- methyl- and N,N-dimethylglucamine, as well as basic amino acids, such as, for example, lysine, arginine, and ornithine, or amides of originally neutral or acidic amino acids.

According to the invention, quite especially preferably metal complexes V, VII, VIII, IX and X (cf. Table 1) are used.

These compounds of general formula Ib are very well suited as MRI contrast media for visualization of plaque.

C @ In another preferred embodiment of the invention, the perfluoroalkyl-containing complexes with sugar radicals of general formula Ic (K)'~G = (Z-R (Ic) (Y-R)p' in which

R represents a mono-or oligosaccharide radical bonded by the 1-OH- or 1-SH- position,

RF is a perfluorinated, straight-chain or branched carbon chain with the formula -CoF2sE, in which E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n stands for numbers 4-30,

K stands for a metal complex of general formula IIc,

COOR? (

SN N RO oN N - N—_ I

R'00C /

NEA

\

COOR? (Ic) in which

R' means a hydrogen atom or a metal ion equivalent of atomic numbers 23-29, 42-46 or 58-70, provided that at least two R! stand for metal ion equivalents,

R? and R’, independently of one another, represent hydrogen, Ci-Cs alkyl, benzyl, phenyl, -CH,OH or -CH,0OCH3, and

U represents -C¢Hs-O-CHa-00. -(CHa2)1-5-0, a phenylene group, -CH>-NHCO-CHz-

@® C CH(CH2COOH)-CsHa-w, -CsHa-(OCH2CH2)o.1-N(CH2COOH)-CH:-, or a C;-

C12 alkylene group or C7-C12-C¢Hs-O group optionally interrupted by one or more oxygen atoms, 1 to 3 -NHCO groups or 1 to 3 -CONH groups and/or substituted with 1 to 3 -(CHz2)o-sCOOH groups, whereby o stands for the binding site to -CO-, or of general formula Illc

COOR"™ (

SN N COOR' 9

R'00OC /

COOR? (IIc) in which R' has the above-mentioned meaning, Rr? represents hydrogen or a metal ion equivalent mentioned under R', and U' represents -C¢Hs-O-CHz-w, whereby w means the binding site to -CO-, or of general formula [Vc ~ OOR"

NTN Re?

R*O0OC / p, J : haS

COOR" (Ve) in which R' and R* have the above-mentioned meaning or of general formula VcA or VcB

2 D200371949 ® ® NEE dé ~~COOR" —N

R'QOC /

NUN GO OR?

N— 1

COOR (Vea) ~—COOR"

NC Coor! nA

Ane C- N

NUNTEO OR" ~— 1

COOR (VB) in which R' has the above-mentioned meaning, or of general formula Vic

RIO0C—"" _—CO—w 1 _ ~— 1

R'O0OC COOR (Vic) in which R' has the above-mentioned meaning, or of general formula Vc

R'00C—_ Q __N A,

R'O0OC U

R'O00C BSN 1 ~~

RIO0C (VIL) in which R' has the above-mentioned meaning, and u' represents -C¢Hi-O-CHz-m, whereby » means the binding site to -CO- or of general formula Vlllc oO a

ON ™

NN N N

~Anf rooc” / TN

NAN J or . \

COOR (VIII) in which R' has the above-mentioned meaning, and in radical K, optionally present free acid groups optionally can be present as salts of organic and/or inorganic bases or amino acids or amino acid amides,

G for the case that K means metal complexes Ic to Vllc, represents a radical that is functionalized in at least three places and is selected from the following radicals a) to) (a) y a ~N— (CH,)~C-CO —at

NH

3

B

(b) ’

Y #-CO-C— (CHIN wp a (©) a ye N ~~ hN \ p w—N NY

No | % a z25 oo © (@ ; a N———e Y

Ne

B

(e)

CO

Bw—N N——w

H H

®

H

NH —CO CCl ye ( NH

NY : ( co-2— CH, )-Nw~a

Ho | ( 2)

I p .

¢® ® 3) :

NH

N—CO—CH—(CH NH

I i

NH—CO—CH—(CH, JHB i

B i) H H

Qt tm N— (CH, ); C—N—CO-C—(CH,)sN—wB

H LH H

I NH

Co

B

® "

HN puw—N—{CH = —CON N——.

NH

NE

SN a oe © 0) gv NH—CH — CO —~ ¥ i

B and

G for the case that K means metal complex VIIIc, represents a radical that is functionalized in at least three places and is selected from k) or 1) (k) pa-N HCH, J GH—COmva 1 kf . 0) come CO Chg CH=CH CO i

P whereby a means the binding site of G to complex K, B is the binding site of G to radical

Y, and y represents the binding site of G to radical Z,

Y means -CHz, 8-(CHz2)1.5CO-B, 8-CH2-CHOH-CO-B or 3-CH(CHOH-CHOH)-

CHOH-CHOH-CO-B, whereby & represents the binding site to sugar radical R, and P is the binding site to radical G,

Z stands for

PO

Y—N ~~ N—S05-€ y-COCH2-N(C:Hs)-SO2-¢,

) ® y-COCH:z-0-(CH2)2-SO2-, 0 @)

Ao ITT N—S05-€ or y - NHCH2CH>-O-CH2CHa-¢ whereby v represents the binding site of Z to radical G, and ¢ means the binding site of Z to perfluorinated radical RF and 1, m', independently of one another, mean integer 1 or 2, and p means integers 1 to 4, can be used.

Since the compounds according to the invention are intended for use in NMR-diagnosis, the metal ion of the signaling group must be paramagnetic. These are especially the divalent and trivalent ions of the elements of atomic numbers 23-29. 42-46 and 58-70. Suitable ions are, for example, the chromium(IlI), iron(II), cobalt(II), nickel(II), copper(I), praseodymium(Ill), neodymium(I1I), samarium(IlI) and ytterbium(lll) ion. Because of their strong magnetic moment, gadolinium(I1l), terbium(IIl), dysprosium(llI), holmium(III), erbium(IiI), iron(III) and manganese(Il) ions are especially preferred.

Preferred are manganese(II), iron(II), iron(Ill), praseodymium(IlI), neodymium(III), samarium(I1I), gadolinium(Ill) and ytterbium(III) ions, especially dysprosium(lII) ions.

InR, optionally present acidic hydrogen atoms, i.e., those that have not been substituted by the central ion, can optionally be replaced completely or partially by cations of inorganic and/or organic bases or amino acids or amino acid amides.

Suitable inorganic cations are, for example, the lithium ion, the potassium ion, the calcium ion and especially the sodium ion. Suitable cations of organic bases are, i.a., those of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine,

Z9 ® @rholine, glucamine, N,N-dimethylglucamine and especially N-methylglucamine. Suitable cations of amino acids are, for example, those of lysine, arginine, and ornithine as well as the amides of otherwise acidic or neutral amino acids.

Especially preferred compounds of general formula Ic are those with macrocyclic compound K of general formula IIc.

Radical U in metal complex K means preferably -CHz- or C¢Hs-O-CHz-0, whereby © stands for the binding site to -CO-.

Alkyl groups R? and R in the macrocyclic compound of general formula IIc can be straight-chain or branched. By way of example, methyl, ethyl, propyl, isopropyl, n-butyl, 1- methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, and 1,2- dimethylpropyl can be mentioned. R?and R’, independently of one another, preferably mean hydrogen or C-Cs-alkyl. In a quite especially preferred embodiment, R? stands for methyl and

R’ stands for hydrogen.

The benzyl group or phenyl group R*orR’ in macrocyclic compound K of general formula llc can also be substituted in the ring.

Radical R in general formula Ic means a mono- or oligosaccharide radical or thiosugar radical that is bonded via the 1-OH- or 1-SH-position, whereby in this connection according to the invention, this can be a deoxy sugar, which contains an H atom instead of one or more OH groups. In a preferred embodiment of the invention, R means a monosaccharide radical with 5 or 6 C atoms, preferably glucose, mannose, galactose, ribose, arabinose or xylose or their deoxy sugars, such as, for example, 6-deoxygalactose (fucose) or 6-deoxymannose (rthamnose) or their thiosugars, whereby glucose, mannose and galactose are especially preferred.

Of the compounds of general formula Ic according to the invention, in addition those are preferred in which RF means -CoFan+1. n preferably stands for numbers 4-15. Quite especially preferred are radicals -Cako, -CsF 13, -CsF17, -C12F25 and -C14F29 as well as the radicals of the compounds that are mentioned in the examples.

Radical G that is functionalized in at least three places in general formula Ic, which represents the "skeleton," means lysine radical (a) or (b) in a preferred embodiment of the

C i@tion.

Y and Z mean the linkers indicated in general formula Ic, whereby independently of one another, radical ‘ [ng f—Nl N—S05-¢ is preferred for Z, and radical 3-CH>CO-B is preferred forY.

The perfluoroalkyl-containing metal complexes with sugar radicals of general formula Ic

K)'-G ~ (Z-R)m' (Ic) (Y-R)p with K in the meaning of a metal complex of general formulas Ilc to Vllc and G in the meaning of formulas a) to j), whereby Y, Z, R, RF, m', p' and 1! have the above-mentioned meaning, are produced by a carboxylic acid of general formula Ii ~ OR’

NTN RR It \ A —N N N~y~—"~0H

R°0OC” / Pp !

Ms

COOR® I) in which R® means a metal ion equivalent of atomic numbers 23-29, 42-46, or 58-70 or a carboxyl protective group, and RZ, R? and U have the above-mentioned meaning, or a carboxylic acid of general formula Ili eo © 20

TN NE ort ¢ \ , —N U-~ "OH rR°00C” / bY

COOR (IIL) in which R*, R’ and U' have the above-mentioned meaning or a carboxylic acid of general formula IVi

O° R®

CNN R2

Rfooc” J N

NUN p 0

LO

COOR® vi) in which R® and R” have the above-mentioned meaning or a carboxylic acid of general formula Vi or Vii

CO-OH 5 a COOR a N ~—COOR> —~—N rR°0OC” / COORS HOOC” A ; a —COOR

NNER NUN ~COOR® vi) (Vii) in which R’ has the above-mentioned meaning or a carboxylic acid of general formula VIi

RO0C— TN CO-OH

R°00C—" ~—COOR’ : (VI)

. . B200371948 ( @hich R® has the above-mentioned meaning or a carboxylic acid of general formula VIIi

R°00C— Q

RS00C—"" son

R°00C J

R°0OC—" VII in which R® and U' have the above-mentioned meanings, being reacted in a way that is known in the art in optionally activated form with an amine of general formula IXc

H-G-(ZRHn' (IXc) (Y-R)y' in which G has the meaning of formulas a) to j), and R, Rf, Y,Z, m' and p' have the indicated meaning, in a coupling reaction and optionally subsequent cleavage of optionally present protective groups to form a metal complex of general formula Ic or if R® has the meaning of a protective group, after cleavage of these protective groups ina subsequent step being reacted in a way that is known in the art with at least one metal oxide or : metal salt of an element of atomic numbers 23-29, 42-46 or 58-70, and then, if desired, optionally present acidic hydrogen atoms being substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides.

The compounds of general formula Ic according to the invention with K in the meaning of a metal complex of general formula VIIIc and G in the meaning of formulas k) or I) are produced by an amine of general formula VIIIi

PY ® | COOR’ (

NT N h ~H rScoc” NTT on ©

N

COOR’ (VIII) in which R® means a metal ion equivalent of atomic numbers 23-29, 42-46 or 58-70 or a carboxyl protective group, being reacted in a way that is known in the art with an optionally activated carboxylic acid of general formula Xc

HO — G — (Z-R%)a" (Xc) (Y-R)* in which G has the meaning of formula k) or 1) and R, RF, Y, Z, m' and p' have the indicated meanings, in a coupling reaction and optionally subsequent cleavage of optionally present protective groups to form a metal complex of general formula lc or if R® has the meaning of a protective group, after cleavage of these protective groups in a subsequent step, being reacted in a way that is known in the art with at least one metal oxide or metal salt of an element of atomic numbers 23-29, 42-46 or 58-70, and then, if desired, optionally present acidic hydrogen atoms being substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides.

The carboxylic acids of general formulas Ili to VIIi that are used are either known compounds or are produced according to the processes that are described in the examples. Thus, the production of carboxylic acids of general formula Ili is known from DE 196 52 386. The production of the carboxylic acids of general formula IVi can be found in DE 197 28 954.

A precursor for compounds of general formula VcA is the N°-(2,6- dioxomorpholinoethyl)-N°-(ethoxycarbonylmethy1)-3,6-diaza-octanedioic acid, which is

@ © iinrr263050

The compounds of general formula VcB are derived from the isomeric diethylenetriamine-pentaacetic acid, which binds via acetic acid on the center N atom. This

DTPA is described in Patents DE 195 07 819 and DE 195 08 058.

Compounds of general formula Vic are derived from N-(carboxymethyl)-N-[2-(2,6- dioxo-4-morpholinyl)-ethyl]-glycine, whose production is described in J. Am. Oil. Chem. Soc. (1982), 39 (2), 104-107.

Compounds of general formula VIIc are derived from the 1-(4-carboxymethoxybenzyl)- ethylenediamine-tetraacetic acid. which is described in Patent US 4,622,420.

The perbenzylated sugar acids that are used as starting substances can be produced analogously to Lockhoff, Angew. Chem. 1998, 110 No. 24, p. 3634 ff. For example, the production of 1-O-acetic acid from perbenzyl-glucose is carried out over 2 stages, via trichloroacetimidate and reaction with hydroxyacetic acid ethyl ester, BFs-catalysis in THF and subsequent saponification with NaOH in MeOH/THEF.

In a more advantageous process, the perbenzylated sugar acids that are used as starting substances can also be produced by the perbenzylated 1-OH-sugar being dissolved in a water- immiscible organic solvent and being reacted with an alkylating reagent of general formula Xlc

Nu-L-COO-Sg (XIc), in which Nu means a nucleofuge, L is -(CHa2)(1-s), -CH2-CHOH-, -CH(CHOH-CH>0H)-CHOH-CHOH-, and Sg represents a protective group, in the presence of a base and optionally a phase transfer catalyst. As a nucleofuge, for example, the radicals -Cl, -Br, -I, -OTs, -OMs, -OS0O2CF3, -OSO2C4Fs or -OSO2CsF 17 can be contained in the alkylating reagent of general formula XIc.

The protective group is a common acid protective group. These protective groups are well known to one 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 according to the invention can be carried out at temperatures from 0-50°C, preferably from 0°C to room temperature. The reaction times are 10 minutes to 24 hours,

® erably 20 minutes to 12 hours.

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

As organic, water-immiscible solvent, for example, toluene, benzene, CF3-benzene, hexane, cyclohexane, diethyl ether. tetrahydrofuran, dichloromethane, MTB or mixtures thereof can be used in the alkylating process according to the invention.

As phase-transfer catalysts, the quaternary ammonium or phosphonium salts or else crown ethers, such as, e.g., [15]-crown-3 or [18]-crown-6, that are known for this purpose are used in the process according to the invention. Quaternary ammonium salts with four identical or different hydrocarbon groups at the cation, selected from methyl, ethyl, propyl, isopropyl, butyl or isobutyl, are preferably suitable. The hydrocarbon groups at the cation must be large enough to ensure good solubility of the alkylating reagent in the organic solvent. According to the invention, N(butyl)s™-Cl, N(butyl)s*-HSO4’, but also N(methyl)s-CI" are especially preferably used.

As quite especially preferred compounds of general formula Ic, metal complex XV of

Table 1 (Example 1) according to the invention is used.

In another preferred embodiment of the invention, the perfluoroalkyl-containing complexes with polar radicals of general formula Id are used

K)'-G — (ZR! ad)

Rp’ in which

Rf is a perfluorinated, straight-chain or branched carbon chain with formula -C aF2nE, in which E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n stands for numbers 4-30,

K stands for a metal complex of general formula IId,

PS PY pe OCR’ = gl IN ? FO

Roo”) NO a \ © : COOR" (11d) in which

R' means a hydrogen atom or a metal ion equivalent of atomic numbers 23-29, 42-46 or 58-70, provided that at least two R' stand for metal ion equivalents,

R? and R’, independently of one another, represent hydrogen, C1-Cr-alkyl, benzyl, phenyl, _CH20H or -CH;0CHj, and

U represents -CsHs-O-CHa-0-, -(CH2)15-0, a phenylene group, -CH2-NHCO-CHo-

CH(CH2COOH)-C¢Hs-0>-, -CsHa-(OCH2CH2)o-1-N(CH2COOH)-CHz-w, or a Ci-

Ciz-alkylene group or C7-Ci2-CsH4-O group optionally interrupted by one or more oxygen atoms, 1 to 3 -NHCO groups, 1 to 3 -CONH groups and/or substituted with 1 to 3 -(CH2)o-sCOOH groups, whereby stands for the binding site to -CO-, or of general formula [11d

COOR" (

SNT N COOR® O \ SL rooc” NU

A

COOR” (11d) in which R' has the above-mentioned meaning, R* represents hydrogen or a metal ion equivalent mentioned under R', and U’ represents -CsHa-O-CHa-0-, whereby means the binding site to -CO-,

® ® or of general formula IVd ~~ OR’

CNN R=

Nr

N ay

R'QOC / > 5

COOR? (IVa) in which R' and R” have the above-mentioned meaning, or of general formula VdA or VdB

N —CO-~

NC coor

JEAN

R'O0OC /

NUN —COOR? ~— 1

COOR (VdA)

N —~COOR" 0 a ~—~COOR'

N

NUN —COOR? ~— 1

COCR (VdB) in which R' has the above-mentioned meaning, ] or of general formula VId ee © RIO0C— Tyre

Sg ~—

R'OOC COOR? (Vid) in which R' has the above-mentioned meaning, or of general formula VIId

R'OOC—_ Q _~ N A,

R'00C J

R'COC SY _

R'O0C (VIId) in which R' has the above-mentioned meaning, and

U' represents -CeHa-O-CHz-w-, whereby w means the binding site to -CO-, and in radical K, optionally present free acid groups optionally can be present as salts of organic and/or inorganic bases or amino acids or amino acid amides,

G represents a radical that is functionalized in at least three places and is selected from the following radicals a) to g) (2) ’ a N(CH) —C—CO —an

NH

4 p (b)

H

Y + CO-C— (CH) Nw B " a '

oo © ©) y

NT ab 8 wa—oN N ——w f as ~b ¢3 (d)

B

Jap

CNY aw—N N ———, ¥

Nd : (e)

Y l prw—0N Nt

0 ~ R2003/1949 oo © (£)

H H a wn—N—(CH,);C—N—-CO C—({CH)rN — 3

H oN *H [ NH ¥

B

(2)

J } a ¥ B (h) Y “COACH, HCO (i) Bw CO-(CHy)5-OH-CO wy

NH NH a [04 whereby a means the binding site of G to complex K, B is the binding site of G to radical R, and v represents the binding site of G to radical Z

Z stands for

A

Y—N ~~ N—S05- ES y-C(O)CH20(CH2)2-¢, whereby y represents the binding site of Z to radical G and € means the binding site of Z to perfluorinated radical RF,

R represents a polar radical that is selected from complexes K of general formulas [Id to VIId, whereby R' here means a hydrogen atom or a metal ion equivalent of atomic numbers 20, 23-29, 42-46 or 58-70,

® ® and radicals R%, B®, R*, U and U' have the above-indicated meaning, or the folic acid radical or

R means a carbon chain with 2-30 C atoms that is bonded to radical G via -CO- or

SO»- and is straight or branched, saturated or unsaturated, optionally interrupted by 1-10 oxygen atoms, 1-5 -NHCO groups, 1-5 -CONH groups, 1-2 sulfur atoms, 1-5 -NH groups or 1-2 phenylene groups, which optionally can be substituted with 1-2 OH groups, 1-2 NH: groups, 1-2 -COOH groups, or 1-2 -SO3H groups, or optionally substituted with 1-8 OH groups, 1-5 -COOH groups, 1-2 SO3H groups, 1-5 NH; groups, 1-5 C;-C4-alkoxy groups, and 1 m', 0 independently of one another, mean integer 1 or 2.

Since the compounds according to the invention are intended for use in NMR diagnosis, the metal ion of the signaling group must be paramagnetic. These are in particular the divalent and trivalent ions of the elements of atomic numbers 23-29, 42-46 and 58-70. Suitable ions are, for example, the chromium(III), iron(II), cobalt(Il), nickel(Il), copper(ll), praseodymium(III), neodymium(III), samarium(IIl) and ytterbium(III) ions. Because of their strong magnetic moment, gadolinium(IID), terbium(IlI), dysprosium(III), holmium(III), erbium(lll), iron(IIT) and manganese(1l) ions are especially preferred.

Preferred are manganese(Il), iron(II), iron(Ill), praseodymium(III), neodymium(III), samarium(III), gadolinium(IIT) and ytterbium(III) ions, especially dysprosium(IlI) ions.

InR', optionally present acidic hydrogen atoms, i.¢., those that have not been substituted by the central ion, can be replaced optionally completely or partially by cations of inorganic and/or organic bases or amino acids or amino acid amides.

Suitable inorganic cations are, for example, the lithium ion, the potassium ion, the calcium ion and especially the sodium ion. Suitable cations of organic bases are, i.a., those of a? ® ar. secondary or tertiary amines, such as, for example. ethanolamine, diethanolamine, morpholine. glucamine, N,N-dimethylglucamine, and especially N-methylglucamine. Suitable cations of amino acids are, for example, those of lysine, arginine, and ornithine as well as the amides of otherwise acidic or neutral amino acids.

Especially preferred compounds of general formula Id are those with macrocyclic compound K of general formulas I1d, 11d, VdB or VIId.

Radical U in metal complex K preferably means -CHy- or C¢Hs-O-CHz-o, whereby stands for the binding site to -CO-.

Alkyl groups R? and R’ in the macrocyclic compound of general formula Ild can be straight-chain or branched. By way of example, methyl, ethyl, propyl, isopropyl, n-butyl, 1- methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, and 1,2- dimethylpropy! can be mentioned. R?and R’, independently of one another, preferably mean hydrogen or C;-Ca-alkyl.

In a quite especially preferred embodiment, R? stands for methyl and R’ stands for hydrogen.

The benzyl group or phenyl group R” or R* in macrocyclic compound K of general formula 11d can also be substituted in the ring.

In a preferred embodiment, polar radical R in general formula Id means complex K, whereby the latter preferably in addition to a Gd**- or Mn" complex also can be a Ca’ complex.

As polar radicals R, complexes K of general formulas I1d, IIld, V dA or VIId are especially preferred. The latter as R' quite especially preferably have a metal ion equivalent of atomic numbers 20, 25, 39 or 64.

In another preferred embodiment, polar radical R has the following meanings: -C(O)CH2CH2SO3H -C(0)CH20CH2CH20CH,CH,OH -C(0)CH,OCH2CH.0OH -C(O)CH>OCH>CH(OH)CH-OH

® ® -C(O)CH-NH-C(O)CH.COOH -C(O)CHCH(OH)CH:0H -C(O)CH20CH,COOH -SO2CH.CH.COOH -C(0)-CsH3-(m-COOH)2 -C(0)CH20(CH2)2-CeH3-(m-COOH)2 -C(0)CH20-CsH4-m-SO3H -C(0)CH2NHC(O)CH2NHC(O)CH20CH:COOH -C(0)CH.0CH>CH,OCH.COOH -C(0)CH,OCH>CH(OH)CH20-CHCH20H -C(0)CH20CH,CH(OH)CH20CH.-CH(OH)-CH20H -C(O)CH2503H -C(0)CH:CH2COOH -C(O)CH(OH)CH(OH)CH20H -C(O)CH20[(CH2)20]:1-9-CH3 -C(0O)CH20[(CH2)20]1-9-H -C(O)CH20CH(CH20H)2 -C(0)CH2,OCH(CH20CH2COOH)2 -C(0)-CsH3-(m-OCH2COOH)2 -CO-CH20-(CH2)20(CH2)20-(CH2)20(CH2).OCHj3 preferably —C(O)CH20[(CH2)20]4-CH.

In another preferred embodiment, polar radical R means the folic acid radical.

Of the compounds of general formula Id according to the invention, in addition those are preferred in which R" means -CoFane1. n preferably stands for numbers 4-15. Quite especially preferred are the radicals -CsF, -CgF13, -CsF17, -C12F25 and -CaFos.

Radical G that is functionalized in at least three places in general formula 1d, which represents the "skeleton," means lysine radical (a) or (b) in a preferred embodiment of the invention.

Z means the linker that is indicated in general formula Id, whereby radical :

ST TCi—<

Qo ¢ Y—N CN=—8C5 C is preferred.

The perfluoroalkyl-containing metal complexes with polar radicals of general formula Id (K)'=G = (ZR )m' (Id) (R)p’ in which K, G, R, Z, RF, I, m', and p have the above-indicated meaning, are produced by a carboxylic acid of general formula I1k a OR?

NTR? Re It \ A s _—N N N-~y~—~0H

R*00C™ / Pp A

COOR? (Ik) in which R® means a metal ion equivalent of atomic numbers 23-29, 42-46 or 58-70 or a carboxyl protective group, and R%, R’ and U have the above-mentioned meaning, or a carboxylic acid of general formula Ik

C0 a d N COOR" 0 _—N NES U-—" OH

R0CQOC /

NAN 2

SI

( cn RY, R’ and U' have the above-mentioned meaning or a carboxylic acid of general formula IVk oo R®

NNN Re \ A —N N OH rR°ooCc” / ) A ~

COOR’ (IVk) in which R® and R” have the above-mentioned meaning or a carboxylic acid of general formula Vk or Vm ~—CO-0OH COOR> (Co NC EooR? \

N .

R°coC” / — Hooc™ J ; a —COOR

NANTES OR’ NUN —COOR® (Vk) (Vm) in which R’ has the above-mentioned meaning or a carboxylic acid of general formula Vk

R00C— /7\ ~—CO-OH ~ ~ 5

RT OOC COCR (VIK) in which R® has the above-mentioned meaning or a carboxylic acid of general formula VIlk

R°00C Q

LA ~5o0e—" on

R°00OC ~ J

R°00C—" VII) in which R® and U' have the above-mentioned meanings, being reacted in a way that is known in the art in optionally activated form with an amine of general formula VIIId

H-G — (Z-Rm' (VIIId) ®R)y’ in which G, R, Z, R", m' and p’ have the above-indicated meaning, in a coupling reaction and optionally subsequent cleavage of optionally present protective groups to form a metal complex of general formula Id or if R® has the meaning of a protective group, being reacted after cleavage of these protective groups in a subsequent step in a way that is known in the art with at least one metal oxide or metal salt of an element of atomic numbers 23-29, 42-46 or 58-70, and then, if desired, optionally present acidic hydrogen atoms being substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides. :

The carboxylic acids of general formulas Ilk to V1lk that are used are either known compounds or are produced according to the processes that are described in the examples. Thus, the production of the carboxylic acids of general formula Ilk is known from DE 196 52 386. The production of the carboxylic acids of general formula IVk can be found in DE 197 28 954.

A precursor of compounds of general formula VdA is the N°-(2.6- dioxomorpholinoethyl)-N°-(ethoxycarbonylmethyl)-3,6-diaza-octanedioic acid, which is described in EP 263 059.

The compounds of general formula VdB are derived from the isomeric o ylenetriamine-pentaacetic acid, which binds via acetic acid on the center N-atom. This

DTPA is described in Patents DE 195 07 819 and DE 195 08 038.

Compounds of general formula VId are derived from N-(carboxymethyl)-N-[2-(2,6- dioxo-4-morpholinyl)-ethyl]-glycine, whose production is described in J. Am. Oil. Chem. Soc. (1982), 59 (2), 104-107.

Compounds of general formula VIId are derived from 1-(4-carboxymethoxybenzyl)- ethylenediamine-tetraacetic acid, whose production was described in Patent US 4,622,420.

Metal complex XVI of Table 1 according to the invention is used as a quite especially preferred compound of general formula Id.

In another preferred embodiment of the invention, galenical formulations can be used that contain paramagnetic and diamagnetic perfluoroallkyl-containing substances. The paramagnetic and diamagnetic substances are preferably present in a dissolved state in an aqueous solvent.

As paramagnetic, perfluoroalkyl-containing compounds, all above-mentioned metal complexes of general formulas I, Ia, Ib, Ic and/or Id according to the invention can be used in the formulations.

The diamagnetic perfluoroalkyl-containing substances are those of general formula XX:

RF.L2-B (XX) in which R represents a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms, L” stands for a linker and B? stands for a hydrophilic group. Linker L* is a direct bond, an -SO; group, or a straight-chain or branched carbon chain with up to 20 carbon atoms, which can be substituted with one or more -OH, -COO-, SO; groups and/or optionally contains one or more -O-, -S-, -CO-, -CONH-, -NHCO-, -CONR’-, -NR’CO-, -SO2-, -POs™-, -NH- or NR’ ‘groups, an aryl ring or a piperazine, whereby R’ stands for a C;- to Cao-alkyl radical, which in turn can contain one or more O atoms, and/or can be substituted with -COO" or SOs groups.

Hydrophilic group B? is a mono- or disaccharide, one or more adjacent -COO" or -SO3 groups, a dicarboxylic acid, an isophthalic acid, a picolinic acid, a benzenesulfonic acid, a tetrahydropyrandicarboxylic acid, a 2,6-pyridinedicarboxylic acid, a quaternary ammonium ion, an aminopolycarboxylic acid, an aminodipolyethylene glycolsulfonic acid, an aminopolyethylene

( 9 group. an SO2-(CH1)2-OH group, a polyhydroxyalky! chain with at least two hydroxyl groups or one or more polyethylene glycol chains with at least two glycol units, whereby the polyethylene glycol chains are terminated by an -OH or ~-OCHj; group. Such substances are partially already known; such substances for the production of formulations according to the : invention were partially newly synthesized. Known perfluoroalkyl-containing substances and their production are described in the following publications:

J. G. Riess, Journal of Drug Targeting, 1994, Vol. 2, pp. 455-468;

J. B. Nivet et al, Eur. J. Med. Chem., 1991, Vol. 26, pp- 953-960;

M.-P. Krafft et al., Angew. Chem., 1994, Vol. 106, No. 10, pp. 1146-1148;

M. Lanier et al., Tetrahedron Letters, 1995, Vol. 36, No. 14, pp- 2491-2492;

F. Guillod et al., Carbohydrate Research, 1994, Vol. 261, pp. 37-35;

S. Achilefu et al., Journal of Fluorine Chemistry, 1995, Vol. 70, pp. 19-26;

L. Clary et al., Tetrahedron, 1995, Vol. 51, No. 47, pp- 13073-13088;

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

H. Wu et al., Supramolecular Chemistry, 1994, Vol. 3, pp. 175-180;

F. Guileri et al., Angew. Chem. 1994, Vol. 106, No. 14, pp. 1583-1585;

M.-P. Krafft et al., Eur. J. Med. Chem., 1991, Vol. 26, pp. 545-550;

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

A. Milius et al., Carbohydrate Research, 1992, Vol. 229, pp. 323-336;

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

G. Merhi et al, J. Med. Chem., 1996, Vol. 39, pp. 4483-4488;

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

A. Ould Amanetoullah et al., Journal of Fluorine Chemistry, 1997, Vol. 84, pp. 149-153;

J. Chen et al., Inorg. Chem., 1996, Vol. 35, pp. 1590-161:

L. Clary et al., Tetrahedron Letters, 1995, Vol. 36, No. 4, pp- 539-542;

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

A. Milius et al., New J. Chem., 1991, Vol. 15, pp. 337-344;

M.-P. Krafft et al., New J. Chem., 1990, Vol. 14, pp. 869-875;

o ® J.-B. Nivet et al., New J. Chem., 1994, Vol. 18, pp. 861-869;

C. Santaella et al., New J. Chem., 1991, Vol. 15, pp. 685-692;

C. Santaella et al., New J. Chem., 1992, Vol. 16, pp. 399-404;

A. Milius et al., New J. Chem., 1992, Vol. 16, pp. 771-773;

F. Szonyi et al., Journal of Fluorine Chemistry, 1991, Vol. 55, pp. 85-92;

C. Santaella et al., Angew. Chem., 1991, Vol. 103, No. 5, pp. 584-586;

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

EP 0 548 096 Bl.

The production of the new perfluoroalkyl-containing substances is carried out analogously to the above-mentioned compounds that are known in the literature and is described in the examples. In this case, these are substances of general formula XXI

RFX! (XX) in which R" represents a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms, and X! is a radical that is selected from the group of the following radicals (n in this case is a number between 1 and 10):

OH

S NNN ~~ 0

OH sole,

HN rr

AN 0

S i. ol

OH 0 e 0 3

HES © oN So

N

Oo

OH

° ¥ .. or oN ~~

HO Oo

OH

HE ©

Oo ,0

NAOT - // "0 0

O oN

OH

AL

0]

HE Q

H

Nel sore, I~

OH O07 In

OH O~_~... yds

Ho OH (a+B)

eo O® 2 en

EAL AN

J

N oY 0

Q 0) a . S

I ~~ T Ne PN ~ 9 0 OH dd ~ No TN {| 0

J NN ~ oH

TL p 0] Nl TN — OH ven 7 IR I Oo n ” i oO OH

SN Sr ~~ 0 es 0 io 6

OH

6 —coo t 0 — COO 0 ad cat 0 EE

Ll N coo

Nelelo}

RES 0 5% oO eee ~~’ ye OH /

HO — OH

HO

HO OH

Coo - cere” ~ p= 0 vr 0 Coo 0 ML coo

H

OH

OH o

HE2 i ~~

COO” 0

COO”

Preferred diamagnetic perfluoroalkyl-containing substances are those with a monosaccharide as hydrophilic group B.

Especially preferred diamagnetic perfluoroalkyl-containing compounds contain a perfluoroalkyl radical Rt with 6 to 12 carbon atoms, a linker L*, which represents an -SOz group, or a straight-chain or branched carbon chain with up to 20 carbon atoms, which in turn contains one or more -O-, -CO-, -CONH-, -NHCO-, -CONR-, -NRCO-, or -SO2 groups or a piperazine, in which R has the above-indicated meaning, and a monosaccharide as hydrophilic group B.

N 0200371949 ® @® Other suitable diamagnetic perfluoroalkyl-containing compounds are conjugates that consist of cyclodextrin and perfluoroalkyl-containing compounds. These conjugates consist of a-, B- or y-cyclodextrin and compounds of general formula XXII

ALLRF (XXII) in which A' stands for an adamantan, biphenyl or anthracene molecule, 1° stands for a linker, and R stands for a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms.

Linker L® is a straight-chain hydrocarbon chain with 1 to 20 carbon atoms, which can be interrupted by one or more oxygen atoms, one or more CO-, SO2-, CONH-, NHCO-, CONR-,

NRCO-, NH- or NR groups or a piperazine, whereby R is a C1-Cs-alkyl radical.

Preferred compounds are the following compounds:

ON SO0;—C,F,;

Oo C

Oo

ON SO;—C,F;

O-LO-y™

Oo 0 H

BT

JoR

® © i oJ @

LN

“SO; CeF yy

SOT

[i ] NS

Si 0 0

Jo ~

N CF 47

H

0 dd

An

N ~S07——C,F,;

H

O .

Ho ~

N CeFy7

H

0) 0

Cry ~CF,

eo ©

The galenical formulations of this invention contain the paramagnetic and diamagnetic perfluoroalkyl-containing compounds in a mixing ratio of between 5:95 and 95:5. Preferred are mixing ratios of between 40:60 and 60:40 of the two substances. Both substances are used in millimolar concentrations. Concentrations of between 0.5 and 1000 mmol/l of solvent are achieved. The solvent is preferably water. The metal concentration of the formulations is preferably in a range of 50-250 mmol/l.

Preferred are mixtures that consist of paramagnetic and diamagnetic perfluoroalkyl- containing compounds, in which the perfluoroalkyl chains have a length of 6 to 12 carbon atoms.

Especially preferred are mixtures in which both the paramagnetic and the diamagnetic perfluoroalkyl-containing compounds have a perfluoroalkyl chain with 8 carbon atoms.

The production of the galenical formulations is carried out in that the paramagnetic perfluoroalkyl-containing compounds (components A) and the diamagnetic perfluoroalkyl- containing substances (components B) are weighed in fractions of a mol of between 0.05 and 0.95 in components A or B and are dissolved in a suitable solvent. An especially well suited solvent is water. Common galenical additives, such as, e.g., buffer solutions and the Ca-salt of the complexing agent, are then added in excess to this solution. At 10 to 100°C, the solutions are stirred vigorously. As an alterative, the solutions can be treated in an ultrasound bath at 10 to 100°C. Another alternative consists in that the solutions are treated with microwaves.

In substances that do not dissolve in water as individual components, it proves advantageous to add a solubilizer such as alcohol (e.g., methanol or ethanol) or another water- miscible solvent, and the latter can then be distilled off slowly. The distillation can be carried out under a vacuum. The residue is then dissolved in water, and the solution is filtered. It is also possible to dissolve each component separately in one solvent each, then to combine them and proceed as indicated above. It has proven advantageous to introduce a relatively strongly concentrated solution (> 100 mmol) of the metal complex (component A) and then to add component B in the pure state, and, as mentioned above, to stir the solution or to treat it with ultrasound or microwaves.

(1) ® In summary, it has been determined that as quite especially preferred compounds, gadolinium complexes [-X VI that are presented in Table 1 meet the criteria according to the invention. The physical parameters of these metal complexes [-XV1 are presented in Table 2.

Both the paramagnetic compounds of general formulas I, Ia, Ib, Ic and Id according to the invention and the formulations that consist of paramagnetic and diamagnetic perfluoroalkyl- containing substances according to the invention are extremely well suited as contrast media in

MR-imaging for visualization of plaque, tumors and necroses.

® he 1: Metal Complexes that are Quite Especially Preferably Used According to the

Invention

Bibliographic Reference, Name

I WO 97/26017, Example 33f

Gadolinium complex of 10-[1-methyl-2-oxo-3-aza-5-0xo-{4-perfluorooctyl- sulfonyl-piperazin-1-yl}-pentyl]-1,4,7-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecane iI WO 97/26017, Example 2c

Gadolinium complex of 10-[2-hydroxy-4-aza-5-ox0-7-0xa-~ 10,10,11,11,12,12,1 3,13,14,14,15,15,16,16,17,17-heptadecafluoroheptadecyl]- 1,4.7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

TI WO 97/26017, Example 34b

Gadolinium complex of 10-[2-hydroxy-4-aza-5,9-dioxo-9- {4-perfluorooctyl)- piperazin-1-yl}-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecane

Iv WO 97/26017, Example 1c

Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctyl- sulfonyl)-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane \Y% Example 2c, this application 1,4,7-Tris(carboxylatomethyl)-10-(3 -aza-4-oxo-hexan-5-ylic)-acid-N-(2,3- dihydroxypropyl)-N-(1H,1 H,2H.2H,4H,4H,5H,5H-3-0xa)-perfluorotridecyl)- amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex

VI WO 97/26017, Example 3¢

Gadolinium complex of 10-[2-hydroxy-4-oxa- 1H,1H,2H,2H,3H,3H,5H,5H,6H,6H-perfluorotetradecyl]-1,4,7- tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane vil Example Se, this application 1,4,7-Tris(carboxylatomethyl)-10- {(3-aza-4-oxo-hexan-5-ylic)acid-[N- (3,6,9,12,15-pentaoxa)-hexadecyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-0xa)- perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

VIII Example 3c, this application 1,4,7-Tris(carboxylatomethyl)-10- { (3-aza-4-oxo-hexan-5-ylic)-acid-N-(5- hydroxy-3-oxa-pentyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-0xa)- perfluorotridecyl]-amide}-1,4.7,10-tetraazacyclododecane, gadolinium complex

IX Example 6b, this application 1,4,7-Tris(carboxylatomethyl)-10- {(3-aza-4-oxo-hexan-5-ylic)-acid-[N- 3,6.9,16-tetraoxa- 1 3-aza-14-0x0-C19-Ca6-hepta-decafluoro)hexacosyl]-amide }- 1,4.7.10-tetraazacyclododecane, gadolinium complex

® ree Bibliographic Reference, Name

X Example 1c, this application 1.4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic]-acid-N-(2- methoxyethyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-0xa)-perfluorotridecyl]- amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex

XI WO 97/26017, Example 32¢

Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-0Xa-~ 10,10,11,11,12,12,13,13,14,14,15,15,16,16,17.17,18,18,19,19-henicosafluoro- nonadecyl]-1,4,7-tris(carboxymethyl)-1.4,7,10-tetraazacyclododecane

XII WO 97/26017, Example 38d

Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-11-aza-1 1-(perfluorooctyl- sulfonyl)-tridecyl]-1-4-7-tris(carboxymethyl) 1,4,7,1 0-tetraazacyclododecane

XIII WO 97/26017, Example 35d

Gadolinium complex of 10-[2-hydroxy-4-aza-5-0x0-7-aza-7-(perfluorooctyl- sulfonyl)-8-phenyl-octyl]-1-4-7-tris(carboxymethyl)-1,4,7,10-tetraaza- cyclododecane

XIV WO 99/01161, Example 1g 1.4,7-Tris{1,4,7-tris(N-(carboxylatomethyl)-10-[N-1-methyl-3 ,6-diaza-2.5,8- trioxooctane-1,8-diyl]-1,4,7,10-tetraazacyclododecane, Gd complex} -10-N- 2H.2H,4H.4H,5H,5H-3-oxa-perfluoro-tridecanoyl]-1,4,7,1 0-tetraazacyclo- dodecane, Gd complex

XV Example 21f, this application 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,1 0O-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-y1)]-2-N-[1 -0-a-D-carbonylmethyl- mannopyranose]-L-lysine-[1 -(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex

XVI Example 54b, this application 2.6-N,N'-Bis[1,4,7-tris(carboxylatomethyl)-1,4,7,1 0O-tetraazacyclododecane-10- (pentanoyl-3-aza-4-0x0-35 -methyl-5-y1)]-lysine-[1-(4-perfluorooctylsulfonyl- piperazine]-amide, Gd complex

®o o-

Physicochemical Parameters of the Complexes of Table 1 that are

Used According to the Invention

Complex No. CMC (mol) 2 Rh (nm) R' Plasma (Vmmol's) 186° 10° 7.06 10°

L0 10° 144107 vi 2.65 10° 60 lus 1.90 10° 2.88 10° 1.07 10° xi 5.90 10° 2.5010" 5.90 10°

CMC: Critical micelle formation concentration 2 Rh: Hydrodynamic micelle diameter

R': Relaxivity

® @odiments

Example 1 a) 2H 2H 4H.4H.5H.5H-3-Oxa-perfluorotridecanoic acid-N-(2-methoxy)-ethyl-amide 8.90 g (70 mmol) of oxaly! chloride is added to 30 g (57.45 mmol) of 2H.2H.4H.4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, and it is stirred for 12 hours at room temperature. It is evaporated to the dry state in a vacuum. The residue is dissolved in 100 ml of dichloromethane and added in drops at 0°C to a solution that consists of 4.51 g (60 mmol) of 2-methoxyethylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It is stirred for 3 hours at 0°C, then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred for minutes. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 20:1).

Yield: 30.28 g (91% of theory) of a colorless solid

Elementary analysis:

Cld: C31.10 H2.44 N242 F 55.76

Fnd: C 30.87 H2.58 N2.35 F 55.51 b) N-(2-Methoxyethyl)-N-(1H,1 H.2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecylamine g (51.79 mmol) of the title compound of Example la is dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M boranedimethyl sulfide (in tetrahydrofuran) is added. Itis refluxed for 16 hours. It is cooled to 0°C, and 200 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is stirred for 8 hours at 40°C. Itis evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous sodium hydroxide solution, and it is extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue o {@ romatographed on silica gel (mobile solvent: dichloromethane/2-propanol = 20:1).

Yield: 26.93 g (92% of theory) of a colorless solid

Elementary analysis (relative to anhydrous substance):

Cld: C31.87 H2.85 N2.48 F57.14

Fnd: C 31.69 H3.10 N2.27 F 56.88 ¢) 1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(2-methoxyethyl)-

N-(1H,1H,2H,2H.4H,4H.5H.5H-3-oxa)-perfluorotridecyl)-amide]-1.4,7,10- tetraazacyclododecane, gadolinium complex (metal complex X) g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 8.98 g (15.88 mmol) of the title compound of Example 1b is added. Itis stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little ethanol/water, and it is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 15.14 g (81% of theory) of a colorless, amorphous powder

Water content: 5.7%

Elementary analysis (relative to anhydrous substance):

Cld: C34.70 H3.77 N 7.14 F27.44 Gd 13.36

Fnd: C 34.51 H3.94 N 7.02 F27.25 Gd 13.18

Example 2 a) 2H.2H,4H,4H,5H.5H-3-Oxa)-perfluorotridecanoic acid-N-(2,3-dihydroxypropyl)-amide 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45 mmol) of o M11 4H 4H 5H.5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, and it is stirred for 12 hours at room temperature. It is evaporated to the dry state in a vacuum. The residue is dissolved in 100 mi of dichloromethane and added in drops at 0°C to a solution that consists of 5.47 g (60 mmol) of 2,3-dihydroxypropylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It is stirred for 3 hours at 0°C, then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred for 15 minutes. The organic phase is separated. dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/ethanol = 15:1).

Yield: 29.70 g (87% of theory) of a colorless solid

Elementary analysis:

Cld: C30.32 H2.20 N2.36 F 54.35

Fnd: C30.12 H241 N2.18 F54.15 b) N-(2,3-Dihydroxypropy!)-N-(1H, 1H,2H,2H 4H,4H,5H,5H-3-oxa-perfluorotridecyl)- amine g (48.8 mmol) of the title compound of Example 2a is dissolved in 300 ml of tetrahydrofuran, and 50 ml of 10 M boranedimethyl sulfide (in tetrahydrofuran) is added. It is refluxed for 16 hours. It is cooled to 0°C, and 300 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 300 ml of ethanol/S0 ml of 10% aqueous hydrochloric acid, and it is stirred for 8 hours at 60°C. Itis evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 15:1).

Yield: 24.07 g (85% of theory) of a colorless solid

Elementary analysis:

Cld: C31.05 H2.61 N2.41 F 55.66

® @® Fnd: C31.91 H2.78 N2.33 F 53547 ¢) 1.4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-3-ylic)-acid-N-(2.3- dihydroxypropy!)-N-(1H,1 H.2H,2H,4H,4H.5 H.5H-3-oxa)-perfluorotridecyl)-amide]- 1,4,7,10-tetraazacyclododecane, gadolinium complex (metal complex V) g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1.4.7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved in 100 ml of dimethyl sulfoxide at 60°C. It is cooled to 15°C, and 9.21 ¢ (15.88 mmol) of the title compound of Example 2b is added. It is stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. Itis stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little ethanol/water, and it is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 16.09 g (85% of theory) of a colorless, amorphous powder

Water content: 6.3%

Elementary analysis (relative to anhydrous substance):

Cid: C 34.26 H3.64 N7.05 F27.10 Gd 13.19

Fnd: C 34.12 H3.83 N 6.91 F 26.88 Gd 12.93

Example 3 a) 2H.,2H,4H.4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-(5-hydroxy-3-oxa-pentyl)- amide 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45 mmol) of 2H.2H,4H,4H,5H.5H-3-oxa-perfluorotridecanoic acid in 300 mi of dichloromethane, and it 1s stirred for 12 hours at room temperature. It is evaporated to the dry state in a vacuum. The

® Que is dissolved in 100 ml of dichloromethane and added in drops at 0°C to a solution that consists of 6.25 g (60 mmol) of 5-hydroxy-3-oxa-pentylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It is stirred for 3 hours at 0°C, then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred for 15 minutes. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 15:1).

Yield: 32.20 g (92% of theory) of a colorless solid

Elementary analysis:

Cld: C31.54 H2.65 N2.30 F 53.01

Fnd: C 31.61 H2.84 N2.14 F 52.85 b) N-(5-Hydroxy-3-oxa-pentyl)-N-(1H,1H,2H,2H,4H,4H.5H,5H-3-oxa-perfluorotridecyl)- amine g (49.24 mmol) of the title compound of Example 3a is dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M boranedimethyl sulfide (in tetrahydrofuran) is added. Itis refluxed for 16 hours. It is cooled to 0°C, and 200 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is stirred for 10 hours at 50°C. Itis evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous sodium hydroxide solution and extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/2-propanol = 20:1).

Yield: 26.09 g (89% of theory) of a colorless solid

Elementary analysis:

Cld: C32.28 H3.05 N2.35 F5425

Fnd: C 32.12 H3.21 N 2.18 F 54.09

. . 0200371949 ® 4 1.4.7-Tris(carboxylatomethyl)-10-[(3-aza-4-ox0-hexan-5-ylic)-acid-N-(5-hydroxy-3-oxa- : pentyl)-N-(1H.1 H,2H,2H.4H,4H,5H,5H-3-0xa)-perfluorotridecyl)-amide]-1,4,7,10- tetraazacyclododecane, gadolinium complex (metal complex VIII) g (15.88 mmol) of the gadolinium complex of 10-[ 1-(carboxymethylcarboamoyl)- ethyl]-1 .4,7.10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 9.45 g (15.88 mmol) of the title compound of Example 3b is added. It is stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little ethanol/water, and it is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 16.10 g (84% of theory) of a colorless, amorphous powder

Water content: 5.7%

Elementary analysis (relative to anhydrous substance): : Cld: C34.83 H3.84 N6.96 F 26.76 Gd 13.03

Fnd: C 34.65 H3.96 N6.84 F 26.62 Gd 12.91

Example 4 a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-(2-hydroxyethyl)-amide 8.90 g (70 mmol) of oxaly! chloride is added to 30 g (57.45 mmol) of 2H,2H,4H 4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, and it is stirred for 12 hours at room temperature. It is evaporated to the dry state in a vacuum. The residue is dissolved in 100 ml of dichloromethane and added in drops at 0°C to a solution that consists of 3.66 g (60 mmol) of 2-aminoethanol and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It is stirred for 3 hours at 0°C, then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred for

( inves. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 20:1).

Yield: 28.90 g (89% of theory)

Elementary analysis:

Cld: C29.75 H2.14 N2.48 F57.14

Fnd: C 29.61 H2.29 N2.37 F 57.01 b) N-(2-Hydroxyethyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amine 28 g (49.54 mmol) of the title compound of Example 4a is dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M boranedimethy! sulfide (in tetrahydrofuran) is added. Itis refluxed for 16 hours. It is cooled to 0°C, and 200 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is stirred for 10 hours at 50°C. Itis evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous sodium hydroxide solution, and it is extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/2-propanol = 15:1).

Yield: 25.12 g (92% of theory) of a colorless solid

Elementary analysis (relative to anhydrous substance):

Cld: C 30.50 H2.56 N 2.54 F 58.59

Fnd: C 30.32 H2.71 N2.48 F 58.45 c) 1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(2-hydroxyethyl)-

N-(1H,1H.2H,2H,4H,4H,5H,5H-3-0xa)-perfluorotridecyl)-amine-amide]-1,4,7,10- tetraazacyclododecane, gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-{1-(carboxymethylcarboamoy!)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium

® ide are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 8.75 ¢ (15.88 mmol) of the title compound of Example 4b is added. Itis stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1.2-dihydroquinoline is added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little ethanol/water, and it is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/ water).

Yield: 16.81 g (91% of theory) of a colorless, amorphous powder

Water content: 7.2%

Elementary analysis (relative to anhydrous substance):

Cld: C34.08 H3.64 N 7.23 F27.77 Gd 13.52

Fnd: C33.91 H3.82 N7.14 F27.58 Gd 13.41

Poamples a) 2H,2H,4H.4H,5H,5H-3-Oxa-perfluorotridecanoic acid amide 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45 mmol) of 2H,2H 4H 4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, and it is stirred for 12 hours at room temperature. It is evaporated to the dry state in a vacuum. The residue is dissolved in 200 ml of dichloromethane. Ammonia gas is then directed into the solution for about 2 hours at 0°C. It is stirred for 4 more hours at 0°C, then for 2 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred for minutes. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 20:1).

Yield: 27.85 g (93% of theory)

Elementary analysis:

Cld: C27.66 H1.55 N 2.69 F 61.97

@ O® rcoioH1I NLS FL b) 1H,1H.2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecylamine, hydrochloride 27 g (51.8 mmol) of the title compound of Example Sa is dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M boranedimethy! sulfide (in tetrahydrofuran) is added. It is refluxed for 16 hours. It is cooled to 0°C, and 200 ml of methanol is added, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 400 ml of ethanol/100 ml of 10% aqueous hydrochloric acid, and it is stirred for 8 hours at 60°C. Tt is evaporated to the dry state in a vacuum, and the residue is recrystallized from a little ethanol/diethyl ether.

Yield: 26.75 g (95% of theory) of a colorless, crystalline solid

Elementary analysis:

Cld: C 26.51 H2.04 N2.58 F 59.41 Cl6.52

Fnd: C 26.37 H2.21 N2.46 F59.25 C16.38 c) 3,6,9,12,15-Pentaoxahexadecanoic acid-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-0xa)- perfluorotridecyl)-amide > 14.24 g (50 mmol) of 3,6,9,12,15-pentaoxahexadecanoic acid chloride is added at 0°C to 26.5 g (48.74 mmol) of the title compound of Example 5b and 14.8 g (146.2 mmol) of triethylamine, dissolved in 300 ml of dichloromethane, and it is stirred for 3 hours at 0°C. 300 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred for 30 minutes. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone: 20:1).

Yield: 32.03 g (87% of theory) of a colorless oil

Elementary analysis:

Cld: C36.57 H4.00 N 1.85 F 42.75

Fnd: C36.46 H4.12 N 1.76 F 42.53

. B2003/71949 oo © d) N-(3,6.9.12,15-Pentaoxahexadecyl)-N-(1H,1 H.2H,2H.4H.4H-3-0xa)-perfluorotridecyl)- amine 31 g (41.03 mmol) of the title compound of Example 5c is dissolved in 300 ml of tetrahydrofuran, and 25 ml of 10 M boranedimethyl sulfide (in tetrahydrofuran) is added. Itis refluxed for 16 hours. Itis cooled to 0°C, and 200 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is stirred for 8 hours at 40°C. Itis evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous sodium hydroxide solution, and it is extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/2-propanol = 15:1).

Yield: 27.68 g (91% of theory)

Elementary analysis:

Cld: C37.26 H4.35 N 1.89 F 43.56

Fnd: C 37.11 H4.51 N 1.73 F 43.41 e) 1,4,7-Tris(carboxylatomethyl)-10-{(3 -aza-4-oxo-hexan-5-ylic)-acid-[N-3,6,9,12,15- pentaoxa)-hexadecyl)-N-(1H,1 H,2H,2H,4H,4H,5H,5H-3 -oxa)-perfluorotridecyl]-amide}- 1,4,7,10-tetraazacyclododecane, gadolinium complex (metal complex VID g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C,and 11.77 g (15.88 mmol) of the title compound of Example 5d 1s added. It is stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1 ,2-dihydroquinoline is added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 mi of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little

C1] @rol/water and chromatographed on silica ge] RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 18.05 g (84% of theory) of a colorless, amorphous powder

Water content: 6.2%

Elementary analysis (relative to anhydrous substance):

Cld: C3728 H4.47 N6.21 F 23.87 Gd 11.62

Fnd: C37.11 H4.61 N 6.03 F 23.64 Gd 11.42

Example 6 a) 1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-ox0-hexan- 5-ylic)-acid-N-(12-amino-3,6,9- trioxa-dodecyl)-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoy!)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 3.51 g (17 mmol) of N,N'-dicyclohexyl- carbodiimide is added, and it is stirred for 5 hours at 15°C. To separate the urea, the solution is filtered. 14.66 g (60 mmol) of 1,12-diamino-3,6,9-trioxa-dodecane and 2.02 g (20 mmol) of triethylamine are added to the filtrate, and it is stirred for 12 hours at room temperature. The solution is poured into 1500 ml of diethyl ether/50 ml of n-butanol, and it is stirred for 30 minutes. The precipitated solid is filtered and chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 12.66 g (69% of theory) of a colorless, amorphous powder

Water content: 3.5%

Elementary analysis (relative to anhydrous substance):

Cld: C30.16 H4.54 N 8.49 F27.96 Gd 13.61

Fnd: C 30.02 H4.68 N 8.35 F27.81 Gd 13.45

® v@ 1,4,7-Tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-3-ylic)-acid-[N-3 ,6.9,16-tetraoxa- 13-aza-14-0x0-C9-Cas-hepta-decafluoro)-hexacosyl]-amide }-1.4,7,10- tetraazacyclododecane, gadolinium complex (metal complex IX) 11.3 g (21.64 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid, 0.85 g (20 mmol) of lithium chloride and 4.95 g (43 mmol) of N-hydroxysuccinimide are dissolved at 25°C in 150 ml of dimethyl sulfoxide. Itis cooled to 15°C, and 6.19 g (30 mmol) of N.N'- dicyclohexylcarbodiimide is added, and it is stirred for 5 hours at 15°C. To separate the urea, the solution is filtered. 12.5 g (10.82 mmol) of the title compound of Example 6a and 3.29 g (32.47 mmol) of triethylamine are added to the filtrate, and it is stirred for 12 hours at room temperature.

The solution is poured into 1300 ml of diethyl ether/100 ml of acetone, and it is stirred for 30 minutes. The precipitated solid is filtered off and chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 13.01 g (90% of theory)

Water content: 6.7%

Elementary analysis (relative to anhydrous substance):

Cld: C 36.86 H4.30 N 7.34 F24.17 Gd 11.77

Fnd: C36.68 H4.41 N 7.25 F24.03 Gd 11.55

Example 7 1,4,7-Tris(carboxylatomethyl)-10-[(3 -aza-4-oxo-hexan-5-ylic)-acid-N- (1H,1H,2H,2H,4H.4H,5 H,SH-3-oxa-perfluorotridecyl)-amide]-1,4,7,1 O-tetraaza-cyclododecane, : gadolinium complex : g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 3.51 g (17 mmol) of N,N'- dicyclohexylcarbodiimide is added, and it is stirred for 5 hours at 15°C. To separate the urea, the solution is filtered. 8.63 g (15.88 mmol) of the title compound of Example 5b and 5.06 g (50

( ph of triethylamine are added to the filtrate, and it is stirred for 12 hours at room temperature.

The solution is poured into 1500 ml of diethyl ether/100 ml of acetone, and it is stirred for 30 minutes. The precipitated solid is filtered off and chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/ acetonitrile/water).

Yield: 13.86 g (78% of theory) of a colorless, amorphous powder

Water content: 9.3%

Elementary analysis (relative to anhydrous substance):

Cld: C33.28 H3.42 N7.51 F28.87 Gd 14.05

Fnd: C33.12 H3.61 N7.37 F28.69 Gd 13.89

Example 8 a) 2H,2H.4H.4H.5H,5H-3-0xa-perfluorotridecanoic acid-N-(2,3,4,5,6-pentahydroxy)- hexylamide 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-0xa-perfluorotridecanoic acid in 300 ml of dichloromethane, and it is stirred for 12 hours at room temperature. It is evaporated to the dry state in a vacuum. The residue is dissolved in 100 ml of dichloromethane and added in drops at 0°C to a solution that consists of 10.87 g (60 mmol) of glucamine and 6.07 g (60 mmol) of triethylamine, dissolved in 150 ml of dichloromethane/150 dioxane. It is stirred for 3 hours at 0°C, then for 8 hours at room temperature. 400 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred for minutes. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 5:1).

Yield: 30.71 g (78% of theory)

Elementary analysis:

Cld: C31.55 H2.94 N2.04 F47.13

Fnd: C31.44 H3.09 N1.97 F47.01

C ry) N-(2.3,4,5.6-Pentahydroxyhexyl)-N-1H, 1 H.2H.,2H.4H 4H,5H.5H-3-0xa- perfluorotridecyl)-amine 30 g (43.77 mmol) of the title compound of Example 8a is dissolved in 300 ml of tetrahydrofuran, and 50 ml of 10 M boranedimethyl sulfide (in tetrahydrofuran) is added. Itis refluxed for 48 hours. It is cooled to 0°C, and 500 ml of methanol is added in drops, then itis evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 500 ml of ethanol/100 ml of 10% aqueous hydrochloric acid, and it is stirred for 15 hours at 60°C. It is evaporated to the dry state in a vacuum, the residue is taken up in 400 ml of 5% aqueous sodium hydroxide solution and extracted 5 times with 400 ml of chloroform each. The organic phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 3:1).

Yield: 19.69 g (67% of theory) of a colorless solid

Elementary analysis:

Cld: C 32.20 H3.30 N2.09 F48.11

Fnd: C32.05 H3.43 N 1.97 F47.93 c) 1,4,7-Tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-3-ylic)-acid-[N-2,3,5,6- pentahydroxy)-hexyl-N-(1H,1 H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl]-amide } - 1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 15.88 g (15.88 mmol) of the title compound of Example 8b is added. It is stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. Itis stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little

® Mol water, and it is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 16.10 g (79% of theory) of a colorless, amorphous powder

Water content: 6.3%

Elementary analysis (relative to anhydrous substance):

Cld: C36.64 H3.93 N6.55 F25.17 Gd 12.26

Fnd: C3449 H4.13 N 6.48 F25.03 Gd 12.11 . Example 9 a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-(2,2-dimethyl-5-hydroxy-1,3- dioxepan-6-yl)-amide 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-0xa-perfluorotridecanoic acid in 300 ml of dichloromethane, and it is stirred for 12 hours at room temperature. It is evaporated to the dry state in a vacuum. The residue is dissolved in 100 ml of dichloromethane and added in drops at 0°C to a solution that consists of 9.67 g (60 mmol) of 5-amino-2,2-dimethyl-1,3-dioxepan-6-ol and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It is stirred for 3 hours at 0°C, then for hours at room temperature. 300 ml of water is added, and it is thoroughly stirred for 15 minutes. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 15:1).

Yield: 27.62 g (85% of theory)

Elementary analysis:

Cld: C3430 H3.03 N2.11 F48.54

Fnd: C 34.15 H3.19 N2.04 F 48.37

® © b) N-(1-Hydroxymethyl-2.3-dihydroxypropyl)-N-(1H,1 H,2H.2H,4H,4H.5H,5H-3-0xa- perfluorotridecyl)-amine 27 g (40.58 mmol) of the title compound of Example 9a is dissolved in 300 ml of tetrahydrofuran, and 26 ml of 10 M boranedimethyl sulfide (in tetrahydrofuran) is added. It is refluxed for 20 hours. It is cooled to 0°C, and 300 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 300 ml of ethanol/100 ml of 10% aqueous hydrochloric acid, and it is stirred for 6 hours at 60°C. ltis evaporated to the dry state in a vacuum, the residue is taken up in 400 ml of 5% aqueous sodium hydroxide solution, and it is extracted 5 times with 250 ml of chloroform each. The organic phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 6:1).

Yield: 20.09 g (81% of theory) of a colorless solid

Elementary analysis:

Cld: C31.44 H2.97 N2.29 F52.83

Fnd: C 31.26 H3.11 N2.18 F 52.67 c) 1,4,7-Tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N-1 -hydroxymethyl- 2,3-dihydroxypropyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3 -oxa-perfluorotridecyl]-amide} - 1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chioride are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 9.71 g (15.88 mmol) of the title compound of Example 9b is added. It is stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little

C e@ol/water, and it is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 13.40 g (69% of theory) of a colorless, amorphous powder

Water content: 9.1%

Elementary analysis (relative to anhydrous substance):

Cld: C3437 H3.79 N6.87 F 24.41 Gd 12.86

Fnd: C34.18 H3.95 N6.71 F24.25 Gd 12.70

Example 10 a) Perfluorooctylsulfonic acid-N-[(2-benzyloxycarbonylamino)-ethyl]-amide 40 g (173.4 mmol) of 1-benzyloxycarbonylamino-2-aminoethane, hydrochloride, 87.1 g (173.4 mmol) of perfluorooctylsulfofluoride and 35.42 g (350 mmol) of triethylamine are heated for 10 hours to 80°C. It is cooled to room temperature and added directly to a silica gel column for chromatographic purification (mobile solvent: dichloromethane/acetone = 20:1).

Yield: 42.22 g (36% of theory) of a colorless solid

Elementary analysis:

Cld: C31.97 H1.94 N4.14 F47.75 S4.74

Fnd: C31.83 H2.11 N4.03 F47.63 S 4.63 b) Perfluorooctylsulfonic acid-N-[(2-amino)-ethyl]-amide g (44.36 mmol) of the title compound of Example 10a is dissolved in 300 ml of methanol, and 5 g of palladium catalyst (10% Pd/C) is added, and it is hydrogenated overnight at room temperature. Catalyst is filtered off, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 24.05 g (quantitative) of a colorless solid

Elementary analysis:

Cld: C22.15 H1.30 N 5.17 F59.57

Fnd: C22.04 H1.41 N5.05 F 59.62

® ©

Cc) 1,4,7-Tris(carboxylatomethyl)-10-{ (3-aza-4-oxo-hexan-3-ylic)-acid-N-[(2- perfluorooctylsulfonylamino)-ethylj-amide 1-1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide are dissolved at 60°C in 100 ml of dimethy! sulfoxide. It is cooled to 15°C, and 3.51 g (17 mmol) of N,N'- dicyclohexylcarbodiimide is added, and it is stirred for 5 hours at 15°C. To separate the urea, the solution is filtered. 8.61 g (15.88 mmol) of the title compound of Example 10b and 2.0 g (20 mmol) of triethylamine are added to the filtrate, and it is stirred for 12 hours at room temperature.

The solution is poured into 1500 ml of diethyl ether/100 ml of acetone, and it is stirred for 30 minutes. The precipitated solid is filtered off and chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 15.76 g (86% of theory) of a colorless, amorphous powder

Water content: 6.5%

Elementary analysis (relative to anhydrous substance): :

Cld: C 30.19 H3.06 N 8.50 F27.99 Gd 13.63 S2.78

Fnd: C 30.03 H3.18 N 8.41 F 27.81 Gd 13.50 S2.6]

Example 11 a) 2H,2H.4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-(2-benzyloxy-carboxylamino- ethyl}-amide 8.90 g (70 mmol) of oxalyl! chloride is added to 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-o0xa-perfluorotridecanoic acid in 300 ml of dichloromethane, and it is stirred for 12 hours at room temperature. It is evaporated to the dry state in a vacuum. The residue is dissolved in 100 ml of dichloromethane and added in drops at 0°C to a solution that consists of 13.84 g (60 mmol) of 1-benzyloxycarbonylamine-2-amino-ethane, hydrochloride and

Qo @ 2 (120 mmol) of triethylamine. dissolved in 200 ml of dichloromethane. It is stirred for 3 hours at 0°C, then for 5 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred for 13 minutes. The organic phase is separated. dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 20:1).

Yield: 33.30 g (83% of theory) of a colorless solid

Elementary analysis:

Cld: C37.84 H2.74 N4.01 F 46.25

Fnd: C 37.67 H2.89 N3.88 F46.11 b) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-[(2-amino)-ethyl]-amide 30 g (42.96 mmol) of the title compound of Example 11a is dissolved in 500 ml of methanol, and 5 g of palladium catalyst (10% Pd/C) is added, and it is hydrogenated overnight at room temperature. It is filtered off in the catalyst, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 24.24 g (quantitative) of a colorless solid

Elementary analysis:

Cld: C29.80 H2.32 N4.96 F 57.24

Fond: C29.67 H2.41 N4.88 F57.15 c) 1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-ox0-hexan-5-ylic)-acid-N-[3-aza-6-oxa-4- ox0-(Cy-C1¢-heptadecafluoro)-hexadecyl]-amide}-1,4,7,10-tetraazacyclododecane- gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1.4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, 3.51 g (17 mmol) of N,N'-dicyclohexylcarbodiimide is added, and it is stirred for 5 hours at 15°C. To separate the urea, the solution is filtered. 8.96 g

¢o @s mmol) of the title compound of Example 11b and 2.02 g (20 mmol) of triethylamine are added to the filtrate and stirred for 12 hours at room temperature. The solution is poured into 1500 ml of diethyl ether/100 ml of acetone, and it is stirred for 30 minutes. The precipitated solid is filtered off and chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 15.31 g (82% of theory) of a colorless, amorphous powder

Water content: 6.3%

Elementary analysis (relative to anhydrous substance):

Cld: C33.71 H3.51 N8.34 F27.46 Gd 13.37

Fnd: C 33.61 H3.63 N8.17 F27.31 Gd 13.20

Example 12 a) '2H,2H,4H.4H,5H,5H-3-Oxa-perfluoroundecanoic acid-N-[(2-hydroxy)-ethyl]-amide 8.90 g (70 mmol) of oxalyl chloride is added to 24.25 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, and it is stirred for 12 hours at room temperature. It is evaporated to the dry state in a vacuum. The residue is dissolved in 100 ml of dichloromethane and added in drops at 0°C to a solution that consists of 3.66 g (60 mmol) of ethanolamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It is stirred for 3 hours at 0°C, then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred for minutes. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 20:1).

Yield: 24.86 g (93% of theory) of a colorless solid

Elementary analysis:

Cld: C 30.98 H2.60 N3.01 F 53.09

Fnd: C 30.71 H2.81 N2.87 F 52.82

® @ N-(2-Hydroxyethyl)-N-1H.1 H.2H.2H,4H.4H,5H.5H-3-oxa-perfluoroundecyl)-amine 24 g (51.59 mmol) of the title compound of Example 12a is dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M boranedimethy! sulfide (in tetrahydrofuran) is added. Itis refluxed for 12 hours. It is cooled to 0°C, and 200 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is stirred for 8 hours at 40°C. Itis evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous sodium hydroxide solution, and it is extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/2-propanol = 20:1).

Yield: 20.95 g (90% of theory) of a colorless solid

Elementary analysis:

Cld: C31.94 H3.13 N3.10 F 54.73

Fnd: C 31.71 H3.31 N3.01 F 54.58 c) 1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-N-[(2-hydroxy)- ethyl-N-(1H,1H,2H,2H,4H,4H,5 H,5H-30xa)-perfluoroundecyl]-amide}-1,4,7,10- tetraazacyclododecane-gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoy!)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 8.98 ¢ (15.88 mmol) of the title compound of Example 12b is added. It is stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little ethanol/water, and it is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

@ ® Yield: 14.01 g (83% of theory) of a colorless, amorphous powder

Elementary analysis:

Cld: C35.03 H3.98 N7.91 F 23.24 Gd 14.79

Fnd: C 34.85 H4.19 N7.75 F 23.05 Gd 14.58

Example 13 a) 2H,2H,4H,4H,5H.5H-3-Oxa-perfluoroundecanoic acid-N-(3,6,9,12-tetraoxa-tridecyl)- amide 8.90 g (70 mmol) of oxalyl chloride is added to 24.25 g (57.45 mmol) of 2H, 2H,4H,4H,5H,5H-3-oxa-perfluoroundecanoic acid in 300 ml of dichloromethane, and it is stirred for 12 hours at room temperature. It is evaporated to the dry state in a vacuum. The residue is dissolved in 100 ml of dichloromethane and added in drops at 0°C to a solution that consists of 12.44 g (60 mmol) of 3,6,9,12-tetraoxa-tridecylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It is stirred for 3 hours at 0°C, then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid is added, and itis thoroughly stirred for 15 minutes. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 15:1).

Yield: 31.61 g (90% of theory) of a colorless solid

Elementary analysis:

Cld: C37.33 H4.29 N2.29 F40.40

Fnd: C37.15 H4.41 N2.12 F40.18 b) N-(3,6.,9,12-Tetraoxatridecyl)-N-(1H,1H,2H,2H,4H .4H.5H,5H-3 -oxa-perfluoroundecyl)- amine 31 g (50.7 mmol) of the title compound of Example 13a is dissolved in 300 ml of tetrahydrofuran, and 32 ml of 10 M boranedimethyl sulfide (in tetrahydrofuran) is added. Itis refluxed for 16 hours. It is cooled to 0°C. and 200 ml of methanol is added in drops, then it is

. ~ 2200371949 @ @orated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is stirred for 8 hours at 40°C. Itis evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous sodium hydroxide solution, and it is extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/2-propanol = 20:1).

Yield: 28.17 g (93% of theory) of a colorless solid

Elementary analysis (relative to anhydrous substance):

Cld: C38.20 H4.72 N2.34 F41.34

Fnd: C 38.05 H4.83 N2.40 F41.50 c) 1,4.7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-N-[(3,6,9,12- tetraoxa)-tridecyl-N-(1H, 1H,2H,2H,4H,4H,5H,5H-3 0xa)-perfluoroundecyl]-amide } - 1,4,7,10-tetraazacyclododecane-gadolinium complex : g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 9.49 g (15.88 mmol) of the title compound of Example 13b is added. It is stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little ethanol/water, and it is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water). :

Yield: 16.13 g (84% of theory)

Elementary analysis:

Cld: C37.75 H4.67 N 6.95 F 20.43 Gd 13.01

Fnd: C3791 H4.81 N 6.83 F 20.60 Gd 13.15 eo ©

Example 14 a) 2-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecyl)-amino-acetic acid-t-buty] ester 6.523 g (40 mmol) of bromoacetic acid-t-butyl ester is added in drops at 50°C to 32.0 g (58.65 mmol) of the title compound of Example 5b and 24.89 g (180 mmol) of potassium carbonate in 300 ml of acetonitrile, and it is stirred for 3 hours at this temperature. 300 ml of dichloromethane is added, precipitated salts are filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/2-propanol = 20:1).

Yield: 28.11 g (57% of theory) of a colorless solid

Elementary analysis:

Cld: C34.80 H3.24 N2.25 F51.98

Fnd: C34.98 H3.31 N2.20 F52.16 b) 1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-N- [(t.butyloxycarbonylmethyl)-N-(1H,1H,2H,2H,4H,4H,5H.5H-3 oxa)-perfluorotridecyl]- amide}-1,4,7,10-tetraazacyclododecane-gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 9.87 g (15.88 mmol) of the title compound of Example 14a is added. It is stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little ethanol/water, and it is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

@ © ii 166::(85% of theory)

Elementary analysis:

Cld: C36.04 H3.92 N6.82 F26.19 Gd 12.72

Fnd: C35.92 H3.83 N6.91 F26.29 Gd 12.84 c) 1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-N-[(carboxymethyl)-

N-(1H,1H,2H,2H,4H,4H,5H,5H-30xa)-perfluorotridecyl]-amide}-1,4,7,10- tetraazacyclododecane-gadolinium complex g (8.11 mmol) of the title compound of Example 14b is dissolved in 50 ml of trifluoroacetic acid, and it is stirred for 5 hours at room temperature. It is evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel RP-18 (mobile solvent: - gradient that consists of tetrahydrofuran/acetonitrile/water). After the product-containing fractions are concentrated by evaporation, the residue is dissolved in water and set at pH 7.2 with 5% aqueous sodium hydroxide solution. The solution is filtered, and the filtrate is freeze-dried.

Yield: 10.48 g (91% of theory)

Elementary analysis (relative to anhydrous substance):

Cld: C33.06 H3.28 N7.01 F26.94 Gd 13.12 Na 1.92

Fnd: C 33.19 H3.40 N720 F27.14 Gd 13.25 Na 2.00

Example 15 a) 2H ,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-(2-hydroxyethyl)-amide 2.96 g (74 mmol) of sodium hydride (that consists of 60% sodium hydride in paraffin oil) in 300 ml of tetrahydrofuran is added to 32 g (56.61 mmol) of the title compound of Example 4a, and it is stirred for 3 hours at room temperature under nitrogen. 7.67 g (74 mmol) of bromoacetic acid-t.butylester, dissolved in 20 ml of tetrahydrofuran, is added in drops, and it 1s stirred for 5 hours at 50°C. 50 ml of methanol is added, and it is evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane(/2- propanol = 20:1). :

Yield: 23.46 g (61% of theory)

C ® Elementary analysis:

Cld: C3536 H3.26 N2.06 F47.54

Fnd: C 35.52 H3.40 N2.17 F 47.40 b) N-(1H,1 H,2H,2H.4H.4H,5H,5H-3-Oxa-perfluorotridecyl)-N-[4-t.butyloxycarbonyl-3- oxa)-butyl]-amine 35.0 g (51.52 mmol) of the title compound of Example 15a is dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M boranedimethyl sulfide (in tetrahydrofuran) is added. It is refluxed for 16 hours. It is cooled to 0°C, and 200 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is stirred for 8 hours at 40°C. Itis evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous sodium hydroxide solution, and it is extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/2-propanol = 20:1).

Yield: 31.88 ¢g (93% of theory)

Elementary analysis:

Cld: C36.10 H3.64 N2.11 F 48.54

Fnd: C3590 H3.75 N 2.20 F 48.71 c) 1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-N-[(4- t.butyloxycarbonyl-3-oxa)-butyl)-N-( 1H,1H,2H,2H,4H,4H,5H,5H-30xa)- perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 10.57 g (15.88 mmol) of the title compound of Example 15b is added. It is stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is stirred

[ 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little ethanol/water, and it is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 16.63 g (82% of theory)

Elementary analysis:

Cld: C 36.68 H4.10 N 6.58 F 25.29 Gd 12.31

Fnd: C 36.81 H4.20 N 6.41 F25.40 Gd 12.19 d) 1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N-(4-carboxy-3- oxa)-butyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-30xa)-perfluorotridecyl]-amide } -1,4,7,10- tetraazacyclododecane, gadolinium complex 12 g (9.40 mmol) of the title compound of Example 15c¢ is dissolved in 50 ml of trifluoroacetic acid, and it is stirred for 5 hours at room temperature. It is evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water). After the product-containing fractions are concentrated by evaporation, the residue is dissolved in water and set at pH 7.2 with 5% aqueous sodium hydroxide solution. The solution is filtered, and the filtrate is freeze-dried.

Yield: 11.41 g (92% of theory)

Water content: 5.8%

Elementary analysis (relative to anhydrous substance):

Cld: C33.82 H3.49 N6.76 F25.98 Gd 12.65 Na 1.85

Fnd: C 33.95 H3.60 N 6.88 F 26.15 Gd 12.49 Na 1.93

@® ui a) 2H.2H.4H,4H,5H.5H-3-Oxa-perfluorotridecanoic acid-N-(2H,2H.4H,4H,5H,5H-3-o0xa- perfluorotridecyl)-amide 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45 mmol) of 2H,2H.4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 m! of dichloromethane, and it is stirred for 12 hours at room temperature. It is evaporated to the dry state in a vacuum. The residue is dissolved in 100 ml of dichloromethane, and it is added in drops at 0°C to a solution that consists of 32.62 g (60 mmol) of the title compound of Example 5b and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It is stirred for 3 hours at 0°C, then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred for 15 minutes. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 15:1).

Yield: 52.87 g (91% of theory)

Elementary analysis:

Cld: C28.50 H1.49 N 1.38 F 63.87

Fnd: C 28.65 H 1.61 N 1.50 F 64.01 b) N-Bis-(1H,1H,2H,2H,4H.4H,5H,5H-3-oxa)-perfluorotridecyl)-amine 52 g (51.42 mmol) of the title compound of Example 16a is dissolved in 500 ml of tetrahydrofuran, and 31 ml of 10 M boranedimethyl sulfide (in tetrahydrofuran) is added. It is refluxed for 16 hours. It is cooled to 0°C, and 200 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 400 ml of ethanol/70 ml of 10% aqueous hydrochloric acid, and it is stirred for 8 hours at 40°C. It is evaporated to the dry state in a vacuum, the residue is taken up in 400 ml of 5% aqueous sodium hydroxide solution and extracted 3 times with 400 ml of dichloromethane each. The organic phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/2-propanol = 20:1).

g8 @ ® Yield: 47.18 g (92% of theory) of a colorless solid

Elementary analysis:

Cld: C28.90 H1.72 N 1.40 F 64.77

Fnd: C30.03 H1.81 N1.55 F 65.00 c) 1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-bis- (1H,1H,2H,2H,4H,4H,5H,5H-3-o0xa-perfluorotridecyl)-amide]-1,4,7,10- tetraazacyclododecane, gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetrazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 15.84 g (15.88 mmol) of the title compound of Example 16b is added. It is stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little ethanol/water, and it is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 20.95 g (82% of theory)

Elementary analysis:

Cld: C32.10 H2.82 N5.22 F 40.14 Gd 9.77

Fnd: C29.87 H2.91 N5.09 F 40.28 Gd 9.98

Example 17 a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-(5-hydroxy-3-oxa-pentyl)- amide 2.80 g (70 mmol) of sodium hydride (that consists of 60% sodium hydride in paraffin oil) in 300 ml of tetrahydrofuran is added to 32 g (52.52 mmol) of the title compound of Example 3a,

5s . Ra00371949

Qo 2 is stirred for 3 hours at room temperature under nitrogen. 9.68 g (70 mmol) of bromoacetic acid-t.butyl ester, dissolved in 20 ml of tetrahydrofuran, is added in drops, and it is stirred for 5 hours at 50°C. 50 ml of methanol is added, and it is evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane(/2- propanol = 20:1).

Yield: 19.31 g (59% of theory)

Elementary analysis:

Cld: C32.76 H291 N2.25 F51.82

Fnd: C 32.98 H2.99 N2.36 F 51.98 b) ~~ N-(3,6-Dioxa-heptyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amine 32 g (51.34 mmol) of the title compound of Example 17a is dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M boranedimethy! sulfide (in tetrahydrofuran) is added. It is refluxed for 16 hours. It is cooled to 0°C, and 200 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 300 ml! of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is stirred for 8 hours at 40°C. ltis evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous sodium hydroxide solution, and it is extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/2-propanol = 20:1).

Yield: 28.47 g (91% of theory)

Elementary analysis:

Cld: C 33.51 H3.31 N2.30 F 55.01

Fnd: C 33.63 H3.41 N221 F52.87

® @ 1.4,7-Tris(carboxylatomethyl)-1 0-[(3-aza-4-oxo-hexan-35-ylic)-acid-N-(3,6-dioxa)-heptvl-

N-(1H.1H,2H,2H,4H 4H.5H.5 H-3-oxa-perfluorotridecyl)-amide]-1,4,7,10- tetraazacyclododecane, gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C. and 9.68 ¢ (15.88 mmol) of the title compound of Example 17b is added. Itis stirred for 10 minutes and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little ethanol/water, and it is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 16.09 g (83% of theory)

Elementary analysis:

Cld: C3541 H3.96 N6.88 F 26.45 Gd 12.88

Fnd: C3557 H4.11 N6.72 F 26.58 Gd 12.97

Example 18 a) 2H,2H,4H,4H,5H,5H-3-0Oxa-perfluorotridecanoic acid-N-(hexyl)-amide 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-0xa-perfluorotridecanoic acid in 300 ml of dichloromethane, and it is stirred for 12 hours at room temperature. It is evaporated to the dry state in a vacuum. The residue is dissolved in 100 ml of dichloromethane and added in drops at 0°C to a solution that consists of 6.07 g (60 mmol) of nhexylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It is stirred for 3 hours at 0°C, then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred for 15 minutes.

The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a

® gpm The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 20:1).

Yield: 30.95 g (89% of theory)

Elementary analysis:

Cld: C3572 H3.33 N2.31 F33.35

Fnd: C 35.60 H3435 N2.43 F53.65 b) N-(Hexyl)-N-(1H. 1H.2H,2H.4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amine 31 g (51.21 mmol) of the title compound of Example 18a is dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M boranedimethyl sulfide (in tetrahydrofuran) is added. It is refluxed for 16 hours. It is cooled to 0°C, and 200 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid. and it is stirred for 8 hours at 40°C. tis evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous sodium hydroxide solution, and it is extracted 3 times with 300 ml of dichloromethane each. The organic phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/2-propanol = 20:1).

Yield: 28.16 g (93% of theory)

Elementary analysis:

Cld: C36.56 H3.75 N 2.37 F 54.62

Fnd: C 36.40 H 3.82 N2.27 F 54.81 c) 1,4,7-Tris(carboxylatomethyl)-10- {(3-aza-4-0x0-hexan-5-ylic)-acid-[N-(hexyl)-N- (1H,1 H.2H.2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl]-amide}-1,4,7,1 0- tetraazacyclododecane, gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1.4,7.10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 10.98 ¢ o gC 2 mmol) of the title compound of Example 18b is added. It is stirred for 10 minutes. and then 7.42 g (50 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml] of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little ethanol/water, and it is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 16.29 g (84% of theory)

Elementary analysis:

Cld: C 36.94 H4.19 N6.99 F 26.85 Gd 13.07

Fnd: C 37.18 H4.31 N7.18 F 26.67 Gd 13.19

F X ample 19 a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-[(10-t.butyloxycarbonyl)- decyl]-amide 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-0xa-perfluorotridecanoic acid in 300 ml of dichloromethane, and it is stirred for 12 hours at room temperature. It is evaporated to the dry state in a vacuum. The residue is dissolved in 100 ml of dichloromethane, and it is added in drops at 0°C to a solution that consists of 15.45 g (60 mmol) of 11-amino-undecanoic acid-t.butylester and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It is stirred for 3 hours at 0°C, then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred for 15 minutes. The organic phase is separated, dried on magnesium sulfate - and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 20:1).

Yield: 42.04 g (92% of theory)

Elementary analysis:

Cld: C42.58 H4.76 N 1.84 F 42.41

C C Fnd: C 42.74 H4.90 N 1.73 F 42.61 b) N-(10-t.Butyloxycarbonyl-decyl)-N-(1H,1 H,2H.2H,4H,4H,5H,5H-3-oxa- perfluorotridecyl)-amine 39 g (51.21 mmol) of the title compound of Example 19a is dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M boranedimethyl sulfide (in tetrahydrofuran) is added. Itis refluxed for 16 hours. It is cooled to 0°C, and 200 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 400 ml of ethanol/70 ml of 10% aqueous hydrochloric acid, and it is stirred for 8 hours at 40°C. Itis evaporated to the dry state in a vacuum, the residue is taken up in 350 ml of 5% aqueous sodium hydroxide solution, and it is extracted 3 times with 400 ml of dichloromethane each. The organic phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/2-propanol = 20:1).

Yield: 34.84 g (91% of theory)

Elementary analysis:

Cld: C43.38 H5.12 N1.87 F43.20

Fnd: C43.22 H5.23 N 1.96 F43.33 ¢) 1,4,7-Tris(carboxylatomethyl)-10-{ (3-aza-4-oxo-hexan-5-ylic)-acid-[N-(10- t.butyloxycarbonyl)-decyl-N-(1H,1 H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl}- amide} -1,4,7,10-tetraazacyclododecane, gadolinium complex : 10 g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved at 60°C in 100 ml of dimethyl! sulfoxide. It is cooled to 15°C, and 11.87 g (15.88 mmol) of the title compound of Example 19b is added. It is stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The

( ipsited precipitate is filtered off, it is dissolved in a mixture that consists of a little ethanol/water, and it is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 17.92 g (83% of theory)

Elementary analysis:

Cld: C 40.65 H4.89 N6.18 F23.76 Gd 11.57

Fnd: C 40.81 H4.99 N 6.32 F23.94 Gd 11.75 d) 1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N-(1 0-carboxy)- decyl-N-(1H,1 H.2H,2H 4H ,4H,5H,5H-30xa)-perfluorotridecyl]-amide +-1,4,7,10- tetraazacyclododecane, gadolinium complex, sodium salt 12 g (8.83 mmol) of the title compound of Example 19¢ is dissolved in 50 ml of trifluoroacetic acid, and it is stirred for 5 hours at room temperature. It is evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water). After the product-containing : fractions are concentrated by evaporation, the residue is dissolved in water and set at pH 7.2 with 5% aqueous sodium hydroxide solution. The solution is filtered, and the filtrate is freeze-dried.

Yield: 12.48 g (92% of theory)

Water content: 6.2%

Elementary analysis (relative to anhydrous substance):

Cld: C 38.07 H4.34 N6.34 F24.37 Gd 11.87 Na 1.73

Fnd: C 37.890 H4.44 N 622 F24.51 Gd 12.01 Nal1.80

Example 20 a) 15-Benzyl-3,6,9,12,15-pentaoxa-hexadecylic acid-N-(1H,1 H.2H,2H,4H.4H,5H,5H- 3oxa)-perfluorotridecyl)-amide 8.90 g (70 mmol) of oxalyl chloride is added to 19.67 g (57.45 mmol) of 15-benzyl- 3,6,9,12,15-pentaoxahexadecylic acid in 250 ml of dichloromethane, and it is stirred for 12 hours

( apm temperature. It is evaporated to the dry state in a vacuum. The residue is dissolved in 100 ml of dichloromethane and added in drops at 0°C to a solution that consists of 32.62 g (60 mmol) of 1H,1H,2H,2H,4H,4H,5H,5H-3-o0xa-perfluoro-tridecylamine, hydrochloride and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It is stirred for 3 hours at 0°C, then for 6 hours at room temperature. 300 ml of 3% aqueous hydrochloric acid is added, and it is thoroughly stirred for 15 minutes. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 20:1).

Yield: 44.91 g (94% of theory) of a colorless solid

Elementary analysis:

Cld: C 41.89 H4.12 N 1.68 F 38.84.

Fnd: C 42.02 H425 N 1.83 F 39.07 : b) N-15-Benzyl-3,6,9,12, 15-pentaoxa-hexadecyl)-N-(1 H,1H,2H,2H,4H,4H,5H,5H-30xa)- perfluorotridecyl)-amine 43 g (51.72 mmol) of the title compound of Example 20a) is dissolved in 400 ml of tetrahydrofuran, and 31 ml of 10 M boranedimethy! sulfide (in tetrahydrofuran) is added. It is refluxed for 16 hours. It is cooled to 0°C, and 200 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 400 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is stirred for 8 hours at 40°C. It is evaporated to the dry state in a vacuum, the residue is taken up in 350 ml of 5% aqueous sodium hydroxide solution, and it is extracted 3 times with 400 mi of dichloromethane each. The organic phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/2-propanol = 20:1).

Yield: 39.32 g (93% of theory)

Elementary analysis:

Cld: C42.60 H4.12 N 1.68 F 38.84

Fnd: C 42.45 H4.23 N 1.57 F 38.99

© c) 1.4,7-Tris-(carboxylatomethyl)-10- {( 3-aza-4-oxo-hexan-5-ylic)-acid-[N-(15-benzyl- 3,6,9,12,15-pentaoxa)-hexadecyl-N-(1H, 1 H,2H.2H,4H,4H,5H,5H-3-0xa)-tridecyl]- amide }-1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-1 -(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 12.98 ¢ (15.88 mmol) of the title compound of Example 20b) is added. It is stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1 .2-dihydroquinoline is added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little ethanol/water, and it is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 18.84 g (83% of theory)

Elementary analysis:

Cld: C 40.34 H4.51 N5.88 F22.60 Gd 11.00

Fnd: C 40.50 H4.62 N 5.76 F22.73 Gd 11.16 od 1,4,7-Tris-(carboxylatomethyl)-1 0-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N~(1 4-hydroxy- 3,6,9,12-tetraoxa)-tetradecyl-N-(1H,1 H,2H,2H,4H,4H,5H,5 H-3-oxa)-perfluorotridecyl]- amide}-1,4,7,1 0-tetraazacyclododecane, gadolinium complex 12 g (8.40 mmol) of the title compound of Example 20c is dissolved in 150 ml of methanol, and 1.0 g of palladium catalyst (10% Pd/C) is added, and it is hydrogenated overnight at room temperature. It is filtered off in the catalyst, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 10.13 g (95% of theory)

Elementary analysis:

® ® Cid: C 38.80 H4.61 N1.10 F2545 Gd 12.59

Fnd: C 38.87 H4.73 N 1.20 F 25.58 Gd 12.50

Example 21 a) 2-N-Trifluoroacetyl-6-N-benzyloxycarbonyl-L-lysine 100.0 g (356.7 mmol) of 6-N-benzyloxycarbonyl-L-lysine is dissolved in a mixture that consists of 1000 ml of trifluoroacetic acid ethyl ester and 500 ml of ethanol, and it is stirred for 24 hours at room temperature. It is evaporated to the dry state, and the residue is crystallized from diisopropyl! ether.

Yield: 128.9 g (96% of theory) of a colorless, crystalline powder.

Melting point: 98.5°C. :

Elementary analysis:

Cld: C51.07 H5.09 N 7.44 F 15.14

Fnd: C 51.25 H5.18 N 7.58 F15.03 b) 2-N-Trifluoroacetyl-6-N-benzyloxycarbonyl-L-lysine [1 -(4-perfluorooctylsulfonyl)- piperazine]-amide 164.2 g (0.664 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1 -carboxylic acid ethyl ester) is added at 0°C to 125.0 g (332.0 mmol) of the title compound of Example 21a) and 188.7 g (332.0 mmol) of 1-perfluorooctylsulfonylpiperazine (produced according to DE 19603033) in 750 ml of tetrahydrofuran, and it is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum, and it is chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

Yield: 286.0 g (93% of theory) of a colorless solid.

Melting point: 92°C.

Elementary analysis:

Cld: C 36.30 H2.83 N 6.05 F41.01 S3.46

Fnd: C 36.18 H2.94 N 598 F40.87 S340 os . B2003/1949 ® c g 6-N-Benzyloxycarbonyl-L-lysine-[1 -(4-perfluorooctylsulfonyl)-piperazine]-amide

Ammonia gas is introduced at 0°C for one hour into a solution that consists of 280.0 g (302.2 mol) of the title compound of Example 21b) in 2000 m! of ethanol. It then is stirred for 4 hours at 0°C. It is evaporated to the dry state, and the residue is absorptively precipitated from water. The solid is filtered off and dried in a vacuum at 50°C.

Yield: 243.5 g (97% of theory) of an amorphous solid.

Elementary analysis:

Cld: C 37.60 H3.28 N6.75 F 38.89 53.86

Fnd: C 37.55 H3.33 N 6.68 F 38.78 S3.81 d) 6-N-Benzyloxycarbonyl-2-N-[1 -0-a-D-carbonylmethyl-(2,3,4,6-tetra-O-benzy!- mannopyranose}-L-lysine-[1 -(4-perfluorooctylsulfonyl)-piperazine]-amide 41.27 g (200.0 mmol) of N,N-dicyclohexylcarbodiimide is added at 0°C to a solution that consists of 100.0 g (120.4 mol) of the title compound of Example 21¢), 72.1 g (120.4 mol) of 1-

O-a-D-carboxymethyl-2,3,4,6-tetra-O-benzyl-mannopyranose and 13.86 g (120.4 mol) of N- hydroxysuccinimide, dissolved in 500 ml of dimethylformamide. It is stirred for 3 hours at 0°C and then overnight at room temperature. Precipitated urea is filtered out, the filtrate 1s evaporated to the dry state in a vacuum and chromatographed on silica gel. (Mobile solvent: dichloromethane/ethanol = 20:1).

Yield: 136.1 g (87% of theory) of a viscous oil.

Elementary analysis:

Cld: C 57.32 H4.89 N4.31 F24.86 S247

Fnd: C 57.38 H5.07 N422 F24.78 S2.39 e) 2-N-[1 -0-a-D-Carbonylmethyl-mannopyranose]-L-lysine-1 -[(4-perfluorooctylsulfonyl)- piperazine]-amide : 130.0 g (100.0 mmol) of the title compound of Example 21d) is dissolved in 2000 ml of

® ‘@°" and 10.0 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated for 12 hours at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state ina vacuum.

Yield: 91.7 g (quantitative) of a colorless solid.

Elementary analysis:

Cld: C 34.07 H3.63 N6.11 S3.50 F35.24

Fnd: C 33.91 H3.72 N 6.04 S3.40 F 35.31 f) 6-N-[1,4,7-Tris(carboxylatomethyl)}-1,4,7,1 0-tetraazacyclododecane-10-N-(pentanoyl-3- aza-4-oxo-5-methyl-5-y1)]-2-N-[1 -0-a-D-carbonylmethyl-mannopyranose]-L-lysine-[1- (4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex (metal complex XV) 50.0 g (54.55 mmol) of the title compound of Example 21e), 6.28 g (54.55 mmol) of N- hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54.55 mol) of 1,4,7- tris(carboxylatomethyl)-1 0-(carboxy-3-aza-4-oxo-5-methyl-pent-5-yl)-1,4,7,10- tetraazacyclododecane, Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 16.88 g (81.8 mol) of N,N-dicyclohexylcarbodiimide is added, and it is then stirred overnight at room temperature. The solution is poured into 3000 ml of acetone, and it is stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (LP-18 mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 75.9 g (91.0% of theory) of a colorless solid.

Water content: 8.6%.

Elementary analysis (relative to anhydrous substance):

Cld: C 35.34 H4.09 N8.24 S2.10 F21.12 Gd 10.28

Fnd: C3528 H4.15 N 8.19 S2.15 F21.03 Gd 10.14

® Oo: a) 6-N-[1 .4.7-Tris(carboxylatomethyl]-1,4.7.1 0-tetraazacvclododecane-10-N-(pentanoyl-3- aza-4-oxo-3-methyl-5-y1)]-2-N-[1 -O-a-D-carbonylmethyl-mannopyranose]-L-lysine-[1- (4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex : 50.0 g (54.55 mmol) of the title compound of Example 21e), 6.28 g (54.55 mmol) of N- hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54.55 mol) of 1,4,7- tris(carboxylatomethyl)-1 0-(carboxy-3-aza-4-0xo-3-methyl-pent-5-yl)-1 4,7,10- tetraazacyclododecane, Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 16.88 g (81.8 mmol) of N,N-dicyclohexylcarbodiimide is added, and it then is stirred overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off, and then it is purified by chromatography (RP-18 mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 76.0 g (92.0% of theory) of a colorless solid.

Water content: 6.88%.

Elementary analysis (relative to anhydrous substance):

Cld: C 34.90 H3.93 N 832 $2.12 F21.33 Gd 10.38

Fnd: C 34.81 H4.02 N827 S2.09 F21.22 Gd 10.19

Example 23 a) 2-[4-3-Oxapropionic acid ethyl ester]-phenylacetic acid methyl ester 233.8 g (1400.0 mmol) of 2-bromoacetic acid ethyl ester is added to 200.0 g (1204.0 mmol) of 4-hydroxyphenylacetic acid methyl ester and 212.0 g (2000.0 mmol) of sodium carbonate in 2000 ml of acetone, and it is refluxed for 5 hours. The solid is filtered off and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel. (Mobile solvent: n-hexane/ethyl acetate = 15:1).

Yield: 288.5 g (95.0% of theory) of a colorless oil.

Elementary analysis:

Cld: C 61.90 H6.39

® ® Fnd: C61.75 H6.51 b) 2-{4-3-Oxapropionic acid ethyl ester)]-phenyl-2-bromoacetic acid methyl ester 201.0 g (1130.0 mmol) of N-bromosuccinimide and 100.0 mg of dibenzoyl peroxide are added to 285.0 g (1130.0 mmol) of the title compound of Example 23a), dissolved in 2000 ml of carbon tetrachloride, and it is refluxed for eight hours. It is cooled in an ice bath, the precipitated succinimide is filtered off, and the filtrate is evaporated to the dry state in a vacuum. The residue is purified on silica gel (mobile solvent: n-hexane/acetone = 15:1).

Yield: 359.2 g (96.0% of theory) of a colorless, viscous oil.

Elementary analysis:

Cld: C 47.28 H4.57 Br24.16

Fnd: C 47.19 H4.71 Br 24.05 c) 2-[4-(3-Oxapropionic acid ethyl ester)]-phenyl-2-[1-(1,4,7,10-tetraazacyclododecan-1 -yl]- acetic acid methyl ester 350.0 g (1057.0 mmol) of the title compound of Example 23b) is added 0 603.0 g (3500.0 mmol) of 1,4.7,10-tetraazacyclododecane, in 6000 ml of chloroform, and it is stirred overnight at room temperature. It is extracted 3 times with 3000 ml of water in each case, the organic phase is dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is used without further purification in the next reaction (Example 23d).

Yield: 448.0 g (quantitative) of a viscous oil.

Elementary analysis:

Cld: €59.70 H8.11 N 13.26

Fnd: C 59.58 H8.20 N 13.18 d) 2-[4-(3-Oxapropionic acid)]-phenyl-2-[1 .4,7-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecan-10-yl]-acetic acid 445.0 g (1053.0 mmol) of the title compound of Example 23c¢) and 496.0 g (5270.0

( y B of chloroacetic acid are dissolved in 4000 ml of water. It is set at a pH of 10 with 30% aqueous sodium hydroxide solution, and it is stirred for 8 hours at 70°C. Then, the pH of the reaction solution is set at 13 by mixing with 30% aqueous sodium hydroxide solution, and it is refluxed for 30 minutes. The solution is cooled in an ice bath and set ata pH of 1 by adding concentrated hydrochloric acid. It is evaporated to the dry state in a vacuum. The residue is taken up in 4000 ml of methanol and absorptively precipitated for one hour at room temperature.

Precipitated common salt is filtered out, the filtrate is evaporated to the dry state, and the residue is purified on RP-18 C (mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 403.0 g (69.0% of theory) of a colorless solid.

Water content: 10.2%

Elementary analysis (relative to anhydrous substance):

Cld: C51.98 H6.18 N 10.10

Fnd: C 51.80 H6.31 N 10.01 e) 2-[4-(3-Oxapropionic acid)]-phenyl-2-[1 ,4.7-tris(carboxylatomethyl)-1,4,7,10- tetraazacyclododecan-10-yl]-acetic acid, Gd complex 130.73 g (360.65 mmol) of gadolinium oxide is added to 400 g (721.3 mmol) of the title compound of Example 23d) in 2000 ml of water, and it is stirred for 5 hours at 80°C. The solution is filtered, and the filtrate is freeze-dried.

Yield: 511 g (quantitative) of an amorphous solid.

Water content: 11.0%.

Elementary analysis (relative to anhydrous substance):

Cld: C 40.67 H4.41 N7.98 Gd 22.19

Fnd: C4051 H4.52 N8.03 Gd 22.05

® '@® 6-N-[2-[4-(3-Oxapropionyl)-phenyl]-2-[1,4,7-tris(carboxylatomethyl)-1.4. 7,10- tetraazacyclododecan-10-vl]-acetic acid)]-2-N-(1-O-a-D-carbonylmethyl- mannopyranose)-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex, sodium salt 50.0 g (54.55 mmol) of the title compound of Example 21e), 6.28 g (54.55 mmol) of N- hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 38.66 g (54.55 mmol) of the title compound of Example 23e) are dissolved in 400 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 16.88 g (81.8 mmol) of N,N-dicyclohexylcarbodiimide is added, and it is then stirred overnight at room temperature. The solution is poured into 3000 ml! of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18; mobile solvent: gradient that consists of water/ethanol/acetonitrile). The product that is obtained is dissolved in a little water, and the pH of the solution is set at 7.4 with aqueous sodium hydroxide solution. Then, the product solution is freeze-dried.

Yield: 79.1 g (89% of theory) of a colorless solid.

Water content: 10.3%.

Elementary analysis (relative to anhydrous substance):

Cld: C 36.86 H3.77 N6.88 S 1.97 F 19.82 Gd 9.65

Fnd: C 36.75 H3.8 N6.80 S2.03 F19.75 Gd 9.57

Example 24 a) 6-N-[1,4,7-Tris(t butyloxycarbonylmethyl)-10-carboxymethyl-1 ,4,7,10- tetraazacyclododecane-10-carbonylmethyl]-2-N-(1 -O-a-D-carbonylmethyl- mannopyranose)-L-lysine-[1 -(4-perfluorooctylsulfonyl)-piperazine]-amide 15.0 g (26.19 mmol) of 1,4,7-tris(t-butyloxycarbonylmethyl)-1 0-carboxymethyl-1,4,7,10- tetraazacyclododecane, 24.0 g (26.19 mmol) of the title compound of Example 21e), and 3.01 g (26.19 mmol) of N-hydroxysuccinimide are dissolved in 150 ml of dimethylformamide, and 8.25 g (40.0 mmol) of N,N-dicyclohexylcarbodiimide is added at 0°C. Itis stirred overnight at room temperature. The precipitated urea is filtered off, and the filtrate is evaporated to the dry state in

C 2 A The residue is chromatographed on silica gel. (Mobile solvent: dichloromethane/ methanol = 20:1).

Yield: 35.45 g (92.0% of theory) of a colorless solid.

Elementary analysis:

Cld: C 44.08 H5.69 N7.62 F2195 S2.18

Fnd: C 44.01 H5.81 N7.53 F21.87 S2.05 b) 6-N-[1,4,7-Tris(carboxylatomethyl]-1,4,7.1 0-tetraazacyclododecane-1 0-carbonyl- methyl-]-2-N-[1 -0-0-D-carbonylmethyl-mannopyranose]-L-lysine-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide, Gd complex 30.0 g (20.39 mmol) of the title compound of Example 24a) is dissolved in 50 ml of chloroform, and 300 ml of trifluoroacetic acid is added. It is stirred for 10 minutes at room temperature. It is evaporated to the dry state in a vacuum, and the residue is dissolved in 300 ml of water. 3.69 g (10.19 mmol) of gadolinium oxide is added, and it is stirred for 5 hours at 80°C.

The solution is evaporated to the dry state in a vacuum and purified on silica gel (RP-18; mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 11.0 g (37.0% of theory) of a colorless and amorphous solid.

Water content: 11.3%. :

Elementary analysis (relative to anhydrous substance):

Cld: C34.62 H3.87 N7.69 F22.16 $2.20 Gd 10.97

Fnd: C 34.57 H3.95 N7.60 F22.05 S2.13 Gd 10.90

Example 25 a) 6-N-[3,6,9-Tris(carboxymethyl)-3 ,6,9-triazaundecanedioic acid-1-carboxy-11 -oyl]-2-N- [1-O-a-D-carbonylmethyl-mannopyrano se]-L-lysine-[1-(4-perfluorooctylsulfonyl)- piperazine]-amide : 12.10 g (30.0 mmol) of 3-N-(2,6-dioxomorpholinoethyl)-6-N-(ethoxycarbonylmethyl)- 3 6-diazaoctanedioic acid is added to 24.0 g (26.19 mmol) of the title compound of Example

® 2 ) dissolved in 100 ml of dimethylformamide/30 ml of pyridine, and it is stirred for 5 hours at 50°C. It is evaporated to the dry state in a vacuum. The residue is dissolved in 200 ml of water, and the pH of the resulting solution is set at 13 by adding 20% aqueous sodium hydroxide solution. It is stirred for 8 hours at 22°C and a pH of 13. The solution is brought to a pH of 7.2 by adding concentrated hydrochloric acid, and then it is evaporated to the dry state in a vacuum.

The residue is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 17.26 g (51.0% of theory) of a colorless solid.

Water content: 9.3%.

Elementary analysis (relative to anhydrous substance):

Cld: C 37.19 H421 N7.59 F25.00 S248

Fnd: C 37.10 H4.30 N 7.48 F25.07 S242 b) 6-N-[3,6,9-Tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid-1-carboxy-11-oyl]-2-

N-[1-O-a-D-carbonylmethyl-mannopyranose]-L-lysine-[1 -(4-perfluorooctylsulfonyl)- piperazine]-amide, Gd complex, sodium salt 1.40 g (3.87 mmol) of gadolinium oxide is added to 10.0 g (7.74 mmol) of the title compound of Example 25a) in 100 mi of water, and it is stirred for 2 hours at 70°C. The solution is filtered. The filtrate is set at a pH of 7.4 with 2N sodium hydroxide solution, and it is freeze- dried.

Yield: 11.36 g (quantitative) of an amorphous solid.

Water content: 10.5%.

Elementary analysis (relative to anhydrous substance):

Cld: C32.72H3.43N 6.68 52.18 Gd 10.71 Na 1.57 F 22.00

Fnd: C32.65H3.51N6.71 $2.08 Gd 10.61 Na 1.68 F 21.87

® ox a) 6-N-Benzyloxycarbonyl-2-N-[1 ,4,7-tris(carboxylatomethyl)-1.4,7,10- tetraazacyclododecane]-1 0-(pentanovl-3aza-4-0xo-5-methyl-5y1)} -L-lysine-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide, Gd complex 50.0 g (60.20 mmol) of the title compound of Example 21¢), 6.93 g (60.20 mmol) of N- hydroxysuccinimide, 5.09 g (120.0 mmol) of lithium chloride and 37.91 g (60.20 mmol) of 1,4,7- tris[carboxylatomethyl)-1,4,7,1 0-tetraazacyclododecane- 10-(pentanoyl-3-aza-4-oxo-5-methyl-5- yl), Gd complex are dissolved in 400 ml of dimethy! sulfoxide while being heated slightly. At 10°C, 20.63 g (100.0 mmol) of N,N-dicyclohexylcarbodiimide is added, and it is then stirred overnight at room temperature. The solution is poured into 3000 ml of acetone, and it is stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18; mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 75.53 g (87.0% of theory) of a colorless solid.

Water content: 10.1%.

Elementary analysis (relative to anhydrous substance):

Cld: C 37.48 H3.84 N 8.74 S2.22 F22.39 Gd 10.90

Fnd: C37.39 H4.02 N 8.70 S2.16 F2229 Gd 10.75 b) 2-N-[1,4,7-Tris(carboxylatomethyl]-1,4,7,1 0-tetraazacyclododecane-Gd complex, 10- (pentanoyl-3 -aza-4-0x0-5-methyl-5-yl)-L-lysine-[1-(4-perfluorooctylsulfonyl)- piperazine]-amide 70.0 g (48.53 mmol) of the title compound of Example 21d) is dissolved in 500 ml of water/100 ml of ethanol, mixed with 5.0 g of palladium catalyst (10% Pd/C) and hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen absorption can be observed. Then, catalyst is suctioned out, it is thoroughly rewashed with ethanol (twice with 75 ml each) and evaporated to the dry state in a vacuum. The title compound is obtained as a strongly viscous and colorless oil.

Yield: 63.5 g (quantitative).

207 ~ 0400371949 ® ® Water content: 9.8%.

Elementary analysis (relative to anhydrous substance):

Cld: C37.48 H3.84 N8.74 $2.22 F22.59 Gd 10.90

Fnd: C 37.39 H4.03 N8.65 $2.20 F22.31 Gd 10.78 c) 6-N-(1-O-a-D-Carbonylmethyl-2,3 4.6-tetra-O-benzyl-mannopyranose)-2-N-[1,4,7- tris(carboxylatomethyl)-1.4,7,1 0-tetraazacyclododecane, Gd-complex-1 0-(pentanoyl-3- aza-40x0-5-methyl-3y1)]-L-lysine-[1 -(4-perfluorooctylsulfonyl)-piperazine]-amide 50.0 g (38.22 mmol) of the title compound of Example 26b), 4.40 g (38.22 mmol) of N- hydroxysuccinimide, 3.39 g (80.0 mmol) of lithium chloride and 22.88 g (38.22 mmol) of 1-O-a-

D-carboxymethyl-2,3,4,6-tetra-O-benzyl-mannopyranose are dissolved in 400 ml of dimethyl sulfoxide while being heated slightly (30 to 40°C). At 10°C, 10.32 g (50.0 mmol) of N,N- dicyclohexylcarbodiimide is added, and it is then stirred overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 64.25 g (89.0% of theory) of a colorless solid.

Water content: 10.9%.

Elementary analysis (relative to anhydrous substance):

Cld: C46.42 H4.54 N6.67 S1.70 F 17.10 Gd 8.33

Fnd: C 46.36 H4.71 N6.60 S1.61 F 17.19 Gd 8.2] d) 6-N-(1-O-a-D-Carbonylmethyl-2.3 4 6-tetra-O-benzyl-mannopyranose)-2-N-[1,4,7- tris(carboxylatomethyl)-1,4,8,1 0-tetraazacyclododecane-10-(pentanoyl-3 -aza-40x0-5- methyl-3yl)]-L-lysine-{1 -(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex 60.0 g (31.77 mmol) of the title compound of Example 26c) is dissolved in 500 ml of ethanol and mixed with 6.0 g of palladium catalyst (10% Pd/C). It is hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen absorption can be

® yA Then, catalyst is suctioned out, it is rewashed thoroughly with ethanol (twice with 150 ml each) and evaporated to the dry state in a vacuum.

Yield: 48.55 g (quantitative) of a colorless solid.

Water content: 3.9%.

Elementary analysis (relative to anhydrous substance):

Cld: C 35.37 H4.02 N8.25 §2.10 F21.13 Gd 10.29

Fnd: C 35.28 H4.13 N 8.17 $2.03 F 21.05 Gd 10.20

Example 27 a) 1,7-Bis-(benzyloxycarbonyl)-4-[2-(N -ethyl-N-perfluorooctylsulfonyl]-amino]-acetyl}- 1,4,7,10-tetraazacyclododecane) 49.46 g (200.0 mmol) of EEDQ (2-ethoxy-1 ,2-dihydroquinoline-1-carboxylic acid ethyl ester) is added at 0°C to 50.0 g (113.5 mmol) of 1,7-bis(benzyloxycarbonyl)-1,4,7,10- tetraazacyclododecane and 66.42 g (113.5 mmol) of 2-(N-ethyl-N-perfluorooctylsulfonyl)- aminoacetic acid (produced according to DE 196 03 033) in 300 ml of tetrahydrofuran, and it is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

Yield: 65.2 g (57% of theory) of a colorless solid.

Elementary analysis:

Cld: C4291 H3.80 N6.95 F32.05 S3.18

Fnd: C42.85 H3.90 N6.87 F31.98 S3.15 b) 1,7-Bis-(benzyloxy)-4-[2-(N -ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-10-[1-O-a-D- carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose}-1,4,7, 10-tetraazacyclododecane 24.73 g (100 mmol of EEDQ (2-ethoxy-1,2-dihydroquinoline- 1-carboxylic acid ethyl ester) is added at 0°C to 60.0 g (59.53 mmol) of the title compound of Example 27a) and 35.64 g (59.53 mmol) of 1-O-a-D-carboxymethyl-2,3,4.6-tetra-O-benzyl-mannopyranose, produced according to DE 19728954, in 300 ml of tetrahydrofuran, and it is stirred overnight at room

¢® igerature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

Yield: 76.6 g (81.0% of theory) of a colorless solid.

Elementary analysis:

Cld: C 54.44 H4.70 N4.41 F20.33 S2.02

Fnd: C 34.37 H4.81 N4.35 F20.27 S1.96 c) 1-[2-(N -Ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-7-(1 -O-a-D-carbonylmethyl- mannopyranose)- 1,4,7,10-tetraazacyclododecane 70 g (44.07 mmol) of the title compound of Example 27b is dissolved in 800 ml of ethanol, and 8 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 42.3 g (quantitative) of a colorless solid.

Elementary analysis:

Cld: C 35.04 H3.99 N7.30 F33.65 S3.34

Fnd: C 35.15 H4.13 N 7.13 F33.48 $3.26 d) 1,7-Bis-[1,4,7-tris(carboxylatomethyl)-1,4,7,1 0-tetraazacyclododecane-Gd-complex-10- (pentanoyl-3-aza-4-oxo-5-methyl-5yl)-4-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino}- acetyl-10-(1-O-a-D-carbonylmethyl-mannopyranose)-1 4,7,1 0-tetraazacyclododecane g (20.84 mmol) of the title compound of Example 27c¢), 5.09 g (120 mmol) of lithium chloride and 37.78 g (60 mmol) of 1,4,7-tris(carboxylatomethyl)-10-pentanoyl-3-aza-4-0xo-3- methyl-5y1)-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 29.67 g (120 mmol) of EEDQ is added, and itis then stirred overnight at room temperature. The solution is poured into 3000 ml of acetone, and it is stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient that consists of water/ethanol/acetonitrile).

® [ Yield: 13.2 g (29.0% of theory) of a colorless solid.

Water content: 11.8%.

Elementary analysis (relative to anhydrous substance):

Cld: C36.31 H4.34 N9.62 S 1.47 F 14.79 Gd 14.4]

Fond: C3624 H4.27 N9.58 S1.51 F14.85 Gd 14.25

Example 28 a) 1,7-Bis(benzyloxycarbonyl)-4-[2-(N -ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-10- [pentanoyl-3-aza-4-oxo-5-methyl-5yl-[1 4, 7-tris(carboxylatomethyl)-Gd complex, 1,4,7,10-tetraazacyclododecan-10-yl}-1,4,7,1 0O-tetraazacyclododecane. 50.0 g (49.61 mmol) of the title compound of Example 27a), 5.71 g (49.61 mmol) of N- hydroxysuccinimide, 4.24 g (100 mmol) of lithium chloride and 31.24 g (49.61 mmol) and 1.4,7- tris(carboxylatomethyl)-1 0-(pentanoyl-3-aza-oxo-5-methyl-5-yl)-1 ,4.7,10-tetraazacyclododecane,

Gd-complex, are dissolved in 350 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 15.47 g (75 mmol) of N.N-dicyclohexylcarbodiimide is added, and it is then stirred overnight at room temperature. The solution is poured into 2000 ml of acetone, and it is stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel

RP-18, mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 65.1 g (81.0% of theory) of a colorless solid.

Water content: 7.9%.

Elementary analysis (relative to anhydrous substance):

Cld: C 40.79 H4.11 N 8.65 S1.98 F19.94 Gd 9.72

Fnd: C 40.71 H4.20 N 8.58 S2.03 F19.87 Gd 9.68 b) 1-[2-(N -Ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-7{ (-pentanoyl-3-aza-4-0x0-5- methyl-5y1)-10-[1,4,7-tris(carboxylatomethyl)-1 ,4.7.10-tetraazacyclododecane, Gd- complex] }-1,4,7,10-tetraazacyclododecane. 60.0 g (37.05 mmol) of the title compound of Example 28a) is dissolved in 600 ml of

C ‘@°" and 6.0 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 50.06 g (quantitative) of a colorless solid.

Water content: 3.9%.

Elementary analysis (relative to anhydrous substance):

Cid: C 34.67 H4.03 N 10.37 S237 F23.90 Gd 11.64

Fnd: C 34.58 H4.15 N 10.28 S2.30 F 23.84 Gd 11.57 c) 1-[2-(N _Ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-4, 0-bis[1-O-a-D- carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose]-7- { (pentanoyl-3-aza-4-0xo0-3- methyl-5-yl)-[1,4,7-tris(carboxylatomethyl)-1,4,7,1 0-tetraazacvclododecan-10-y1]-Gd- complex}-1,4,7,1 0-tetraazacyclododecane 40.0 g (29.60 mmol) of the title compound of Example 28b), 2.54 g (60.0 mmol) of lithium chloride and 44.9 g (75.0 mmol) of 1-0-a-D-carboxymethyl-2,3,4,6-tetra-O-benzy!- mannopyranose are dissolved in 300 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 24.73 g (100.0 mmol) of EEDQ is added, and it is then stirred overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 31.98 g (43.0% of theory) of a colorless solid.

Water content: 3.5%.

Elementary analysis (relative to anhydrous substance):

Cld: C 53.06 H5.05 N5.57 S1.28 F 12.85 Gd 6.26

Fnd: C52.95 H5.19 N548 S1.23 F12.77 Gd 6.14

12 . 0400371949 ( x) 1-[2-(N-Ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-4,10-bis(1-O-a-D- carbonylmethyl-2,3.4,6-tetra-O-benzyl-mannopyranose]-7-{ (pentanoyl-3-aza-4-0x0-5- methyl-5-y1)-[1,4,7-tris(carboxylatomethyl)-1,4,7,1 0O-tetraazacyclododecan- 10-yl}-Gd- complex }-1,4,7.1 0-tetraazacyclododecane 30.0 g (11.94 mmol) of the title compound of Example 28c) is dissolved in 300 ml of ethanol/30 ml of water, and 4.0 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature, catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 21.39 g (quantitative) of a colorless solid.

Water content: 3.4%.

Elementary analysis (relative to anhydrous substance):

Cid: C 36.87 H4.39 N7.82 S1.79 F 18.03 Gd 8.78

Fnd: C 36.80 H4.50 N7.85 S1.68 F17.91 Gd&8.70

Example 29 a) 6-N-[3,6-Bis(carboxymethyl)-octane-1,8-dicarboxylic acid-1 -carboxy-8-0y1]-2-N-(1-O-a-

D-carboxymethyl-mannopyranose)-lysine-[1 ~(4perfluorooctylsulfonyl)-piperazine]-amide 25.62 g (100.0 mmol) of ethylenediamine-N,N,N',N'-tetraacetic acid dianhydride is added to 27.5 g (30.0 mmol) of the title compound of Example 21e), dissolved in 300 ml of dimethylformamide/100 ml of pyridine, and it is stirred for 5 hours at 50°C. It is evaporated to the dry state in a vacuum. The residue is dissolved in 300 ml of water, set at a pH of 10 by adding 20% aqueous sodium hydroxide solution, and then the basic product solution is brought to a pH of 3 by adding concentrated hydrochloric acid, and itis evaporated to the dry state ina vacuum. The residue is chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 18.22 g (51.0% of theory) of a colorless solid.

Water content: 7.9%.

Elementary analysis (relative to anhydrous substance):

® [ Cld: C 36.31 H3.98 N7.06 F27.12 §2.69

Fnd: C 36.23 H4.07 N 6.98 F27.05 S2.62 b) 6-N-[3,6-Bis(carboxylatomethyl)-octane-1,8-dicarboxylic acid-1 -carboxylato-8-oyl-]-2-

N-(1-0-a-D-carboxymethyl-mannopyranose)-L-lysine-[1 -(4-perfluorooctylsulfonyl)- piperazine]-amide, Mn complex, sodium salt g (8.397 mmol) of the title compound of Example 29a) is dissolved in 200 ml of water. 965 mg (8.397 mmol) of manganese(II) carbonate is added, and it is stirred for 3 hours to 60°C. The solution is set at a pH of 7.4 with 5% aqueous sodium hydroxide solution, filtered, and then freeze-dried.

Yield: 10.52 g (99.0% of theory) of a colorless solid.

Water content: 7.8%.

Elementary analysis (relative to anhydrous substance):

Cld: C 34.16 H3.50N 6.64 S 2.53 F 25.52 Mn 4.34 Na 1.82

Fnd: C 34.06 H3.61 N6.58S 2.47 F 25.47 Mn 4.30 Na 1.97

Example 30 a) 1,2,3,4,6-Penta-O-acetyl-a,3-D-mannopyranose

Analogously, as described in the literature [M. L. Wolfrom and A. Thompson in Methods in Carbohydrate Chemistry (R. L. Whistler, M. L. Wolfrom and J. N. BeMiller, Eds.), Academic

Press, New York, Vol. II, 53, pp. 211-215, (1963)], the reaction of 150 g (832.5 mmol) of a,B-D- mannopyranose with a mixture that consists of 1500 ml of absolute pyridine and 1500 ml of acetic acid anhydride after working-up yields 315 g (96.7%) of the above-mentioned title compound as crude product in the form of a viscous and colorless oil. By 'H-NMR- spectroscopic study of the thus obtained title compound, it was possible to determine the a to ratio of both anomers at 4:1. A separation of the a,B-anomers of the above-mentioned title compound can thus be eliminated in performing the subsequent reaction steps.

Elementary analysis:

o ® Cld: C49.21 H5.68

Fnd: C 49.12 H3.78 b) 1-0-a-D-(3-Ethoxycarbonyl)-pentyl-2,3,4,6-tetra-O-acetyl-mannopyranose

Analogously. as described in the literature for the synthesis of aryl glycopyranosides {J.

Conchie and G. A. Levvy in Methods in Carbohydrate Chemistry (R. L. Whistler, M. L. Wolfrom and J. N. BeMiller, Eds.) Academic Press, New York, Vol. II, 90, pp. 345-347, (1963)], the reaction of 156.2 g (400 mmol) of the title compound of Example 21a) as an a,B-anomer mixture with 67 ml (400 mmol) of 6-hydroxy-hexanoic acid ethyl ester and 60.8 ml (520 mmol) of tin(IV) chloride results in a total of 600 ml of 1,2-dichloroethane after purification by column chromatography (eluant: hexane/ethyl acetate 2:1) for the formation of 100.05 g (51% of theory) of the above-mentioned title compound as a colorless and viscous oil. By 'H-NMR- spectroscopic study of the thus obtained title compound, it was possible to show that the above- mentioned title compound is exclusively the pure a-anomer.

Elementary analysis:

Cld: C52.94 H6.77

Fnd: C 52.80 H6.78 c) 1-0-a-D-(5-Carboxy)-pentyl-2,3 4 6-tetra-O-benzyl-mannopyranose

A stirred suspension of 141.0 g (289 mmol) of the title compound of Example 30b) in 200 mi of dioxane is mixed at room temperature and with simultaneous vigorous stirring in portions with a total of 238.5 g (4.26 mmol) of fine-powder potassium hydroxide powder. To make it easier to stir, the reaction mixture is mixed with another 200 ml of dioxane, and the thus obtained suspension is subsequently heated to boiling and mixed drop by drop at this temperature with a total of 372 ml (3.128 mol) of benzyl bromide over a period of two hours. After a reaction time of 4 hours at 110°C followed by 12 hours at room temperature, the reaction mixture is slowly poured into a total of 2.5 liters of ice water for the purpose of working-up, and the aqueous phase is subsequently completely extracted with diethyl ether. After the thus obtained

® y phase is washed and after the subsequent drying of the same on sodium sulfate, salt is suctioned out, and the diethyl ether is removed in a vacuum. Excess benzyl bromide is then distilled off from the reaction mixture in an oil pump vacuum quantitatively at an oil bath temperature of 180°C. The thus obtained, resinous-oily residue is purified on silica gel with use of ethyl acetate/hexane (1:10) as an eluant.

Yield: 172.2 g (91.0% of theory) of the above-mentioned title compound in the form of a colorless and extremely viscous oil.

Elementary analysis:

Cid: C75.68 H7.16

Fnd: C 75.79 H7.04 d) 6-N-Benzyloxycarbonyl-2-N-[1-O-a-D-(5-carbonyl)-pentyl-2.3 ,4,6-tetra-O-benzyl- mannopyranose]-L-lysine-[1 -(4-perfluorooctylsulfonyl)-piperazine]-amide 100.0 g (134.0 mmol) of the carboxylic acid that is produced under Example 30c) and 32.4 g (281.4 mmol) of N-hydroxysuccinimide are dissolved in 500 ml of dimethylformamide and mixed in portions at 0°C with a total of 58.0 g (281.4 mmol) of N,N'- dicyclohexylcarbodiimide, and it is stirred for 3 more hours at this temperature. A solution of 111.3 g (134.0 mmol) of the title compound of Example 21c) that is cooled to 0°C and dissolved in 300 ml of dimethylformamide is added drop by drop to the thus produced active ester solution, and it is stirred for 2 hours at 0°C and for 12 hours at room temperature. For working-up, precipitated dicyclohexylurea is filtered out, and the solution is drawn off until a dry state is reached. The thus obtained residue is then chromatographed on silica gel (mobile solvent: dichloromethane/ethanol 20:1; the chromatography is carried out with use of a solvent gradient with continuous increase of the proportion of ethanol).

Yield: 132.5 g (67.4% of theory) of the title compound in the form of a colorless and strongly viscous oil.

Elementary analysis:

Cld: C 354.02 H4.88 N 3.82 F22.01 S2.19 o ® Fnd; C 53.87 H4.85 N4.02 F22.55 S2.06 e) 2-N-[1-0-a-D-(5-C arbonyl)pentyl-mannopyranose]-L-lysine-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide 120.0 g (81.77 mmol) of the compound that is produced under 30d) is dissolved in 800 ml of ethanol, mixed with 4.5 g of Pearlman's catalyst (Pd 20%, C) and hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen absorption can be observed (about 8 hours). Catalyst is suctioned out, it is thoroughly rewashed with ethanol (about 200 ml) and evaporated to the dry state in a vacuum. The title compound is obtained as a strongly viscous and colorless oil.

Yield: 78.5 g (98.7% of theory).

Elementary analysis:

Cld: C37.04 H425 N 5.76 F 33.20 S3.30

Fnd: C 36.96 H4.85 N541 F34.13 S322 f) 2-N-{1 -0-0-D-(5-Carbonyl)pentyl-mannopyranose]-6-N-[1 _4,7-tris-(carboxylatomethyl)- 10-(-3-aza-4-oxo-5-methyl-5-yl-pentanoyl)-1,4,7,1 O-tetraazacyclododecane]-L-lysine-[1- (4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex 99.8 g (158.4 mmol; 2.2 molar equivalents relative to the amine components of Example 30e) that are used) of the Gd complex, described in Patent Application DE 197 28 954 C1 under

Example 31h), of 10-(4-carboxy-1-methyl-2-0xo0-3-azabutyl)-1,4,7,10-tetraazacyclododecane- 1,4,7-triacetic acid and 6.7 g of anhydrous lithium chloride (158.4 mmol) are dissolved at 40°C in 800 ml of absolute dimethyl sulfoxide while being stirred. At this temperature, it is subsequently mixed with a total of 18.2 g (158.4 mmol) of N-hydroxysuccinimide and 70.0 g (71.96 mmol) of the title compound of Example 30e), dissolved in 250 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 32.7 g (158.4 mmol) of N,N'- dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The suspension that is obtained is then mixed with sufficient acetone until the above-mentioned title compound is

( c@plctely precipitated, the precipitate is suctioned off, dried, taken up in water, insoluble dicyclohexvlurea is filtered off. and the filtrate is desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off: 3,000 Da), and low-molecular components are removed. The retentate is then freeze-dried.

Yield: 93.0 g (81.6% of theory) as a colorless lyophilizate.

HO content (Karl-Fischer): 9.53%.

Elementary analysis (relative to anhydrous substance):

Cld: C37.15 H4.39 N7.96 F20.38 S2.02 Gd 9.92

Fnd: C 36.92 H4.50 N7.68 F19.77 S 1.91 Gd 10.08

Example 31 a) 2-N-[1-0-0-D-(5-Carbonyl)pentyl-mannopyranose]-6-N-{ 2-[4-(3-oxapropionyl)-phenyl]- 2-[1,4,7-tris(carboxylatomethyl)-1,4,7,1 0-tetraazacyclododecan-10-yl}-acetic acid}-L- lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex, sodium salt

A stirred suspension of 5.0 g (9.06 mmol) of the title compound of Example 23¢) in 15 ml of absolute dimethyl sulfoxide is mixed at 70°C with 0.68 g (15.9 mmol) of lithium chloride.

After 30 minutes of stirring at 70°C, the now clear reaction solution is mixed in portions with a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide, and the reaction mixture is kept at this temperature for 1 more hour. After cooling to 0°C, it is mixed with 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide, and the reaction solution is stirred for 1 more hour at 0°C, followed by 12 hours at 22°C. The thus obtained reaction solution of the N-hydroxysuccinimide ester of the title compound of Example 3e) is now mixed at 22°C drop by drop with a solution of 4.0 g (4.12 mmol) of the title compound of Example 10Ae) in 15 ml of absolute dimethyl sulfoxide, and it is stirred for another 12 hours at room temperature. For working-up, the reaction solution is added in drops at 22°C into 900 ml of acetone, whereby the title compound precipitates as a colorless precipitate. The precipitate is suctioned off, dissolved in 200 ml of distilled water, and then the pH of this solution is set precisely at 7.2 with 1 molar sodium hydroxide solution. The thus obtained aqueous product solution is ultrafiltered three times with a YM3-ultrafiltration -

® {| Re (AMICON™: cut-off: 3,000 Da) for the purposes of desalination and separation of low-molecular components. The thus obtained retentate is then freeze-dried.

Yield: 6.33 g (92.4% of theory, relative to the amine component used) as a colorless lyophilizate with a water content of 7.38%.

Elementary analysis (relative to anhydrous substance):

Cld: C3848 H4.13N 6.65F 19.16 S1.90 Gd 9.33 Na 1.36

Fnd: C39.52H4.12N 6.67 F 19.70 S 1.89 Gd 9.30 Na 1.41

Example 32 a) 3,5-Bis-benzyloxycarbonylamino-benzoic acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H- perfluorotridecyl)-amide g (47.5 mmol) of 3,5-bisbenzyloxycarbonylamino-benzoic acid (synthesis according to the subsequent bibliographic reference: Skulnick, Harvey L; Johnson, Paul D.; Aristoff, Paul A.;

Morris, Jeanette K.; Lovasz, Kristine D.; et al.; J. Med. Chem.; 40; 7; 1997; 1149-1164) and 4.78 g (47.5 mmol) of triethylamine are dissolved in a solvent mixture that consists of 125 ml of dry tetrahydrofuran and 125 ml of dry dioxane. After cooling to -15°C, a solution of 6.56 g (48 mmol) of isobutyl chloroformate in 30 ml of dry tetrahydrofuran is slowly added in drops while being stirred, whereby the internal temperature is to be kept below -10°C. After a reaction time of 15 minutes at -15°C, a solution of 58.6 g (47.5 mmol) of 1-amino-1H,1H,2H,2H,4H 4H, 5H,5H-3-oxo-perfluorotridecane and 4.78 g (47.5 mmol) of triethylamine in 100 ml of dry tetrahydrofuran is added in drops at -20°C. After a reaction time of one hour at -15°C and two hours at room temperature, the reaction solution is evaporated to the dry state in a vacuum. The remaining residue is taken up in 300 ml of ethyl acetate and washed twice with 200 ml each of saturated sodium bicarbonate solution and once with 300 ml of water. After the organic phase is dried on sodium sulfate, salt is suctioned out, and the ethyl acetate is removed in a vacuum. The remaining oily residue is purified on silica gel with use of dichloromethane/hexane/2-propanol (10:5:1) as an eluant.

Yield: 36.2 g (82.5% of theory) of the title compound as a colorless oil.

C ® Elementary analysis: :

Cld: C 46.82 H3.27 N4.55 F 3497

Fnd: C4721 H3.31 N4.61 F 34.438 b) 3,5-Di-amino-benzoic acid-N-(3-oxa-1H,1H,2H,2H 4H,4H, 5H,5H-perfluorotridecyl)]- amide 30.0 g (32.4 mmol) of the amide that is produced under 32a) is dissolved in 300 ml of ethanol and mixed with 1.2 g of Pearlman's catalyst (Pd 20%, C). Itis hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hvdrogen absorption can be observed. Catalyst is suctioned out, it is thoroughly rewashed with ethanol (about 300 ml), and 1t is evaporated to the dry state in a vacuum. The title compound is obtained as a strongly viscous, yellowish oil.

Yield: 20.12 g (94.8% of theory).

Elementary analysis:

Cld: C 36.66 H2.77 N 6.41 F 49.28

Fnd: C 36.07 H2.87 N 6.23 F 49.43 c) 3-N-[-(1-O-a-D-Carbonylmethyl-2,3 .4,6-tetra-O-benzyl-mannopyranose)-5-amino- benzoic acid-N-(3-oxa-1H, 1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide 10.95 g (18.30 mmol) of 1-carboxymethyloxy-2,3,4-tetra-O-benzyl-a-D- mannopyranoside [Production as described in Patent DE 197 28 954 C1] is dissolved in 150 ml of dimethylformamide and mixed with a total of 2.09 g (18.3 mmol) of N-hydroxysuccinimide.

It is cooled to 0°C, and 3.78 g (18.3 mmol) of dicyclohexylcarbodiimide is added. It is stirred for one hour at 0°C and then for 4 hours at room temperature. It is cooled to 0°C, and a solution that consists of 24.0 g (36.6 mmol, 2 molar equivalents relative to the carboxylic acid used) of the diamino compound that is described under Example 32b), dissolved in 350 ml of : dimethylformamide, is slowly added in drops within 3 hours. Then, it is stirred for one more hour at 0°C, then overnight at room temperature. It is evaporated to the dry state in a vacuum,

¢ @o™ residue is taken up in 300 ml of ethyl acetate. Precipitated urea is filtered out, and the filtrate is washed twice with 100 ml each of 3% aqueous soda solution. The organic phase is dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue 1S chromatographed on silica gel (mobile solvent: n-hexane/isopropanol 13:1). 16.8 g (74.3% of theory, relative to the carboxylic acid used) of the title compound is obtained in the form of a colorless oil. By increasing the polarity of the eluant composition in n-hexane/isopropanol to 5:1, a total of 10.15 g of unreacted diamino compound 32b) is recovered in the subsequent chromatography fractions, which can be reacted again according to the above-mentioned reaction instructions.

Elementary analysis:

Cld: C5442 H4.40 N3.40 F26.13

Fnd: C 54.32 H4.49 N3.48 F25.94 d) 3-N-[-(1 -0-a-D-Carbonylmethyl-mannopyranose)]-5-amino-benzoic acid-N-(3-oxa- 1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide

Similar to what is described for the synthesis of the title compound of Example 32b), the hydrogenolysis of 12.0 g (9.70 mmol) of the title compound of Example 32¢), with use of 0.5 g of Pearlman's catalyst (Pd 20%, C) in an ethanol/water (9:1) mixture after working-up yields 8.08 g (96.7% of theory) of the above-mentioned title compound in the form of a yellowish-colored and viscous oil. : Elementary analysis:

Cld: C37.64 H3.28 N4.88 F 37.49

Fnd: C3732 H3.17 N4.97 F 37.55

( ) 3-N-(1-O-a-D-Carbonylmethyl-mannopyranose)-5-N-{ 2-[4-(3-oxapropionyl)-phenyl]-2- [1.4,7-tris-(carboxylatomethyl)-1,4,7.10-tetraazacyclododecan-1 0-yl]-acetic acid} - benzoic acid-N-(3-oxa-1H,1H.2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide, Gd complex, sodium salt 13.6 g (19.2 mmol; 2.2 molar equivalents relative to the amine component of Example 32d) that is used) of the Gd complex that is described under Example 23Ae)and 0.81 g of anhydrous lithium chloride (19.2 mmol) are dissolved at 40°C in 100 ml of absolute dimethyl sulfoxide while being stirred and mixed at this temperature with a total of 2.2 g (19.2 mmol) of

N-hydroxysuccinimide and 7.5 g (8.7 mmol) of the title compound of Example 32d), dissolved in 50 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 3.96 g (19.2 mmol) of N,N'-dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The suspension that is obtained is then mixed with sufficient acetone until the above-mentioned title compound is completely precipitated, the precipitate is suctioned off, dried, taken up in water, insoluble dicyclohexylurea is filtered off, and the filtrate is desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off: 3,000 Da), and low-molecular components are removed. The retentate is then freeze-dried.

Yield: 11.51 g (84.5% of theory) as a colorless lyophilizate.

H>O content (Karl-Fischer): 6.77%

Elementary analysis (relative to anhydrous substance):

Cld: C 40.05 H3.94 N629 F20.71 Gd 10.08 Na 1.47

Fnd: C 39.98 H4.00 N6.31 F20.73 Gd 10.11 Na 1.42 :

Example 33 a) 3,5-Bis-(benzyloxycarbonylamino)-1-{N-{1 -(4-perfluorooctylsulfonyl)-piperazine] } - benzamide g (23.75 mmol) of 3,5-bis-benzyloxycarbonylamino-benzoic acid (synthesis according to the subsequent bibliographic reference: Skulnick, Harvey I; Johnson, Paul D.; Aristoff, Paul

A.; Morris, Jeanette K.; Lovasz, Kristine D.; et al.; J. Med. Chem.; 40; 7; 1997; 1149-1164) and

( 2 E (23.75 mmol) of triethylamine are dissolved in a solvent mixture that consists of 60 ml of dry tetrahydrofuran and 70 ml of dry dioxane. After cooling to -15°C, a solution of 3.28 g (24 mmol) of isobutyl chloroformate in 20 ml of dry tetrahydrofuran is slowly added in drops while being stirred, whereby the internal temperature does not exceed -10°C. After a reaction time of minutes at -15°C, a solution of 23.0 g (23.75 mmol) of perfluorooctylsulfonyl-piperazine and 2.39 g (23.75 mmol) of triethylamine in 50 ml of dry tetrahydrofuran is added in drops at 20°C.

After a reaction time of one hour at -15°C and two hours at room temperature. the reaction solution is evaporated to the dry state in a vacuum. The remaining residue is taken up in 200 ml : of ethyl acetate and washed twice with 100 ml each of saturated sodium bicarbonate solution and once with 300 ml of water. After the organic phase is dried on sodium sulfate, salt is suctioned out, and the ethyl acetate is removed in a vacuum. The remaining oily residue is purified on silica gel with use of dichloromethane/hexane/2-propanol (15:5:1) as an eluant.

Yield: 18.35 g (79.6% of theory) of the title compound as a colorless oil.

Elementary analysis:

Cld: C 43.31 H2.80 N5.77 F 33.27 $3.30

Fnd: C 43.21 H2.75 N5.61 F33.38 $3.22 b) 3.5-Di-amino-1-{N-[1-(4-perfluorooctylsulfonyl)-piperazine] -benzamide 9.70 g (10.0 mmol) of the amide that is produced under 33a) is dissolved in 100 ml of ethanol and mixed with 0.4 g of Pearlman's catalyst (Pd 20%, C). Itis hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen absorption can be observed. Catalyst is suctioned out, it is thoroughly rewashed with ethanol (about 150 ml) and evaporated to the dry state in a vacuum. The title compound is obtained as a strongly viscous, yellowish oil.

Yield: 6.9 g (98.2% of theory).

Elementary analysis:

Cld: C32.49 H2.15 N7.98 F4598 S4.56

Fnd: C32.56 H2.17 N 8.09 F 45.63 S4.61 ud Ag 5-Amino-3-N-(1-O-a-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)-benzoic acid-N-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide 5.48 g (9.15 mmol) of | -carboxymethyloxy-2,3,4,-tetra-O-benzyl-a-D-mannopyranoside [production as described in Patent DE 197 28 954 C1] is dissolved in 100 ml of dimethylformamide and mixed with a total of 1.04 g (9.15 mmol) of N-hydroxysuccinimide. It is cooled to 0°C, and 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide is added. It is stirred for one hour at 0°C and then for 4 hours at room temperature. After renewed cooling to 0°C, a solution that consists of 12.85 g (18.30 mmol, 2 molar equivalents relative to the carboxylic acid used) of the diamino compound that is described under Example 33b) and that is dissolved in 250 ml of dimethylformamide is slowly added in drops within 3 hours. Then, it is stirred for one more hour at 0°C, and then overnight at room temperature. It is evaporated to the dry state in a vacuum, and the residue is taken up in 100 ml of ethyl acetate. Precipitated urea is filtered out, and the filtrate is washed twice with 100 ml each of 5% aqueous soda solution. The organic phase 1s dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/isopropanol 13:1). 8.14 g (69.4% of theory, relative to the carboxylic acid used) of the title compound is obtained in the form of a colorless oil. By increasing the polarity of the eluant composition during the chromatography to 6:1 (n- hexane/isopropanol), a total of 4.36 g of unreacted diamino compound 33b) is recovered in the subsequent chromatography fractions, and the compound can be reacted again according to above-mentioned reaction instructions.

Elementary analysis:

Cld: C51.49 H4.01 N4.37 F25.17 S2.50

Fnd: C 51.60 H4.19 N428 F25.14 S2.44 d) 5-Amino-3-N-(1-O-a-D-carbonylmethyl-mannopyranose)-benzoic acid-N-{1 -(4- perfluorooctylsulfonyl)-piperazine]-amide

Similar to what is described for the synthesis of the title compound of Example 33b), the

- . 0003/1949 ® hggpeenolysis of 6.4 g (5.0 mmol) of the title compound of Example 33c¢), with use of 0.3 g of

Pearlman's catalyst (Pd 20%, C), in an ethanol/water (8:1) mixture after working-up vields 4.43 ¢ (96.2% of theory) of the above-mentioned title compound in the form of a vellowish-colored and viscous oil.

Elementary analysis:

Cld: C35.15 H2.95 N6.07 F35.01 S3.48

Fnd: C 35.32 H3.02 N5.89 F35.05 S3.58 e) 3-N-(1-0-a-D-Carbonylmethyl-mannopyranose)-5-N-[1 ,4,7-tris(carboxylatomethyl)-10- (3-aza-4-0x0-3-methyl-5-yl-pentanoyl)-1,4,7,1 0-tetraazacyclododecane]-benzoic acid-N- [1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex 5.54 g (8.8 mmol; 2.2 molar equivalents relative to the amine components of Example 33d) that are used) of the Gd complex, described in Patent Application DE 197 28 954 C1 under

Example 31h), of 10-(4-carboxy- 1-methyl-2-0x0-3-azabutyl)-1,4,7,10-tetraazacyclododecane- 1,4,7-triacetic acid and 0.37 g of anhydrous lithium chloride (8.8 mmol) are dissolved at 40°C in 60 ml of absolute dimethyl sulfoxide while being stirred and mixed at this temperature with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.7 g (4.0 mmol) of the title compound of Example 13Ad), dissolved in 40 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 1.82 g (8.8 mmol) of N,N'- dicyclohexylcarbodiimide, and it is stirred for 12 hours at room temperature. The suspension that is obtained is then mixed with sufficient acetone until the above-mentioned title compound is completely precipitated, the precipitate is suctioned off, dried, taken up in water, insoluble dicyclohexylurea is filtered out, and the filtrate is desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off, 3,000 Da), and low-molecular components are removed. The retentate is then freeze-dried.

Yield: 5.36 g (87.4% of theory) as a colorless lyophilizate.

H,O-content (Karl-Fischer): 6.77%.

Elementary analysis (relative to anhydrous substance):

® o Cld: C36.01 H3.61 N8.22 F21.05 Gd 10.25 S2.09

Fnd: C 35.87 H3.70 N 8.22 F20.91 Gd 10.18 S2.16

Example 34 : a) 1.4,7-Triazaheptane-1 _7-bis-(2-N-trifluoroacetyl-6-N-benzyloxycarbonyl-L-lysine)- diamide 100 g (107.9 mmol) of the carboxylic acid that is produced under Example 21a) and 26.1 g (226.59 mmol) of N-hydroxysuccinimide are dissolved in 500 ml of dimethylformamide and mixed in portions at 0°C with a total of 46.7 g (226.59 mmol) of N,N'-dicyclohexylcarbodiimide, and it is stirred for 3 more hours at this temperature. A solution of 5.57 g (53.95 mmol) of diethylenetriamine that is cooled to 0°C and dissolved in 60 ml of dimethylformamide is added drop by drop to the thus produced active ester solution, and it is stirred for 2 hours at 0°C and for 12 hours at room temperature. For working-up, precipitated dicyclohexylurea is filtered out, and the solvent is drawn off until a dry state is reached. The thus obtained residue is then chromatographed on silica gel (mobile solvent: dichloromethane/ethanol 15:1; chromatography is carried out with use of a solvent gradient with continuous increase of the proportion of ethanol).

Yield: 26.0 g (58.8% of theory, relative to the amine component that is used) of the title compound in the form of a colorless and strongly viscous oil.

Elementary analysis:

Cld: C52.74 H5.78 N 11.96 F 13.90

Fnd: C 52.66 H5.89 N 11.88 F 14.02 b) 1,4,7-Triazaheptane-1,7-bis-(2 -N-trifluoroacetyl-6-N-benzyloxycarbonyl-L-lysine)- diamide-4-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl 16.18 g (27.0 mmol) of 2-[N-ethyl-N-perfluorooctylsulfonyl)-aminoacetic acid (production according to: DE 196 03 033), dissolved in 50 ml of tetrahydrofuran, is added at 0°C and under nitrogen atmosphere to a solution that consists of 20 g (24.4 mmol) of the diamide that

® igrauced under 34a) and that is dissolved in a mixture that consists of 150 ml of tetrahydrofuran and 15 ml of chloroform. Then, a total of 18.0 g (36.6 mmol) of EEDQ [2- ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is added in portions at 0°C and allowed to stir overnight at room temperature, and it is then concentrated by evaporation in a vacuum. The remaining oil is chromatographed on silica gel (mobile solvent: n-hexane/isopropanol 15:1). 24.74 g (72.4% of theory, relative to the sec-amine that is used) of the title compound is obtained in the form of a colorless oil.

Elementary analysis:

Cld: C42.01 H3.96 F31.19 N 8.00 S229

Fnd: C4192 H4.07 F31.22 N7.87 S234 c) 1,7-Bis-(6-N-benzyloxycarbonyl-L-lysine)-diamide-4-[2-(N -ethyl-N- perfluorooctylsulfonyl)-amino]-acetyl-1,4,7-triazaheptane 22.0 g (15.7 mmol) of the title compound that is produced under Example 34b) is dissolved in 100 ml of ethanol, and ammonia gas is introduced at 0°C in this solution for 40 minutes. Then, it is stirred for another 4 hours at 0°C and for 3 hours at room temperature, and it is evaporated to the dry state in a vacuum at a bath temperature of 40°C. The remaining oily residue is purified on silica gel with use of dichloromethane/hexane/2-propanol (20:10:1) as an eluant.

Yield: 12.92 g (98.4% of theory) of the above-mentioned title compound as a colorless and strongly viscous oil.

Elementary analysis:

Cld: C4422 H4.64 N9.38 S2.68 F27.03

Fnd: C4431 H472 N9.30 S274 F 26.99

® 9 1,7-Bis-[6-N-benzyloxycarbonyl-2-N-(1-O-u-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl- mannopyranose)-L-lysine]-diamide-4-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino}- acetyl-1,4,7-triazaheptane 5.47 g (9.15 mmol) of 1-carboxymethyloxy-2,3,4,-tetra-O-benzyl-a-D-mannopyranoside [production as described in Patent DE 197 28 954 C1] is dissolved in 80 ml of dimethylformamide and mixed with a total of 1.05 g (9.15 mmol) of N-hydroxysuccinimide. Itis cooled to 0°C, and 1.9 g (9.15 mmol) of dicyclohexylcarbodiimide is added. It is stirred for one hour at 0°C and then for 4 hours at room temperature. It is cooled to 0°C, and a solution that consists of 7.65 g (9.15 mmol) of the amino compound that is described under Example 34e) and that is dissolved in 50 ml of dimethylformamide is slowly added in drops within 3 hours. Then, it is stirred for one more hour at 0°C, then overnight at room temperature. It is evaporated to the dry state in a vacuum, and the residue is taken up in 100 ml of ethyl acetate. Precipitated urea is filtered out, and the filtrate is washed twice with 50 ml each of 5% aqueous soda solution. The organic phase is dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/isopropanol 20:1). 1701 ¢g (78.9% of theory, relative to the carboxylic acid used) of the title compound is obtained in the form of a colorless oil.

Elementary analysis:

Cld: C59.13 H5.43 N4.76 F 13.71 S1.36

Fnd: C 59.22 H5.39 N4.85 F13.70 S1.40 e) 1,7-Bis-[2-N-(1 -O-0-D-carbonylmethyl-mannopyranose)-L-lysine]-diamide-4-[2-(N- ’ ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl- 1,4,7-triazaheptane 15.0 g (6.36 mmol) of the amide that is produced under 34d) is dissolved in 150 ml of ethanol and mixed with 0.3 g of Pearlman's catalyst (Pd 20%, C). It is hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen absorption can be observed. Catalyst is suctioned out, it is thoroughly rewashed with ethanol (about 100 ml) and evaporated to the dry state in a vacuum. The title compound is obtained as a strongly viscous,

¢ ygvish oil.

Yield: 8.54 g (97.2% of theory).

Elementary analysis:

Cld: C39.13 H5.04 N8.11 F2338 S2.32

Fnd: C 39.07 H4.98 N8.18 F23.40 S230 f) 1,7-Bis-[2-N-(1 -O-a-D-carbonylmethyl-mannopyranose)-6-N-[1,4,7- tris(carboxylatomethyl)-1 0-(3-aza-4-oxo-5-methyl-3-yl-pentanoyl)-1,4,7.10- tetraazacyclododecane]-L-lysine]-diamide-4-[2-(N -ethyl-N-perfluorooctylsulfonyl)- amino]-acetyl-1,4,7-triazaheptane, digadolinium complex

A stirred suspension of 5.7 g (9.06 mmol) of the Gd complex, described in Patent

Application DE 197 28 954 C1 under Example 31h), of 10-(4-carboxy-1-methyl-2-oxo0-3- azabutyl)-1,4,7,1 0-tetraazacyclododecane-1,4,7-triacetic acid in 75 ml of absolute dimethyl sulfoxide is mixed at 70°C with 0.68 g (15.9 mmol) of lithium chloride. After 30 minutes of stirring at 70°C, the now clear reaction solution is mixed in portions with a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide, and the reaction mixture is kept at this temperature for 1 more hour. After cooling to 0°C, it is mixed with 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide, and the reaction solution is stirred for another hour at 0°C, followed by 12 hours at 22°C. The thus obtained reaction solution of N-hydroxysuccinimide ester of the Gd complex of 10-(4- carboxy-1-methyl-2-oxo0-3-azabutyl)-1 .4,7,10-tetraazacyclododecane-1,4,7-triacetic acid is now mixed at 22°C drop by drop with a solution of 2.84 g (2.06 mmol) of the title compound of

Example 34e) in 15 ml of absolute dimethyl sulfoxide, and it is stirred for another 12 hours at room temperature. For working-up, the reaction solution is added in drops at 22°C into 500 ml of acetone, whereby the title compound precipitates as a colorless precipitate. The precipitate is suctioned off, dissolved in 200 ml of distilled water and ultrafiltered three times with a YM3- ultrafiltration membrane (AMICON®: cut-off: 3,000 Da) for the purpose of desalination and separation of low-molecular components. The thus obtained retentate is then freeze-dried.

Yield: 4.80 g (89.6% of theory, relative to the amine component that is used) as a

126 ~ BR003/71949 ( gies lyophilizate with a water content of 8.98%.

Elementary analysis (relative to anhydrous substance):

Cld: C3828 H4.84 N9.68 F 12.40 S1.23 Gd 12.07

Fnd: C 38.20 H4.91 N9.77 F 12.45 S1.19 Gd 12.10

Example 35 a) 1,7-Bis(benzyloxycarbonyl)-4-{3-oxa-pentane-1, 5-dicarboxylic acid-1-oyl-5-[1-(4- perfluorooctylsulfonyl)-piperazine}-amide }-1,4,7,10-tetraazacyclododecane 16.56 g (24.4 mmol) of the title compound of Example 35e), dissolved in 150 ml of tetrahydrofuran, is added at 0°C and under nitrogen atmosphere to a solution of 10.75 g (24.4 mmol) of 1,7-bis-[benzyloxycarbonyl]-1,4,7,10-tetraazacyclododecane, dissolved in a mixture that consists of 150 ml of tetrahydrofuran and 15 ml of chloroform. Then, a total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is added in portions at 0°C, and it is allowed to stir overnight at room temperature and then concentrated by evaporation in a vacuum. The remaining oil is chromatographed on silica gel (mobile solvent: n- hexane/isopropanol 12:1). 17.22 g (64.3% of theory relative to the sec-amine that is used) of the monoamide and 3.8 g (8.8% of theory) of the diamide are obtained as a by-product. The title compound is isolated in the form of a colorless oil.

Elementary analysis:

Cid: C 43.41 H3.92 F29.18 N 7.59 S2.60

Fnd: C 43.52 H4.07 F29.24 N 7.67 S 2.55 b) I 7-Bis(benzyloxycarbonyl)-4- {3-oxa-pentane-1,5-dicarboxylic acid-1 -oyl-5-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide}-1 0-[1-0-a-D-(5-carbonyl)-pentyl-2,3,4,6- tetra-O-benzyl-mannopyranose]-1,4,7,1 0-tetraazacyclododecane 10.0 g (13.4 mmol) of the carboxylic acid that is produced under Exarnple 30c) and 3.24 g (28.1 mmol) of N-hydroxysuccinimide are dissolved in 100 ml of dimethylformamide and mixed in portions at 0°C with a total of 5.8 g (28.1 mmol) of N,N'-dicyclohexylcarbodiimide, and o grid for 3 more hours at this temperature. A solution of 14.83 g (13.4 mmol) of the title compound of Example 35a) that is cooled to 0°C and that is dissolved in 100 ml of dimethylformamide is added drop by drop.to the thus produced active ester solution, and it is stirred for 2 hours at 0°C and for 12 hours at room temperature. For working-up, precipitated dicyclohexylurea is filtered out, and the solvent is then drawn off until a dry state is reached. The thus obtained residue is then chromatographed on silica gel (mobile solvent: dichloromethane/ethyl acetate 20:1; chromatography was carried out with use of a solvent gradient with continuous increase of the proportion of ethyl acetate).

Yield: 18.3 g (78.2% of theory) of the title compound in the form of a colorless and strongly viscous oil.

Elementary analysis: :

Cld: C 55.11 H5.03 N4.82 F18.52 S1.84 :

Fnd: C 54.87 H4.85 N4.92 F 18.55 S1.86 c) 1-{3-Oxa-pentane-1 5 -dicarboxylic acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)- piperazine]-amide}-7-[1 -O-a-D-(5-carbonyl)-pentyl-mannopyranose]-1,4,7,10- tetraazacyclododecane : 17.0 g (9.75 mmol) of the compound that is produced under 34b) is dissolved in 150 mi of ethanol, mixed with 1.0 g of Pearlman's catalyst (Pd 20%, C) and hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until.no more hydrogen absorption can be observed. Catalyst is suctioned out, it is thoroughly rewashed with ethanol (twice with 75 ml each) and evaporated to the dry state in a vacuum. The title compound is obtained as a strongly viscous and colorless oil.

Yield: 10.76 g (99.0% of theory).

Elementary analysis:

Cld: C38.78 H4.61 N7.54 F 8.97 S2.88

Fnd: C 38.86 H4.65 N 7.41 F29.02 S292

( @® 1,7-Bis-[1,4,7-tris(carboxylatomethyl)-1,4,7.1 0-tetraazacyclododecane-Gd-complex-10- (pentanoyl-3-aza-4-oxo-3-methyl-5yl)-4-[2-(N -ethyl-N-perfluorooctylsulfonyl]-amino]- acetyl-2-oxa-acetyl]-10-[1 -O-a-D-6-carbonylpentyl-mannopyranose]-1,4,7,10 tetraazacyclododecane 24.86 g (39.46 mmol; 4.4 molar equivalents relative to the amine component 35c¢) that is used) of the Gd complex, described in Patent Application DE 197 28 954 C1 under Example 31h), of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4.7,1 O-tetraazacyclododecane-1,4,7- triacetic acid and 1.67 g of anhydrous lithium chloride (39.46 mmol) are dissolved at 40°C in 200 ml of absolute dimethyl sulfoxide while being stirred and mixed at this temperature with a total of 4.53 g (39.46 mmol) of N-hydroxysuccinimide and 10.0 g (8.97 mmol) of the title compound of Example 34c¢), dissolved in 100 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 8.14 g (39.46 mmol) of N,N'- dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The suspension that is obtained is then mixed with sufficient acetone until the above-mentioned title compound is completely precipitated, the precipitate is suctioned off, dried, taken up in water, insoluble dicyclohexylurea is filtered out, and the filtrate is desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off; 3,000 Da), and low-molecular components are removed. The retentate is then freeze-dried.

Yield: 16.37 g (79.3% of theory) as a colorless lyophilizate.

H>0 content (Karl-Fischer): 7.65%.

Elementary analysis (relative to anhydrous substance): : Cld: C 38.01 H4.61 N9.58 F13.81 S1.37 Gd 13.45

Fnd: C 37.92 H4.55 N 9.58 F 13.77 S1.31 Gd 13.48 e) 3-Oxa-pentane-1,5-dicarboxylic acid-mono-{1 -(4-perfluorooctylsulfonyl)-piperazine]- amide g (44.0 mmol) of 1-perfluorooctylsulfonylpiperazine is dissolved in 150 ml of tetrahydrofuran and mixed at room temperature with a total of 5.1 g (44.0 mmol) of diglycolic

@® agande. and the thus obtained reaction solution is refluxed for 12 hours. After cooling to room temperature, it is evaporated to the dry state, and the remaining oily residue is purified on "silica gel with use of dichloromethane/2-propanol (16:1) as an eluant.

Yield: 27.94 g (92.8% of theory) of the above-mentioned title compound in the form of a colorless and viscous oil.

Elementary analysis:

Cld: C 58.52 H4.27 N 1.98 S2.26 F22.80

Fnd: C 58.42 H4.41 N1.80 S2.28 F23.02

Example 36 a) 1,7-Bis(benzyloxycarbonyl)-4-{3-(oxa-pentane-1 ,5-dicarboxylic acid-1-oyl-5-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide }-1 0-[1-O-p-D-6-carbonylpentyl-2,3,4,6-tetra-

O-benzyl-glucopyranose}-1,4,7,1 0-tetraazacyclododecane) 68.5 2 (91.79 mmol) of 1 -carboxymethyloxy-2,3,4,-tetra-O-benzyl-a-D-mannopyranoside [production as described in Patent DE 197 28 954 C1] is dissolved in 750 ml of dry tetrahydrofuran, and then 9.25 g (91.79 mmol) of triethylamine is added. After the reaction solution is cooled to -15°C to -20°C, a solution of 12.64 g (92.5 mmol) of isobutyl chloroformate in 150 ml of dry tetrahydrofuran is slowly added in drops at this temperature while being stirred, whereby the rate of addition by drops can be selected so that an internal temperature of -10°C is not exceeded. After a reaction time of 15 minutes at -15°C, a solution of 101.6 g (91 .79 mmol) of the title compound of Example 35a) and 9.25 g (91.79 mmol) of triethylamine are then slowly added in drops as a solution in 500 ml of dry tetrahydrofuran at -20°C. After a reaction time of one hour at -15°C and two hours at room temperature, the reaction solution is evaporated to the dry state in a vacuum. The remaining residue is taken up in 45 0 ml of ethyl acetate and washed twice with 300 ml each of saturated sodium bicarbonate solution and once with 400 ml of water.

After the organic phase is dried on sodium sulfate, salt is suctioned out, and the ethyl acetate is drawn off in a vacuum. The remaining oily residue is purified on silica gel with use of dichloromethane/hexane/2-propanol (10:20:1) as an eluant.

o ) Yield: 130.6 g (81.6% of theory) of the above-mentioned title compound as a colorless and strongly viscous oil.

Elementary analysis:

Cld: C55.11 H3.03 N4.82 F 18.52 S1.84

Fnd: C5520 H5.09 N491 F 18.48 S 1.80 b) 1-{3-Oxa-pentane-1.5-dicarboxylic acid-1-oyl-3-[1 -(4-perfluorooctylsulfonyl)- piperazine]-amide}-7-{1 -O-a-D-(5-carbonyl)-pentyl-mannopyranose]-1,4,7,10- tetraazacyclododecane 110.0 g (63.08 mmol) of the compound that is produced under 36a) is dissolved in 1000 ml of ethanol, mixed with 5.0 g of Pearlman's catalyst (Pd 20%, C) and hydrogenated until quantitative hydrogen uptake is reached. Catalyst is suctioned out, it is rewashed with ethanol and evaporated to the dry state in a vacuum. The title compound is obtained as a viscous and colorless oil.

Yield: 92.61 g (99.5% of theory)

Elementary analysis:

Cld: C52.10 H5.12 N5.70 F21.89 S2.17

Fnd: C 52.20 H5.09 N5.71 F21.87 S220

Cc) 1,7-Bis-[1,4,7-tris(carboxylatomethyl)-10-(3 -aza-4-0x0-5-methyl-3-yl-pentanoyl)-4-{3- oxa-pentane-1,5-dicarboxylic acid-1-oyl-5-{1 -(4-perfluorooctylsulfonyl)-piperazine]- amide }-10-[1 -0-a-D-(5-carbonyl)-pentyl-mannopyranose]-1,4,7,10- tetraazacyclododecane, digadolinium complex 55.4 g [88.0 mmol; 4.4 molar equivalents relative to the diamine component of Example 33d) that is used] of the Gd complex, described in Patent Application DE 197 28 954 C1 under

Example 31h), of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane- 1,4,7-triacetic acid and 3.7 g of anhydrous lithium chloride (88.0 mmol) are dissolved at 40°C in 500 ml of absolute dimethyl sulfoxide while being stirred and mixed at this temperature with a

® > 10.1 g (88.0 mmol) of N-hydroxysuccinimide and 29.5 g (20.0 mmol) of the title compound of Example 36b), dissolved in 200 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 18.2 g (88.0 mmol) of N,N'- dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The suspension that is obtained is then mixed with sufficient acetone until the above-mentioned title compound is completely precipitated, the precipitate is suctioned off, dried, taken up in water, insoluble dicyclohexylurea is filtered out, and the filtrate is desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off 3,000 Da), and low-molecular components are removed. The retentate is then freeze-dried.

Yield: 33.96 g (76.9% of theory) as a colorless lyophilizate.

H>O content (Karl-Fischer): 5.98%

Elementary analysis (relative to anhydrous substance):

Cld: C 38.01 H4.61 N822 F13.81 Gd 13.45 S1.37

Fnd: C 37.87 H4.70 N 8.22 F 13.90 Gd 13.48 S136

Example 37 a) 5. (Ethoxycarbonyl)pentyl-2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside

Similar to what is described in the literature for the synthesis of arylglycopyranosides [J.

Conchie and G. A. Levvy in Methods in Carbohydrate Chemistry (R. L. Whistler, M. L. Wolfrom and J. N. BeMiller, Eds.), Academic Press, New York, Vol. II, 90, pp. 345-347, (1963)], the reaction of 156.2 g (400 mmol) of D-mannose pentaacetate as an a.,p-(a,B-ratio = 4:1)-anomer mixture [for synthesis of 1,2,3,4,6-penta-O-acetyl-a,-D-mannopyranose cf: M. L. Wolfrom and

A. Thompson in Methods in Carbohydrate Chemistry (R. L. Whistler, M. L. Wolfrom and J. N.

BeMiller, Eds.), Academic Press, New York, Vol. II, 53, pp. 211-215, (1963)] with 67 ml (400 mmol) of 6-hydroxy-hexanoic acid ethyl ester and 60.8 ml (520 mmol) of tin(IV) chloride results in a total of 600 ml of 1,2-dichloroethane after purification by column chromatography (eluant: hexane/ethyl acetate 2:1) for the formation of 100.05 g (51% of theory) of the above-mentioned title compound as a colorless and viscous oil. By "H-NMR -spectroscopic study of the thus

1 ~ W2003/1949 @® og title compound, it was possible to show that the above-mentioned title compound is only the pure a-anomer.

Elementary analysis:

Cld: C352.94 H6.77

Fnd: C 352.80 H6.78 b) 5-(Carboxy)pentyl-2,3 4 6-tetra-O-benzyl-a-D-mannopyranoside

A stirred suspension of 141.0 g (289 mmol) of the title compound of Example 37a) in 200 ml of dioxane is mixed in portions at room temperature and with simultaneous vigorous stirring with a total of 238.5 g (4.26 mol) of fine-powder potassium hydroxide powder. To make it easier to stir, the reaction mixture is mixed with another 200 ml of dioxane, and the thus obtained suspension is subsequently heated to boiling heat and mixed drop by drop at this temperature with a total of 372 ml (3.128 mol) of benzyl bromide over a period of two hours. After a reaction time of 4 hours at 110°C, followed by 12 hours at room temperature, the reaction mixture is slowly poured into a total of 2.5 liters of ice water for the purpose of working-up, and the aqueous phase is subsequently completely extracted with diethyl ether. After the thus obtained ether phase is washed and the ether phase is subsequently dried on sodium sulfate, salt is suctioned out, and the diethyl ether is drawn off in a vacuum. Excess benzyl bromide is then distilled off quantitatively in an oil pump vacuum at an oil bath temperature of 1 80°C from the reaction mixture. The thus obtained, resinous-oily residue is purified on silica gel with use of ethyl acetate/hexane (1:10) as an eluant.

Elementary analysis:

Cld: C75.68 H7.16

Fnd: C75.79 H7.04

® ® 3-[(Carboxy)-pentyl-2,3,4,6-tetra-O-benzyl-a-D-mannopyranoside-]N- hydroxysuccinimide ester 60.0 g (91.5 mmol) of the title compound of Example 37b) is dissolved in 750 ml of dimethylformamide and mixed with a total of 10.4 g (91.5 mmol) of N-hydroxysuccinimide. It is cooled to 0°C, and 18.9 g (91.5 mmol) of dicyclohexylcarbodiimide is added. It is stirred for one hour at 0°C and then for 4 hours at room temperature. The solvent is drawn off in a vacuum, and the remaining residue is mixed with 100 ml of ethyl acetate and cooled to 0°C. Precipitated urea is filtered out, and the filtrate that is obtained is evaporated to the dry state in a vacuum. The thus obtained, resinous-oily residue is purified on silica gel with use of ethyl acetate/hexane (1:20) as an eluant.

Yield: 61.23 g (89.0% of theory) of the above-mentioned title compound in the form of a colorless and viscous oil.

Elementary analysis:

Cld: C70.29 H6.57 N 1.86

Fnd: C 70.39 H5.64 N 191 d) 2,6-Bis-{6-N¢-2-Ng-[-[1-O-a-D-6-carbonyl-pentyl-(2,3 ,4,6-tetra-O-benzyl)- mannopyranose }-L-lysine}-methyl ester

A solution of 27.51 g (36.6 mmol) of the title compound of Example 37¢) in 150 mi of dimethylformamide is added in drops to a solution, cooled to 0°C, that consists of 4.26 g (18.30 mmol; 0.5 molar equivalent relative to the carboxylic acid that is used) of L-lysine methyl ester- dihydrochloride (commercially available from the Bachem Company) and 4.05 g (40.26 mmol) of triethylamine in 100 ml of dimethylformamide. After the addition is completed, it is stirred for one more hour at 0°C and then overnight at room temperature. It is evaporated to the dry state in a vacuum, and the residue is taken up in 300 ml of ethyl acetate. Precipitated urea is filtered out, and the filtrate is washed twice with 100 ml each of 5% aqueous soda solution. The organic phase is dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/isopropanol 25:1). 39.56 g

® @ of theory) of the title compound is obtained in the form of a colorless oil.

Elementary analysis:

Cld: C 72.88 H7.31 N1.95

Fnd: C 72.90 H7.29 N2.02 e) 2,6-Bis-[6-Ne-2-Ng-[1-O-a-D-6-carbonyl-pentyl-(2,3 ,4.6-tetra-O-benzyl)- mannopyranose]]-L-lysine 30.0 g (20.92 mmol) of the compound that 1s produced under Example 37d) is dissolved in 150 ml of ethanol. The solution of 4 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water is then added to it, and it is stirred for 3 hours at 50°C. According to the thin-layer chromatogram, saponification is quantitative. It is evaporated to the dry state in a vacuum, the remaining residue is taken up in 300 ml of ethyl acetate, and the organic phase is extracted twice with 100 ml each of dilute, aqueous citric acid solution. After drying on sodium sulfate, it is filtered, and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/isopropanol 13:1). 25.56 g (88.5% of theory) of the title compound is obtained in the form of a colorless oil.

Elementary analysis: :

Cld: C 72.88 H7.31 N 1.95

Fnd: C 72.78 H7.33 N 1.96 ) 2,6-Bis-[6-Ng-2-Ng-[1-0-a-D-6-carbonyl-pentyl-(2,3 ,4,6-tetra-O-benzyl)- mannopyranose]-L-lysine]-N-hydroxysuccinimide ester 14.0 g (9.15 mmol) of the title compound of Example 37¢) is dissolved in 100 ml of dimethylformamide and mixed with a total of 1.04 g (9.15 mmol) of N-hydroxysuccinimide. Itis cooled to 0°C, and 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide is added. It is stirred for one hour at 0°C and then for 4 hours at room temperature. The solvent is then drawn off in a vacuum, and the remaining residue is mixed with 100 ml of ethyl acetate and cooled to 0°C.

Precipitated urea is filtered out, and the filtrate that is obtained is evaporated to the dry state in a

® ‘or The thus obtained, resinous-oily residue is purified on silica gel with use of ethyl acetate/n-hexane (1:20) as an eluant.

Yield: 12.94 g (92.4% of theory) of the above-mentioned title compound in the form of a colorless and viscous oil.

Elementary analysis:

Cld: C71.40 H7.05 N2.74

Fnd: C 71.39 H7.14 N2.81 2) 2.6-N,N'-Bis[1-O-a-D-(6-carbonyl)-pentyl-2,3 4 6-tetra-O-benzyl-mannopyranose]-L- lysine-1,7-(1,4,7-triazaheptane)-diamide

A solution that consists of 14.0 g (9.15 mmol; 2 molar equivalents relative to the amine that is used) of the title compound of Example 37f) in 100 ml of dimethylformamide is slowly added in drops to a solution, cooled to 0°C, of 0.47 g (4.57 mmol) of diethylenetriamine in 25 ml of dimethylformamide. After the addition is completed, it is stirred for one more hour at 0°C and then overnight at room temperature. It is evaporated to the dry state in a vacuum, and the residue is taken up in 200 ml of ethyl acetate. Precipitated urea is filtered out, and the filtrate is washed twice with 50 ml each of 5% aqueous soda solution. The organic phase is dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/isopropanol 25:1). 9.53 g (71.4% of theory) of the title compound is obtained in the form of a colorless oil.

Elementary analysis:

Cld: C72.79 H7.42 N3.36 :

Fnd: C 72.90 H 7.39 N3.32 h) 2-N-[2-(N -Ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-6-N-(benzyloxycarbonyl)-L- lysine-methyl ester 208g (3 5.6 mmol) of the 2-[N-ethyl-N-perfluorooctylsulfonyl)-aminoacetic acid and 3.60 g (35.6 mmol) of triethylamine are dissolved in 200 ml of dimethylformamide, and 4.09 g

® X mol) of N-hydroxysuccinimide is added. It is cooled to 0°C, and 7.34 g (35.6 mmol) of dicyclohexvlcarbodiimide is added. It is stirred for one hour at 0°C and then for 4 hours at room temperature. It is cooled to 0°C, and a solution that consists of 11.77 g (35.6 mmol) of 6-N- benzyloxycarbonyl-L-lysine-methyl ester-hydrochloride and 4.0 g (40.0 mmol) of triethylamine in 100 ml of dimethylformamide is added in drops within 10 minutes. It is stirred for one hour at 0°C, then overnight at room temperature. It is evaporated to the dry state in a vacuum, and the residue is taken up in 100 ml of ethyl acetate. Precipitated urea is filtered out, and the filtrate is washed twice with 100 ml each of 5% aqueous soda solution. The organic phase is dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/ethyl acetate 20:1). 27.43 g (88.0% of theory) of a colorless oil is obtained.

Elementary analysis:

Cld: C 38.41 H3.45 N4.80 F36.89 S3.66

Fnd: C 38.45 H3.38 N4.88 F37.02 S3.71 1) 2-Na-{[2-(N-Ethyl-N-perfluorooctylsulfonyl]-amino-acetyl} -6-Ng-(benzyloxycarbonyl)-

L-lysine 25.0 g (28.55 mmol) of the compound that is produced under Example 37h) is dissolved in 150 ml of ethanol. The solution of 4 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water is then added to it, and it is stirred for 3 hours at 50°C. According to the thin-layer chromatogram, saponification is quantitative. It is evaporated to the dry state in a vacuum, and the remaining residue is taken up in 300 ml of ethyl acetate, and the organic phase is extracted : twice with 100 ml each of dilute, aqueous citric acid solution. After drying on sodium sulfate, it is filtered and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/isopropanol 10:1). 22.73 g (92.4% of theory) of the title compound is obtained in the form of a colorless oil.

Elementary analysis:

Cld: C37.64 H3.28 N4.88 F37.49 S3.72

® ( Fnd: C 37.65 H3.38 N4.88 F37.52 S3.73 j) 1,4,7-Triazaheptane-4-{2-N-[2-(N -ethyl-N-perfluorooctylsulfonyl)-amino}-acetyl-6-N- benzyloxycarbonyl}-L-lysine-amide-1,7-bis{ 2,6-N N'-bis[1-O-a-D-(5-carbonyl)-pentyl- 2.3,4.6-tetra-O-benzylmannopyranose}-L-lysine-diamide } 15.33 g (17.8 mmol) of the title compound of Example 37i) and 1.80 g (17.8 mmol) of triethylamine are dissolved in 250 ml of dry tetrahydrofuran. After the reaction solution is cooled to -15°C to -20°C, a solution of 4.92 g (35.6 mmol) of isobutyl chloroformate, dissolved in 50 ml of dry tetrahydrofuran, is slowly added in drops at this temperature while being stirred, whereby the rate of addition by drops can be selected so that an internal temperature of -10°C is not exceeded. After a reaction time of 15 minutes at -15°C, a solution of 52.0 g (17.8 mmol) of the title compound of Example 37g) and 1.80 g (17.8 mmol) of triethylamine in 300 ml of dry tetrahydrofuran is then slowly added in drops at 20°C. After a reaction time of one hour at -15°C and two hours at room temperature, the reaction solution is evaporated to the dry state in a vacuum. The remaining residue is taken up in 500 ml of ethyl acetate and washed twice with 200 ml each of saturated sodium bicarbonate solution and once with 200 ml of water. After the organic phase is dried on sodium sulfate, salt is suctioned out, and the ethyl acetate is drawn off in a vacuum. The remaining oily residue is purified on silica gel with use of ethyl acetate/n- hexane (1:20) as an eluant.

Yield: 54.6 g (81.6% of theory) of the above-mentioned title compound as a colorless and strongly viscous oil.

Elementary analysis:

Cld: C 65.09 H6.45 N3.72 F858 S0.85

Fnd: C 65.13 H4.41 N3.69 F852 S090

[ ‘® 1,4,7-Triazaheptane-4-{2-N-[2-(N -ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl }-L- lysine-amide-1,7-bis {2,6-N,N'-bis[1 -0-a-D-(3-carbonyl)-pentyl-mannopyranose]-L- lysine-diamide} 50.0 g (13.28 mmol) of the compound that is produced under 37j) is dissolved in 500 ml of ethanol, mixed with 4.0 g of Pearlman's catalyst (Pd 20%, C) and hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen absorption can be observed. Catalyst is suctioned out, it is thoroughly rewashed with ethanol (about 400 ml) and evaporated to the dry state in a vacuum. The title compound is obtained as a strongly viscous and colorless oil.

Yield: 26.85 g (93.0% of theory)

Elementary analysis:

Cld: C45.85 H6.35 N6.44 F 14.86 S147

Fnd: C 45.76 H6.35 N6.41 F14.92 S139 1) 1,4,7-Triazaheptane-4-{2-N-[2-(N -ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-6-N- [1,4,7-tris(carboxylatomethyl)-1 0-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)-1,4,7,10- tetraazacyclododecane}-L-lysine-amide-1,7-bis{2,6-N,N'-bis[ 1 -O-a-D-(5-carbonyl)- pentyl-mannopyranose]-L-lysine-diamide}, gadolinium complex 554g (8.8 mmol; 2.2 molar equivalents relative to the amine component of Example 37K) that is used) of the Gd complex, described in Patent Application DE 197 28 954 C1 under

Example 31h), of 10-(4-carboxy-1-methyl-2-0x0-3-aza-butyl)-1,4,7,10-tetraazacyclododecane- 1,4,7-triacetic acid and 0.37 g of anhydrous lithium chloride (8.8 mmol) are dissolved at 40°C in 60 ml of absolute dimethyl sulfoxide while being stirred and mixed at this temperature with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 1.84 g (4.0 mmol) of the title compound of Example 37k), dissolved in 40 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 1.82 ¢ (8.8 mmol) of N,N'- dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The suspension that is obtained is then mixed with sufficient acetone until the above-mentioned title compound is

( c@pleely precipitated, the precipitate is suctioned off, dried, taken up in water, insoluble dicyclohexylurea is filtered out, and the filtrate is desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off 3,000 Da), and low-molecular components are removed. The retentate is then freeze-dried.

Yield: 8.77 g (78.7% of theory) as a colorless lyophilizate.

H>O content (Karl-Fischer): 4.43%.

Elementary analysis (relative to anhydrous substance):

Cld: C4398 H597 N7.54 F11.59 Gd 5.64 S1.15

Fnd: C 43.97 H6.02 N7.62 F11.61 Gd 10.18 S 1.15

Example 38 a) 2-No-6-Ne-Bis-[1-0-a-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose]-L- lysine]-methyl ester 10.95 g (18.30 mmol) of 1-carboxymethyloxy-2,3,4,-tetra-O-benzyl-a-D- mannopyranoside [production as described in Patent DE 197 28 954 Cl] is dissolved in 150 ml of dimethylformamide and mixed with a total of 2.09 g (18.3 mmol) of N-hydroxysuccinimide.

Tt is cooled to 0°C, and 3.78 g (18.3 mmol) of dicyclohexyl-carbodiimide is added. It is stirred for one hour at 0°C and then for 4 hours at room temperature. It is cooled to 0°C, and a solution that consists of 2.13 g (9.15 mmol; 0.5 molar equivalent relative to the carboxylic acid that is used) of L-lysine methyl ester-dihydrochloride (commercially available from the Bachem

Company) and 2.02 g (20.13 mmol) of triethylamine in 70 ml of dimethylformamide is added in drops within one hour. After the addition is completed, it is stirred for one more hour at 0°C and then overnight at room temperature. It is evaporated to the dry state in a vacuum, and the residue 1s taken up in 300 ml of ethyl acetate. Precipitated urea is filtered out, and the filtrate is washed twice with 100 ml each of 5% aqueous soda solution. The organic phase is dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/isopropanol 25:1). 10.05 g (82.3% of theory) of the title compound is obtained in the form of a colorless oil.

@® [ Elementary analysis:

Cld: C71.94 H6.79 N 2.10

Fnd: C 71.90 H6.79 N 2.09 b) 2-Na-6-Ne-Bis-[1-0-a-D-carbonylmethyl-2.3 4 6-tetra-O-benzyl-mannopyranose]-L- lysine

Similar to what is described in Example 37¢) for the synthesis of the title compound that is relevant there, the methyl! ester saponification of 15 g (11.23 mmol) of the title compound of

Example 38a) results in the formation of 13.89 g (93.6% of theory) of the above-mentioned title compound in the form of a colorless and viscous oil.

Elementary analysis:

Cld: C 71.80 H6.71 N 2.12

Fnd: C 71.84 H 6.69 N 2.15

Cc) 2-Na-6-Ng-Bis-[ 1-O-a-D-carbonylmethyl-2,3 4 6-tetra-O-benzyl-mannopyranose]-L- lysine-N-hydroxysuccinimide ester 12.09 g (9.15 mmol) of the title compound of Example 38b) is dissolved in 100 ml of dimethylformamide and mixed with a total of 1.04 g (9.15 mmol) of N-hydroxysuccinimide. Itis cooled to 0°C, and 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide is added. It is stirred for one hour at 0°C and then for 4 hours at room temperature. The solvent is then drawn off in a vacuum, and the remaining residue is mixed with 100 ml of ethyl acetate and cooled to 0°C.

Precipitated urea is filtered out, and the filtrate that is obtained is evaporated to the dry state in a vacuum. The thus obtained, resinous-oily filtrate is purified on silica gel with use of ethyl acetate/n-hexane (1:20) as an eluant. :

Yield: 12.24 g (94.4% of theory) of the above-mentioned title compound in the form of a colorless and viscous oil.

Elementary analysis:

Cld: C 70.27 H 6.47 N 2.96

= ~ BR2003/1949 @ @ rn C7031 HEM NI d) 6-N-Benzyloxycarbonyl-2-N-{[2,6-N,N'-bis(1 -0-a-D-carbonylmethyl-2.3,4,6-tetra-O- benzyl-marmnopyranose)]-L-lysyl-}-L-lysine-[1 -(4-perfluorooctylsulfonyl)-piperazine]- amide 19.0 g (13.4 mmol) of the carboxylic acid-N-hydroxysuccinimide ester that is produced under Example 38¢) is dissolved in 75 ml of dimethylformamide and mixed drop by drop at 0°C with a solution, cooled to 0°C, of 11.13 g (13.4 mmol) of the title compound of Example 21c¢), dissolved in 50.0 ml of dimethylformamide. The resulting reaction solution is stirred for 2 more hours at 0°C and for 12 hours at room temperature. For working-up, precipitated dicyclohexylurea is filtered out, and the solvent is then drawn off until a dry state is reached in a vacuum. The thus obtained residue is chromatographed on silica gel [mobile solvent: dichloromethane/ethanol 28:1; and chromatography is performed here with use of a solvent gradient with a proportion of the polar eluant component that is used (here: ethanol) that rises continuously in the course of the chromatography].

Yield: 25.28 g (88.4% of theory) of the title compound in the form of a colorless and strongly viscous oil.

Elementary analysis:

Cld: C 59.10 H5.34 N3.94 F15.13 S1.50

Fnd: C 59.18 H5.35 N4.02 F 15.15 S 1.56 €) 2-N-{[2,6-N,N'-Bis(1-O-a-D-carbonylmethyl-mannopyrano se)]-L-lysyl-L-lysine-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide 20.0 g (9.37 mmol) of the compound that is produced under 38d) is dissolved in 200 ml of ethanol, mixed with 1.5 g of Pearlman's catalyst (Pd 20%, C) and hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen absorption can be observed. Catalyst is suctioned out, it is thoroughly rewashed with ethanol (twice with about 100 mi each) and evaporated to the dry state in a vacuum. The title compound is obtained as a

® s@pely viscous and colorless oil.

Yield: 11.62 g (97.0% of theory).

Elementary analysis:

Cld: C 38.50 H4.65 N6.57 F25.25 S2.51

Fnd: C 38.46 H4.65 N6.51 F2523 S252 f) 6-N-[1,4,7-Tris(carboxylatomethyl)-1 0-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)-1 4,7,10- tetraazacyclododecane)-2-N-{[2,6-N,N'-bis(1 -O-0-D-carbonylmethyl-mannopyranose)]-

L-lysyl}-L-lysine-[1-(4-perfluorooctylsulfony!)-piperazine]-amide, Gd complex 9.98 g (15.84 mmol; 2.2 molar equivalents relative to the amine component of Example 38e) that is used) of the Gd complex, described in Patent Application DE 197 28 954 C1 under

Example 31h), of 10-(4-carboxy- 1-methyl-2-ox0-3-azabutyl)-1,4,7,1 0-tetraazacyclododecane- 1,4,7-triacetic acid and 0.67 g of anhydrous lithium chloride (15.84 mmol) are dissolved at 40°C in 100 ml of absolute dimethyl sulfoxide while being stirred and mixed at this temperature with a total of 1.82 g (15.84 mmol) of N-hydroxysuccinimide and 9.19 g (7.19 mmol) of the title compound of Example 38e), dissolved in 50 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 3.27 g (15.84 mmol) of N,N'- dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The suspension that is obtained is then mixed with sufficient acetone until the above-mentioned title compound is completely precipitated, the precipitate is suctioned off, dried, taken up in water, insoluble dicyclohexylurea is filtered off, and the filtrate is desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off 3,000 Da), and in this case possible, still present low-molecular components are simultaneously removed. The retentate is then freeze-dried.

Yield: 11.85 g (87.2% of theory) as a colorless lyophilizate.

H,0 content (Karl-Fischer): 5.54%

Elementary analysis (relative to anhydrous substance):

Cid: C 38.12 H4.64 N8.15 F20.38 S1.70 Gd 8.32

Fnd: C38.16 H4.59 N 8.18 F20.37 S1.68 Gd_g.28

0 gn a) 1,7-Bis(benzyloxycarbonyl)-4-(3 -oxa-2H,2H.4H,4H.5H,5H-pertluorotridecanoyl)- 1,4,7,10-tetraazacyclododecane

At 0°C and under nitrogen atmosphere, 12.74 g (24.4 mmol) of the title compound of

Example 39g), dissolved in 150 ml of tetrahydrofuran, is added to a solution of 10.75 g (24.4 mmol) of 1,7-bis-[benzyloxycarbonyl]-1,4,7,10-tetraazacyclododecane, dissolved in a mixture that consists of 150 ml of tetrahydrofuran and 15 ml of chloroform. Then, a total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is added in portions at 0°C, allowed to stir overnight at room temperature, and then concentrated by evaporation in a vacuum.

The remaining oil is chromatographed on silica gel (mobile solvent: n-hexane/isopropanol 16:1). 15.89 g (69.0% of theory, relative to the sec-amine that is used) of the monoamide and 3.8 g (8.8% of theory) of the diamide are obtained as by-products. The title compound is isolated in the form of a colorless oil.

Elementary analysis:

Cld: C 45.77 H3.95 F34.19 N5.93

Fnd: C 45.72 H4.01 F 34.22 N 5.88 b) 1 ,7-Bis(benzyloxycarbonyl)-4-(3-oxa-2H,2H,4H,4H,5H, 5H-perfluorotridecanoyl)-10-[1-

S-a-D-(2-carbonyl)-ethyl-2,3 4 6-tetra-O-acetyl-mannopyranose]-1,4,7,1 0- tetraazacyclododecane 7.09 g (13.4 mmol) of 3-(2,3,4,6-tetra-O-acetyl-1 -thio-0-D-mannopyranosyl)-propionic acid-N-hydroxysuccinimide ester (production according to: J. Haensler et al., Bioconjugate

Chem. 4, 85, (1993); Chipowsky, S., and Lee, Y. C. (1973), Synthesis of 1-Thio-Aldosides;

Carbohydrate Research 31, 339-346) is dissolved in 100 ml of dimethylformamide and mixed drop by drop at 0°C with a solution, precooled to 0°C, of 12.65 g (13.4 mmol) of the title . compound of Example 39a), dissolved in 100 ml of dimethylformamide. It is stirred for 2 hours at 0°C and for 12 hours at room temperature. For working-up, the solvent is drawn off in a vacuum until a dry state is reached, and the thus obtained residue is then chromatographed on

C @ gel (mobile solvent: dichloromethane/ethyl acetate 20:1; the chromatography was performed with use of a solvent gradient with continuous increase of the proportion of ethyl acetate).

Yield: 16.23 g (88.9% of theory) of the title compound in the form of a colorless and strongly viscous oil.

Elementary analysis:

Cld: C 46.70 H4.36 N4.11 F 23.69 S2.35

Fnd: C 46.66 H4.35 N4.12 F23.65 S2.30 c) 1-(3-Oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoyl)-7-[ 1 -S-a-D-(2-carbonyl)-ethyl- 2,3,4,6-tetra-O-acetyl-mannopyranose]-1,4,7,10-tetraazacyclododecane 15.0 g (11.0 mmol) of the compound that is produced under 39b) is dissolved in 150 ml of ethanol, mixed with 1.0 g of Pearlman's catalyst (Pd 20%, C) and hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen absorption can be observed. Catalyst is suctioned out, it is thoroughly rewashed with ethanol (twice with 75 ml each) and evaporated to the dry state in a vacuum. The title compound is obtained as a strongly viscous and colorless oil.

Yield: 11.56 g (96.0% of theory).

Elementary analysis:

Cld: C40.59 H4.33 N5.12 F29.50 S2.93 :

Fnd: C40.63 H4.35 N5.11 F29.52 S2.92 d) 1-(3-Oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoyl)-7-[ 1-S-a-D-(2-carbonyl)-ethyl- mannopyranose]-1,4,7,10-tetraazacyclododecane 10.0 g (9.13 mmol) of the title compound of Example 39c¢) is suspended in 100 ml of absolute methanol and mixed at 5°C with a catalytic amount of sodium methanolate. After a reaction time of 5 hours at room temperature, even thin-layer chromatographic checking (eluant: chloroform/methanol 4:1) of the course of the reaction indicates a quantitative reaction. For the

( ges of working-up, the now clear reaction solution is neutralized by mixing with Amberlite

IR 120 (H™ form)-cation-exchange resin, exchanger is suctioned out, rewashed with methanol, and the thus obtained methanolic filtrate is drawn off in a vacuum until a dry state is reached.

The oily residue that is obtained is purified by column chromatography on silica gel (mobile solvent: dichloromethane/n-hexane/ethyl acetate 15:20:1; and chromatography is performed with use of a solvent gradient with continuous increase of the proportion of ethyl acetate). After 'H-

NMR spectroscopic study of the title compound, the presence of the a-configuration at the anomeric center of the D-mannopyranose was definitively established based on the size of the coupling constant of Ji 2 = 0.9 Hz. This a-configuration is the existing configuration that is exclusive to the anomeric center, i.e., the amount of the B-configured anomer of the title compound that can possibly be formed thus lies below the 'H-NMR-spectroscopic detection limit. The above-mentioned title compound was accordingly shown only in the form of the pure a-configured anomer.

Yield: 8.28 g (98.0% of theory) of the title compound in the form of a colorless and strongly viscous oil.

Elementary analysis:

Cld: C37.59 H4.24 N6.05 F 34.85 S3.46

Fnd: C 37.57 H4.28 N6.02 F34.85 S3.44 e) 1-(3-Oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoyl)-7-[1 _S-0-D-(2-carbonyl)-ethyl- mannopyranose]-4,10-bis[1,4,7-tris(carboxylatomethyl)-10-(3 -aza-4-0x0-5-methyl-5-yl- pentanoyl)]-1,4,7,10-tetraazacyclododecane, digadolinium complex

Amide conjugate of the 1,4,7,10-tetraazacyclododecane with [1,7-bis-[gadolinium complex of 10-(4-carboxy- 1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1 ,4,7-triacetic acid]; 3-(2,3,4,6-tetra-O-acetyl- 1 -thio-a-D-mannopyranosyl)-propionic acid 2.48 g [(3.94 mmol); 4.4 molar equivalents relative to the diamine component 39d) that is used] of the Gd complex, described in Patent Application DE 197 28 954 C1 under Example 31h), of 10-(4-carboxy-1-methyl-2-0xo0-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1.4,7-

145 . W2003/1949 @® ugptic acid and 167 mg of anhydrous lithium chloride (3.94 mmol) are dissolved at 40°C in 40 ml of absolute dimethyl sulfoxide while being stirred and mixed at this temperature with a total of 453 mg (3.94 mmol) of N-hydroxysuccinimide and 980 mg (0.895 mmol) of the title compound of Example 19Ad), dissolved in 10 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 814 mg (3.946 mmol) of N,N'- dicvclohexylcarbodiimide and stirred for 12 hours at room temperature. The suspension that is obtained is then mixed with sufficient acetone until the above-mentioned title compound is completely precipitated, the precipitate is suctioned off, dried, taken up in water, insoluble dicyclohexylurea is filtered out, and the filtrate is desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off 3,000 Da), and low-molecular components are removed. The retentate is then freeze-dried.

Yield: 1.32 g (69.1% of theory) as a colorless lyophilizate.

H>O content {(Karl-Fischer): 7.65%

Elementary analysis (relative to anhydrous substance):

Cld: C37.43 H4.45 N9.12 F 15.02 S 1.49 Gd 14.63

Fnd: C 37.42 H 4.50 N9.18 F 15.07 S 1.51 Gd 14.58 f) 3-Oxa-2H,2H 4H,4H,5H,5H-perfluorotridecanoic acid-t-butyl ester 25.0 g (53.8 mmol) of 1H,1H,2H,2H-perfluoro-1-decanol [commercially available from the Lancaster Company] is dissolved in 250 ml of absolute toluene and mixed at room temperature with a catalytic amount (about 0.75 g) of tetra-n-butyl-ammonium hydrogen sulfate.

Then, a total of 7.55 g (134.6 mmol; 2.5 equivalents relative to the alcohol component that is used) of fine-powder potassium hydroxide powder is added at 0°C, followed by 15.73 g (80.7 mmol; 1.5 equivalents relative to the alcohol component that is used) of bromoacetic acid-tert- butylester, and it is allowed to stir for 2 more hours at 0°C. The thus obtained reaction solution is stirred for 12 hours at room temperature, and for the purpose of working-up, it is mixed with a total of 500 ml of ethyl acetate and 250 ml of water. The organic phase is separated and washed twice with water. After the organic phase is dried on sodium sulfate, salt is suctioned out, and

[ thggptvent is drawn off in a vacuum. The remaining oily residue is purified on silica gel with use of ethyl acetate/hexane (1:10) as an eluant.

Yield: 26.3 g (84.6% of theory) of the above-mentioned title compound as a colorless and strongly viscous oil.

Elementary analysis:

Cld: C33.23 H2.61 F55.85

Fnd: C 33.29 H2.61 F55.90 2) 3-Oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanecarboxylic acid 20.0 g (34.58 mmol) of the title compound of Example 391) is suspended in 200 ml of a mixture that consists of methanol and 0.5 molar sodium hydroxide solution at a ratio of 2:1 while being stirred at room temperature, and then it is heated to 60°C. After a reaction time of 12 hours at 60°C, the now clear reaction mixture is neutralized for working-up by mixing with Amberlite

IR 120 (H" form)-cation-exchange resin, exchanger is suctioned out, and the thus obtained methanolic-aqueous filtrate is drawn off in a vacuum until a dry state is reached. The amorphous-oily residue that is obtained is purified on silica gel with use of ethyl acetate/n- hexane (1:3) as an eluant.

Yield: 16.0 g (88.6% of theory) of the above-mentioned title compound as a colorless and strongly viscous oil.

Elementary analysis:

Cid: C27.60 H1.35 F61.85

Fnd: C27.58 H1.36 F61.90

Example 40 a) 6-Benzyloxycarbonyl-2-[2-(N -ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-L-lysine- methyl ester 16.18 g (27.0 mmol) of 2-[N-ethyl-N-perfluorooctylsulfonyl)-aminoacetic acid (production according to: DE 196 03 033), dissolved in 50 ml of tetrahydrofuran, is added drop

( bor at 0°C and under nitrogen atmosphere to 8.0 g (24.4 mmol) of e-carbonyloxybenzyl-L- lvsinemethyl ester hydrochloride (commercially available from the Bachem Company), dissolved in a mixture that consists of 150 ml of tetrahydrofuran, 15 ml of chloroform and 2.62 g (26.0 mmol) of triethylamine. Then, a total of 18.0 g (36.6 mmol) of EEDQ [2-ethoxy-1- ethoxycarbonyl-1,2-dihydroquinoline] is added in portions at 0°C and allowed to stir overnight at room temperature. It is then concentrated by evaporation in a vacuum, and the remaining oil is chromatographed on silica gel (mobile solvent: n-hexane/isopropanol 15:1). 17.0 g (79.6% of theory, relative to the primary amine used) of the title compound is obtained in the form of a colorless oil.

Elementary analysis:

Cld: C 38.41 H3.45 F36.89 N 4.80 S3.66

Fnd: C 38.42 H3.47 F36.92 N 4.87 S3.64 b) 2-[2-(N-Ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-L-lysine-methyl ester 15.0 g (20.23 mmol) of the compound that is produced under Example 40a) is dissolved in 200 ml of ethanol, mixed with 800 mg of Pearlman's catalyst (Pd 20% on activated carbon) and hydrogenated until the calculated amount of hydrogen is taken up. Catalyst is suctioned out, thoroughly rewashed with ethanol and evaporated to the dry state in a vacuum. The title compound is obtained as a colorless oil.

Yield: 14.68 g (97.9% of theory)

Elementary analysis:

Cld: C32.40 H3.26 F43.56 N5.67 S4.32

Fnd: C32.42 H3.27 F43.60 N5.67 S4.34

Cc) 6-(1 -O-a-D-Carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose) 2-[2-(N-ethyl-N- perfluorooctylsulfonyl)-amino]-acetyl-L-lysine-methyl ester 21.31 g (35.6 mmol) of 1-carboxymethyloxy-2,3,4,-tetra-O-benzyl-a-D-mannopyranoside [production as described in Patent DE 197 28 954 C1} and 3.60 g (35.6 mmol) of triethylamine o afissolved in 500 ml of dry tetrahydrofuran. After the reaction solution is cooled to -15°C to - 20°C, a solution of 4.92 g (35.6 mmol) of isobutyl chloroformate in 75 ml of dry tetrahydrofuran is slowly added at this temperature while being stirred. whereby the rate of addition by drops can be selected so that an internal temperature of -10°C is not exceeded. After a reaction time of 15 minutes at -15°C, a solution of 26.39 g (35.6 mmol) of the title compound of Example 40b) and 3.60 g (35.6 mmol) of triethylamine in 100 ml of dry tetrahydrofuran is then slowly added in drops at -20°C. After a reaction time of one hour at -1 5°C and two hours at room temperature, the reaction solution is evaporated to the dry state in a vacuum. The remaining residue is taken up in 250 ml of ethyl acetate and washed twice with 100 ml each of saturated sodium bicarbonate solution and once with 200 ml of water. After the organic phase is dried on sodium sulfate, salt is suctioned out, and the ethyl acetate is drawn off in a vacuum. The remaining oily residue is . purified on silica gel with use of ethyl acetate/n-hexane (1:10) as an eluant.

Yield: 38.12 g (81.0% of theory) of the above-mentioned title compound as a colorless and strongly viscous oil.

Elementary analysis:

Cld: C49.92 H3.92 N2.53 F29.18 S2.90

Fnd: C49.99 H4.11 N 2.69 F29.22 S3.01 d) 6-(1-0-a-D-Carbonylmethyl-2,3 ,4,6-tetra-O-benzyl-mannopyranose) 2-[2-(N-ethy!-N- perfluorooctylsulfonyl)-amino]-acetyl-L-lysine 27.65 g (20.92 mmol) of the compound that is produced under Example 40c) is dissolved in 250 ml of methanol. The solution of 4.0 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water is then added, and it is stirred for 3 hours at 50°C. After the course of the reaction is checked by means of thin-layer chromatography, methyl ester saponification has already taken place quantitatively. It is evaporated to the dry state in a vacuum, the remaining residue is taken up in 300 ml of ethyl acetate, and the organic phase is extracted twice with 100 ml each of dilute, aqueous citric acid solution. After drying on sodium sulfate, it is filtered and evaporated to the drv state in a vacuum. The residue that is obtained is chromatographed on silica gel (mobile

@® { n-hexane/chloroform/isopropanol 15:10:1). 24.31 g (88.9% of theory) of the title compound is obtained in the form of a colorless and viscous oil.

Elementary analysis:

Cld: C51.46 H4.70 N3.21 F24.71 S2.45

Fnd: C51.49 H4.71 N3.19 F 24.72 S2.41 e) 6-(1-O-a-D-Carbonylmethyl-mannopyranose) 2-[2-(N -ethyl-N-perfluorooctylsulfonyl)- amino]-acetyl-L-lysine 20.0 g (15.30 mmol) of the title compound of Example 40d) is dissolved in a mixture that consists of 250 ml of 2-propanol and 25 ml of water, and it is mixed with 1.0 g of palladium catalyst (10% Pd on activated carbon). It is hydrogenated for 12 hours at room temperature and a hydrogen pressure of one atmosphere. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is dissolved in 200 ml of methanol, and the reaction product is precipitated by mixing with a total of 800 ml of diethyl ether. After the thus obtained solid is suctioned off, the latter is dried in a vacuum at 50°C.

Yield: 14.32 g (99.0% of theory) of an amorphous solid.

Elementary analysis: ~ Cld: C35.56 H3.84 N4.44 S3.39 F 34.15

Fnd: C 35.58 H3.81 N4.45 S3.40 F 34.17 f) 6-(1-0-a-D-Carbonylmethyl-mannopyranose) 2-[2-(N -ethyl-N-perfluorooctylsulfonyl)- amino}-acetyl-L-lysine-N-{2-hydroxyprop-3-yl-[1,4,7-tris(carboxylatomethyl)-1,4,7, 10- tetraazacyclododecan-10-yl]}-amide, Gd complex 7.48 g (7.91 mmol) of the title compound of Example 40e) is dissolved in 50 ml of dimethyl sulfoxide at 40°C, and 1.00 g (8.70 mol) of N-hydroxysuccinimide is added. It is cooled to 20°C, and 1.795 g (8.7 mmol) of dicyclohexylcarbodiimide is added. It is stirred for one hour at 20°C and then for 4 hours at 40°C. Then, a solution that consists of 4.53 g (7.91 mmol) of the gadolinium complex of 10-(2-hydroxy-3-aminopropyl)-4,7,10-tris(carboxymethyl)-

1.4,7,10-tetraazacyclododecanine [for production, cf.: WO 97/02051] in 20 ml of dimethyl sulfoxide is added in drops at this temperature within 10 minutes. It is stirred for one hour at 40°C, then overnight at room temperature. The thus obtained suspension is then mixed with sufficient acetone until the above-mentioned title compound is completely precipitated, the precipitate is suctioned off, dried, taken up in water, insoluble dicyclohexylurea is filtered out, and the filtrate 1s desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off 3,000

Da), and low-molecular components are removed. The retentate is then freeze-dried.

Yield: 9.71 g (81.7% of theory) as a colorless lyophilizate.

H,0 content (Karl-Fischer): 3.97%

Elementary analysis (relative to anhydrous substance):

Cld: C35.16 H4.16 N 7.45 F21.48 Gd 10.46 S 2.13

Fnd: C35.17 H4.20 N 7.42 F21.49 Gd 10.48 S 2.09

Example 41 a) 6-N-[1-0-a-D-(5-Carbonyl)-penty!-2,3 ,4 6-tetra-O-benzyl-mannopyranose]-2N-[2-(N- ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-L-lysine-methyl ester 5.23 g (8.0 mmol) of the 5-(carboxy)pentyl-2,3,4,6-tetra-O-benzyl-a-D-mannopyranoside described in Example 30c), 1.3 g (8.0 mmol) of 1-hydroxybenzotriazole and 2.6 g (8.0 mmol) of 2-(1H-benzotriazol-1-y1)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU; Peboc Limited,

UK) are dissolved in 75 ml of DMF and stirred for 15 minutes. This solution is then mixed with 5.16 ml (30 mmol) of N-ethyldiisopropylamine and with 5.93 g (8.0 mmol) of the amine that is described under Example 40b), and it is stirred for 1.5 days at room temperature. For working- up, the solvent is drawn off in a vacuum until a dry state is reached, and the thus obtained residue is then chromatographed on silica gel (mobile solvent: dichloromethane/ethyl acetate 30:1, chromatography was carried out with use of a solvent gradient with a proportion of ethyl acetate that rises continuously). ® o

® ® Yield: 9.70 g (88.0% of theory) of the title compound in the form of a colorless and strongly viscous oil.

Elementary analysis:

Cld: C52.29 H4.97 N3.05 F23.43 S2.33 : Fnd: C 52.33 H4.95 N3.12 F23.50 S2.30 b) 6-N-[1-O-a-D-(5-Carbonyl)-pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose]- 2N-[2-(N- ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-L-lysine 9.0 g (12.40 mmol) of the compound that is produced under Example 412) is dissolved in 150 ml of methanol. The solution of 2.48 g (62.0 mmol) of sodium hydroxide in 15 ml of distilled water is then added to it, and it is stirred for 3 hours at 50°C. After the course of the reaction is checked by means of thin-layer chromatography, methyl ester saponification has already taken place quantitatively according to the above-mentioned reaction time. Itis evaporated to the dry state in a vacuum, and the remaining residue is taken up in 300 ml of ethyl acetate, and the organic phase is extracted twice with 100 ml each of dilute, aqueous citric acid solution. After drying on sodium sulfate, it is filtered and evaporated to the dry state in a vacuum. The residue that is obtained is chromatographed on silica gel (mobile solvent: n- hexane/chlorofornv/isopropanol 25:10:1). 15.88 g (93.9% of theory) of the title compound is obtained in the form of a colorless and strongly viscous oil.

Elementary analysis:

Cld: C51.95 H4.88 N3.08 F23.67 S2.35

Fnd: C 51.99 H4.91 N3.09 F23.70 S2.33 c) 6-N-[1-O-a-D-(5-Carbonyl)-pentyl-mannopyranose]-2N-[2-(N-ethyl-N- perfluorooctylsulfonyl)-amino]-acetyl-L-lysine 13.0 g (9.52 mmol) of the title compound of Example 41b) is dissolved in a mixture that consists of 150 ml of 2-propanol and 25 ml of water, and 1.0 g of the palladium catalyst (10% Pd

® ® carbon) is added. It is hydrogenated for 12 hours at 1 atmosphere of hydrogen pressure and room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue that is obtained is chromatographed on silica gel (mobile solvent: n-hexane/chloroform/isopropanol 15:10:1). 9.09 g (95.1% of theory) of the title compound is obtained in the form of a colorless and strongly viscous oil.

Elementary analysis:

Cld: C37.10 H4.22 N4.19 F32.18 S3.10

Fnd: C37.09 H421 N4.19 F32.20 S3.13 d) 6-N-[1-O-a-D-(5-Carbonyl)-pentyl-mannopyranose]-2N-[ 2-(N-ethyl-N- perfluorooctylsulfonyl)-amino]-acetyl-L-lysine-N- {2-hydroxy-prop-3-yl-[1,4,7- tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-10-yl]}-amide, Gd complex - 7.93 g (7.91 mmol) of the title compound of Example 41c) is dissolved at 40°C in 75 ml of dimethyl sulfoxide, and it is mixed with 1.00 g (8.70 mol) of N-hydroxysuccinimide. Itis cooled to room temperature, and a total of 1.795 g (8.7 mmol) of dicyclohexylcarbodiimide is added. It is stirred for one hour at 20°C and then for 4 hours at 40°C. Then, a solution that consists of 4.53 g (7.91 mmol) of the gadolinium complex of 10-(2-hydroxy-3-aminopropyl)- 4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecanine [for production, cf.: WO 97/02051] in 20 ml of dimethyl sulfoxide is added in drops at 40°C within 10 minutes to this solution of the active ester of the title compound of Example 41c). It is stirred for one hour at 40°C, then overnight at room temperature. The thus obtained suspension is then mixed with a sufficient amount of a mixture that consists of acetone/2-propanol (2:1) until the above-mentioned title compound is completely precipitated, the precipitate is suctioned off, rewashed with ethyl acetate, dried, taken up in water, insoluble dicyclohexylurea is filtered out, and the filtrate is desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off 3,000 Da), and low- molecular components are removed. The retentate is then freeze-dried.

® @® Yield: 9.71 g (78.8% of theory) as a colorless lyophilizate.

H,O content (Karl-Fischer): 6.65%

Elementary analysis (relative to anhydrous substance):

Cld: C 36.97 H4.52 N7.19 F20.71 Gd 10.08 S 2.06

Fnd: C 37.02 H4.50 N 7.22 F20.69 Gd 10.08 S 2.09 )

Example 42 a) 6-N- {4-[2,3-Bis-(N,N-bis(t-butyloxycarbonylmethyl)-amino)-propyl]-phenyl} -3-oxa- propionyl-2-N-(1-a-D-carbonylmethyl-mannopyranose) L-lysine-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide 5.25 g (7.72 mmol) of the tetra-t.bu-ester of "Tyr-EDTA-carboxylic acid" and 781 mg (7.72 mmol) of triethylamine are dissolved in 50 ml of methylene chloride. At -15°C, a solution that consists of 1.16 g (8.5 mmol) of isobutyl chloroformate in 10 ml of methylene chloride is added in drops within 5 minutes, and it is stirred for another 20 minutes at -15°C. Then, the solution is cooled to -25°C, and a solution that consists of 7.07 g (7.72 mmol) of the title compound of Example 30e) and 2.12 g (21.0 mmol) of triethylamine, in 70 ml of tetrahydrofuran, is added in drops within 30 minutes, and subsequently stirred for 30 more minutes at -15°C, and then stirring is continued overnight at room temperature. For working-up, the solvent is drawn off in a vacuum, and the remaining oily residue is taken up in 250 ml of chloroform.” The chloroform phase is extracted twice with 100 ml each of a 10% aqueous ammonium chloride solution, the organic phase is dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol = 20:1).

Yield: 9.60 g (79.0% of theory) of a colorless and very viscous oil.

Elementary analysis:

Cld: C 46.39 H5.55 N5.32 F20.45 S2.03

Fnd: C4642 H5.51 N 5.29 F20.49 $2.09

¢ @ 6-N-{4-[2,3-Bis-(N,N-bis(carboxymethyl)-amino)-propyl]-phenyl} -3-oxa-propionyl-2-

N-(1-a-D-carbonylmethyl-mannopyranose) L-lysine-[ 1-(4-perfluorooctylsulfonyl)- piperazine]-amide 9.0 g (5.70 mmol) of the compound produced under Example 42a) is dissolved in 150 ml of methanol. The solution of 4.0 g (100.0 mmol) of sodium hydroxide in 25 ml of distilled water is then added to it, and it is stirred for 6 hours at 60°C. After the course of the reaction is checked by means of thin-layer chromatography, saponification of the tetra-t-butyl ester has already taken place quantitatively according to the above-mentioned reaction time. It 18 evaporated to the dry state in a vacuum, and the remaining residue is taken up in 50 ml of dimethyl sulfoxide in the heat, and then it is mixed with a sufficient amount of a mixture that consists of acetone/ethyl acetate (1:1) until the above-mentioned title compound is completely precipitated, the thus obtained precipitate is suctioned off, thoroughly rewashed with ethyl acetate, dried, taken up in water, the pH of the product solution is set at 35 with 1 molar hydrochloric acid, possibly present insoluble components are filtered out, and the filtrate 1s desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off 3,000 Da), and low- molecular components are removed. The retentate is then freeze-dried.

Yield: 6.76 g (87.6% of theory) as a colorless lyophilizate.

H,O content (Karl-Fischer): 3.30%.

Elementary analysis (relative to anhydrous substance): :

Cld: C 39.89 H4.09 N6.20 F 23.84 S2.37

Fnd: C 39.92 H4.15 N6.22 F2392 S229 c) 6-N-{4-[2,3-Bis-(N,N-bis(carboxylatomethyl)-amino)-propyl]-phenyl}-3 -oxa-propionyl- 2-N-(1-a-D-carbonylmethyl-mannopyranose) L-lysine-[1-(4-p erfluorooctyl sulfonyl)- piperazine]-amide, Mn complex, disodium salt 3.0 g (2.22 mmol) of the title compound of Example 42b) is dissolved in 150 ml of a water/ethanol (3:1) mixture at boiling heat, and it is mixed in portions with 0.25 g (2.22 mmol)

® ofensaneselld carbonate at 80°C. Then, the thus obtained reaction solution is refluxed for 5 hours. After cooling to room temperature, the solvent mixture is completely drawn off in a vacuum, and the remaining residue is dissolved in a mixture that consists of 200 ml of distilled water/n-butanol (1:1). A pH of 7.2 is set by mixing with IN sodium hydroxide solution while being stirred vigorously. After the n-butanol is completely drawn off in a vacuum, the remaining aqueous phase is desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off 3,000

Yield: 3.19 g (99.0% of theory) as a colorless lyophilizate.

H,O content (Karl-Fischer): 5.08%.

Elementary analysis (relative to anhydrous substance):

Cld: C3723 H3.54F22.25Mn 3.78 N5.79 Na 3.17 S 2.21

Fnd: C37.30H 3.49 F 22.29 Mn 3.81 N5.76 Na 3.19 S 2.18

Example 43 a) 3-Benzyloxycarbonylamino-glutaric acid-[1 -(4-perfluorooctylsulfonyl)-piperazine]- monoamide

A stirred solution of 25.0 g (94.96 mmol) of 3-N-(benzyloxycarbonyl)-glutaric acid- anhydride [synthesis according to: Hatanaka, Minoru, Yamamoto, Yu-ichi; Nitta, Hajime;

Ishimaru, Toshiyasu; TELEAY; Tetrahedron Lett.: EN; 22; 39; 1981; 3883-3886;] in 150 ml of absolute tetrahydrofuran is mixed drop by drop while being stirred with a solution of 53.97 g (95.0 mmol) of 1-petfluorooctylsulfonylpiperazine in 150 ml of tetrahydrofuran, and the thus obtained reaction solution is refluxed for 12 hours. After cooling to room temperature, itis concentrated by evaporation to the dry state, and the remaining oily residue is purified on silica gel with use of dichloromethane/2-propanol (20:1) as an eluant.

Yield: 75.80 g (96.0% of theory) of the above-mentioned title compound in the form of a colorless and viscous oil.

1 . B2003/1949 @ ® Elementary analysis:

Cld: C 36.11 H2.67 N5.05 S3.86 F 38.84

Fnd: C 36.12 H2.61 N5.08 S3.88 F 38.82 b) 3-Amino-glutaric acid-[1 -(4-perfluorooctylsulfonyl)-piperazine]-monoamide 31.50 g (37.88 mmol) of the compound that is produced under 43b) is dissolved in 300 ml of ethanol, it is mixed with 2.5 g of Pearlman's catalyst (Pd 20%, C) and hydrogenated until quantitative hydrogen uptake is reached at 1 atmosphere of hydrogen pressure. Catalyst is suctioned out, it is rewashed with ethanol and evaporated to the dry state in a vacuum. The title compound is obtained as a whitish-yellow, viscous oil.

Yield: 25.22 g (95.5% of theory)

Elementary analysis:

Cld: C29.28 H2.31 N6.03 S4.06 F 46.31

Fnd: C29.32 H2.29 N6.08 S4.08 F 46.28 c) 3-N-(1-a-D-Carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)- glutaric acid-[1-(4- perfluorooctylsulfonyl)-piperazine]-monoamide 21.52 g (18.96 mmol) of 1-carboxymethyloxy-2,3,4,-tetra-O-benzyl-a-D- mannopyranoside [production as described in Patent DE 197 28 954 C1] is dissolved at room temperature in 100 ml of absolute dimethylformamide, and it is mixed at 0°C with 2.56 g (22.2 mmol) of N-hydroxysuccinimide, followed by 4.55 g (22.2 mmol) of dicyclohexylcarbodiimide.

After a reaction time of 60 minutes at 0°C and 3 hours at 22°C, insoluble dicyclohexylurea is filtered out, and the thus obtained clear active ester solution of the above-mentioned title compound is slowly added in drops at 0°C to a stirred solution of 13.22 g (18.96 mmol) of the compound of Example 43b), dissolved in 100 ml of dimethylformamide. After a reaction time of 12 hours at room temperature, the solvent is drawn off in a vacuum, and the remaining residue is taken up in 300 ml of ethyl acetate, urea is filtered out, and the organic filtrate is washed twice

Qo 9 100 ml each of saturated sodium bicarbonate solution and once with 100 ml of 10% aqueous citric acid solution and once with 200 ml of water. After the organic phase is dried on sodium sulfate, salt is suctioned out, and the ethyl acetate is drawn off in a vacuum. The remaining oily residue is purified on silica gel with use of ethyl acetate/n-hexane (1:15) as an eluant.

Yield: 21.39 g (88.3% of theory) of the above-mentioned title compound as a colorless and strongly viscous oil.

Elementary analysis:

Cld: C 49.81 H4.10 N3.29 F25.27 $2.51

Fnd: C 49.89 H4.11 N 3.32 F25.22 S2.51 d) 3-N-(1 -a-D-Carbonylmethyl-mannop yranose)-glutaric acid-[1-(4- perfluorooctylsulfonyl)-piperazine]-monoamide 19.55 g (15.30 mmol) of the title compound of Example 43c) is dissolved in a mixture that consists of 250 ml of 2-propanol and 25 ml of water and mixed with 1.5 g of palladium catalyst (10% Pd on activated carbon). It is hydrogenated for 12 hours at room temperature and a hydrogen pressure of one atmosphere. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a a" The residue is dissolved in 200 ml of methanol, and the reaction product is precipitated by mixing with a total of 800 ml of diethyl ether. After the thus obtained solid is suctioned off, the latter is dried in a vacuum at 40°C.

Yield: 17.49 g (97.5% of theory) of an amorphous solid.

Elementary analysis:

Cld: C32.73 H3.08 N4.58 $3.49 F35.20

Fnd: C 32.68 H3.15 N4.55 S3.50 F35.17

L 4 3-N-(1-a-D-Carbonylmethyl-mannopyranose)-glutaric acid-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide-5-N- {2-hydroxy-prop-3-yl-[1,4,7- tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-10-y1} } -amide, Gd complex 14.43 g (15.84 mmol) of the title compound of Example 43d) and 0.67 g of anhydrous lithium chloride (15.84 mmol) are dissolved at 40°C in 100 ml of absolute dimethyl sulfoxide while being stirred, and it is mixed at this temperature with a total of 1.82 g (15.84 mmol) of N- hydroxysuccinimide and a solution of 9.08 g (15.84 mmol) of the gadolinium complex of 10-(2- hydroxy-3-aminopropyl)-4,7,10-tris(carboxymethyl)-1,4,7,1 0-tetraazacyclododecanine {for production, ¢f.: WO 97/02051}, in 50 ml of dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 3.27 g (15.84 mmol) of N,N'- dicyclohexylcarbodiimide, and it is stirred for 12 hours at room temperature. The suspension that is obtained is then mixed with sufficient acetone until the above-mentioned title compound is completely precipitated, the precipitate is suctioned off, dried, taken up in water, insoluble dicyclohexylurea is filtered out, and the filtrate is desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off 3,000 Da) and in this case possible, still present low-molecular components are simultaneously removed. The retentate is then freeze-dried.

Yield: 18.71 g (80.2% of theory) as a colorless lyophilizate.

H,O content (Karl-Fischer): 4.87%.

Elementary analysis (relative to anhydrous substance):

Cld: C3424 H3.83 N7.61 F21.92 S2.18 Gd 10.67

Fnd: C 34.26 H3.79 N 7.58 F21.87 S2.18 Gd 10.68

¢ Ou a) 1,7-Bis(benzyloxycarbonyl)-4-{3-oxa-pentane-1 ,S-dicarboxylic acid-1-oyl-5-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide}-1 0-[2,6-N,N'-bis(1-O-a-D-carbonylmethyl- 2,3,4,6-tetra-O-benzyl-mannopyranose)}-L-lysyl-1,4,7,1 O-tetraazacyclododecane 33.04 g (25.0 mmol) of the title compound of Example 18c), dissolved in 250 ml of tetrahydrofuran, is added at 0°C and under nitrogen atmosphere to a solution that consists of 27.0 g (24.4 mmol) of the sec-amine that is produced under Example 35a), in a mixture that consists of 150 ml of tetrahydrofuran and 15 ml of chloroform. Then, a total of 18.0 g (36.6 mmol) of

FEDQ [2-ethoxy- 1-ethoxycarbonyl-1,2-dihydroquinoline] is added in portions at 0°C and allowed to stir overnight at room temperature. It is then evaporated to the dry state 1n a vacuum, and the remaining oil is chromatographed on silica gel (mobile solvent: n-hexane/isopropanol 25:1). 45.87 g (78.0% of theory, relative to the sec-amine that is used) of the title compound is obtained in the form of a colorless oil.

Elementary analysis:

Cld: C 59.30 H5.39 F13.40 N4.65 S1.33

Fnd: C 59.32 H5.37 F13.37 N4.70 S1.34 b) 1-{3-Oxa-pentane-1,5-dicarboxylic acid-1-oyl-5-{1 -(4-perfluorooctylsulfonyl)- piperazine]-amide}-7-[2,6-N,N'-bis(1 -O-a-D-carbonylmethyl-mannopyranose)]-L-lysyl- 1,4,7,10-tetraazacyclododecane 24.1 g (10.0 mmol) of the title compound that is produced under Example 44a) is dissolved in 250 ml of ethanol, and it is mixed with 1.4 g of Pearlman's catalyst (Pd 20%, C). It is hydrogenated until quantitative hydrogen uptake is reached, then catalyst is suctioned out, it is thoroughly rewashed with ethanol and evaporated to the dry state in a vacuum. The product is yellowish in color, and extremely viscous oil is obtained.

Yield: 12.80 g (90.1% of theory)

@ C Elementary analysis:

Cld: C39.72 H4.89 F22.73 N7.838 S226

Fnd: C39.72 H4.87 F22.77 N7.90 52.24 c) 1-{3-Oxa-pentane-1,5-dicarboxylic acid-1 -oyl-5-[1-(4-perfluorooctylsulfonyl)- piperazine]-amide}-7-[2,6-N,N'-bis(1 -O-a-D-carbonylmethyl-mannopyranose)]-L-lysyl- 4,10-bis[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-0x0-5 -methyl-5-yl-pentanoyl)]- 1,4,7,10-tetraazacyclododecane, digadolinium complex 5.54 g [8.8 mmol; 2.2 molar equivalents relative to the amine component of Example 44b) that is used] of the Gd-complex, described in Patent Application DE 197 28 954 C1 under

Example 31h), of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane- 1,4,7-triacetic acid and anhydrous lithium chloride (0.37 g, 8.8 mmol) is dissolved at 40°C in 60 ml of absolute dimethyl sulfoxide while being stirred, and a total of 1.01 g (8.8 mmol) of N- hydroxysuccinimide and 5.68 g (4.0 mmol) of the title compound of Example 44b), dissolved in 40 ml of absolute dimethyl sulfoxide, is mixed at this temperature. After cooling to room temperature, the reaction solution is mixed with 1.82 g (8.8 mmol) of N,N'- dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The suspension that is obtained is then mixed with sufficient acetone until the above-mentioned title compound is completely precipitated, the precipitate is suctioned off, dried, taken up in water, insoluble dicyclohexylurea is filtered out, and the filtrate is desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off 3,000 Da), and low-molecular components are removed. The retentate is then freeze-dried.

Yield: 8.52 g (80.6% of theory; relative to the diamine component that 1s used) as a colorless lyophilizate.

H,O content (Karl-Fischer): 6.09%

Elementary analysis (relative to anhydrous substance):

Cld: C 38.61 H4.76 N9.53 F12.21 Gd 11.89 S1.12

@ ® Fnd: C 38.57 H4.82 N9.52 F12.21 Gd 11.93 S 1.15

Example 45 a) 1,7-Bis(benzyloxycarbonyl)-4- {3-oxa-pentane-1,5-dicarboxylic acid-1 -oyl-5-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide}-10- {2,6-N,N'-bis(1-0-a-D-(5-carbonyl)- pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose)} -L-lysyl-1 ,4,7,10-tetraazacyclododecane 35.80 g (25.0 mmol) of the title compound of Example 37¢), dissolved in 250 ml of tetrahydrofuran, is added at 0°C and under nitrogen atmosphere to a solution that consists of 27.0 g (24.4 mmol) of the sec-amine that is produced under Example 35a), in a mixture that consists of 150 ml of tetrahydrofuran and 15 ml of chloroform. Then, a total of 18.0 g (36.6 mmol) of

EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is added in portions at 0°C, and it is allowed to stir overnight at room temperature. It is then evaporated to the dry state in a vacuum, and the remaining oil is chromatographed on silica gel (mobile solvent: n-hexane/isopropanol 20:1). 49.48 g (80.4% of theory, relative to the sec-amine that is used) of the title compound is obtained in the form of a colorless oil.

Elementary analysis:

Cld: C 60.47 HS5.79 F 12.80 N4.44 S 1.27

Fnd: C 60.52 HS5.77 F 12.77 N4.50 S 1.30 b) 1-{3-Oxa-pentane-1,5-dicarboxylic acid-1-0yl-5-[1 -(4-perfluorooctylsulfonyl)- piperazine]-amide}-7-[2,6-N,N'"-bis(1-O-a-D-(5 -carbonyl)-pentyl-mannopyranose)]-L- lysyl-1,4,7,10-tetraazacyclododecane 25.2 g (10.0 mmol) of the title compound that is produced under Example 45a) is dissolved in 250 ml of ethanol and mixed with 1.8 g of Pearlman's catalyst (Pd 20%, C). Itis hydrogenated until quantitative hydrogen uptake is reached, then catalyst is suctioned out, it is "thoroughly rewashed with ethanol and evaporated to the dry state in a vacuum. The product is yellowish in color, and extremely viscous oil is obtained.

@ @ vied: 1411g(92:5% of theory)

Elementary analysis:

Cld: C 49.60 H7.20 F21.17 N7.34 S2.10

Fnd: C 49.62 H7.17 F21.20 N7.30 S2.14

Cc) 1-{3-Oxa-pentane-1,5-dicarboxylic acid-1-0yl-3-[1 -(4-perfluorooctylsulfonyl)- piperazine]-amide}-7-[2,6-N,N'-bis(1-O-0-D-(5 ~carbonyl)-pentyl-mannopyranose)]-L- lysyl-4,10-bis[1,4,7-tris(carboxylatomethyl)-1 0-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)]- 1,4,7,10-tetraazacyclododecane, digadolinium complex 5.54 g [8.8 mmol; 2 molar equivalents relative to the amine component of Example 45b) that is used] of the Gd complex, described in Patent Application DE 197 28 954 C1 under

Example 31h), of the 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triacetic acid and anhydrous lithium chloride (0.37 g, 8.8 mmol) are dissolved at 40°C in 60 ml of absolute dimethyl sulfoxide while being stirred, and it is mixed at this temperature with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 6.10 g (4.0 mmol) of the title compound of Example 45b), dissolved in 40 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 1.82 g (8.8 mmol) of N,N'-dicyclohexylcarbodiimide, and it is stirred for 12 hours at room temperature. The suspension that is obtained is then mixed with sufficient acetone until the above-mentioned title compound is completely precipitated, the precipitate is suctioned off, dried, taken up in water, insoluble dicyclohexylurea is filtered out, and the filtrate is desalinated with an AMICON® YM- 3 ultrafiltration membrane (cut-off 3,000 Da), and low-molecular components are removed. The retentate is then freeze-dried. :

Yield: 9.26 g (84.0% of theory; relative to the diamine component that is used) as a colorless lyophilizate.

H,O content (Karl-Fischer): 5.89%.

‘ 167 W2003/1949 @ [ J Elementary analysis (relative to anhydrous substance):

Cld: C 40.52 H5.16 N9.15 F11.72 Gd 11.41 S 1.16

Fond: C40.57 H5.20 N9.12 F11.69 Gd 11.43 S1.18

Example 46 a) 6-N-t-Butyloxycarbonyl-2-N-benzyloxycarbonyl-L-lysine-[1 -(4-perfluorooctylsulfonyl)- piperazine]-amide 19.02 g (50.0 mmol) of a-N-(benzyloxycarbonyl)-e-N'-(tert-butyloxycarbonyl)-L-lysine (commercially available from the Bachem Company) is dissolved in 150 ml of absolute tetrahydrofuran. 8.31 g (50.0 mmol) of carbonyl diimidazole and 5.03 g (50.0 mmol) of triethylamine, dissolved in 75 ml of dry tetrahydrofuran, are added drop by drop at 0°C, and stirring is allowed to continue for 10 minutes at this temperature. Then, a solution 0f 48.42 g (50.0 mmol) of perfluorooctylsulfonyl-piperazine and 5.03 g (50.0 mmol) of triethylamine in 250 ml of dry tetrahydrofuran is added in drops at 0°C. After stirring overnight, the tetrahydrofuran is drawn off in a vacuum, and the remaining oil is chromatographed on silica gel (mobile solvent: n-hexane/isopropanol 15:1). 49.48 g (80.4% of theory, relative to the sec-amine that is used) of the title compound is obtained in the form of a colorless oil. :

Elementary analysis (relative to anhydrous substance):

Cld: C 40.01 H3.79 N 6.02 F 34.70 S345

Fnd: C 40.07 H3.82 N 6.02 F 34.67 S3.48 b) 6-N-t-Butyloxycarbonyl-L-lysine-[ 1-(4-perfluorooctylsulfonyl)-piperazine]-amide 30.0 g (32.2 mmol) of the title compound of Example 46a) is dissolved in 300 ml of isopropanol and mixed with 1.5 g of Pearlman's catalyst (20% palladium hydroxide on carbon).

It is hydrogenated for 10 hours at room temperature, whereby after the course of the reaction is checked by means of thin-layer chromatography, hydrogenolytic cleavage of the benzyloxycarbonyl protective group has already taken place quantitatively according to the

@® aifffje-mentioned reaction time. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The remaining residue is chromatographed on silica gel (mobile solvent: n- hexane/isopropanol 25:1). 25.13 g (98.0% of theory) of the title compound is obtained in the form of a colorless oil.

Elementary analysis:

Cld: C 34.68 H3.67 F40.55 N 7.03 S4.03

Fnd: C 34.72 H3.70 F40.60 N7.01 S3.98 c) 6-N-t-Butyloxycarbonyl-2-N-[1-S-a-D-(2-carbonyl)-ethyl-2,3,4,6-tetra-O-acetyl- mannopyranose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide 15.53 g (35.60 mmol) of 3-(2,3,4,6-tetra-O-acetyl-1-thio-a-D-mannopyranosyl)- propionic acid (production according to: J. Haensler et al., Bioconjugate Chem. 4, 85, (1993);

Chipowsky, S. and Lee, Y. C. (1973), Synthesis of 1-Thio-aldosides; Carbohydrate Research 31, 339-346) and 3.60 g (35.60 mmol) of triethylamine are dissolved in 300 ml of dry tetrahydrofuran. After the reaction solution is cooled to -15°C to -20°C, a solution 0f 4.92 g (35.60 mmol) of isobutyl chloroformate in 75 ml of dry tetrahydrofuran is slowly added in drops at this temperature while being stirred, whereby the rate of addition by drops can be selected in such a way that an internal temperature of -10°C is not exceeded. After a reaction time of 15 minutes at -15°C, a solution of 28.35 g (35.60 mmol) of the title compound of Example 42b) and 3.60 g (35.60 mmol) of triethylamine is then slowly added in drops to 200 ml of dry tetrahydrofuran at 20°C. After a reaction time of one hour at -15°C and two hours at room temperature, the reaction solution is evaporated to the dry state in a vacuum. The remaining : residue is taken up in 250 ml of ethyl acetate and washed twice with 100 ml each of saturated sodium bicarbonate solution and once with 200 ml of water. After the organic phase is dried on sodium sulfate, salt is suctioned out, and the ethyl acetate is drawn off in a vacuum. The remaining oily residue is purified on silica gel with use of ethyl acetate/n-hexane (1:25) as an : eluant.

@ 4» Yield: 34.21 g (79.1% of theory) of the above-mentioned title compound as a colorless and strongly viscous oil.

Elementary analysis:

Cld: C 39.54 H4.23 N4.61 F26.58 535.28

Fnd: C 39.49 H4.21 N4.59 F26.52 S5.31 d) 6-N-t-Butyloxycarbonyl-2-N-[1 -S-a-D-(2-carbonyl)-ethyl-mannopyranose]-L-lysine-(1- (4-perfluorooctylsulfonyl)-piperazine]-amide 29.93 g (24.64 mmol) of the title compound of Example 46c) is suspended in 400 ml of : absolute methanol, and it is mixed at 5°C with a catalytic amount of sodium methanolate. After a reaction time of 3 hours at room temperature, even thin-layer chromatographic checking (eluant: chloroform/methanol = 9:1) of the course of the reaction indicates a quantitative reaction. For the purpose of working-up, the now clear reaction solution is neutralized by mixing with Amberlite® IR 120 (H'-form)-cation-exchange resin, exchanger is suctioned out, and the thus obtained methanolic filtrate is evaporated to the dry state in a vacuum. The amorphous residue that is obtained is purified by chromatography on silica gel with use of 2- propanol/ethyl acetate/n-hexane (1:1:15) as an eluant. : Yield: 23.42 g (90.8% of theory) of a colorless and viscous oil.

Elementary analysis:

Cld: C 36.72 H4.14 N5.35 F30.85 S6.13

Fnd: C 36.69 H4.11 N535 F30.82 S6.11 e) 2-N-[1-S-a-D-(2-Carbonyl)-ethyl-mannopyranose]-L-lysine-{ 1-(4- perfluorooctylsulfonyl)-piperazine]-amide 20.93 g (20.0 mmol) of the title compound of Example 46d) is dissolved in a mixture that consists of 50 ml of trifluoroacetic acid and 100 ml of dichloromethane at 0°C while being stirred vigorously, and it is stirred for 10 minutes at this temperature. Then, it is evaporated to the dry

® s@in a vacuum, and the residue is taken up in 150 ml of water. The pH of this aqueous product solution is set at 9.5 by adding 2 molar aqueous sodium hydroxide solution drop by drop.

The aqueous product solution is desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off: 3,000 Da), and in this case, possible, still present, low-molecular components are simultaneously removed. The retentate is then freeze-dried.

Yield: 17.79 g (94.2% of theory) of the free amine as a colorless lyophilizate.

H,O content (Karl-Fischer): 3.09%.

Elementary analysis (relative to anhydrous substance):

Cld: C3426 H3.73 N5.92 F34.12 §6.77

Fnd: C 34.26 H3.79 N 5.88 F34.07 S6.80 i) 2-N-[1 -S-a-D-(2-Carbonyl)-ethyl-mannopyranose}-6-N-[1 ,4,7-tris(carboxylatomethyl)- 10-(3-aza-4-oxo0-5-methyl-5-yl-pentanoyl)-1,4,7, 10-tetraazacyclododecane]-L-lysine-[1- (4-perfluorooctylsulfonyl)-piperazine}-amide, gadolinium complex 5.54 g [(8.8 mmol, 2.2 molar equivalents relative to the amine component of Example 46e) that is used] of the Gd complex, described in Patent Application DE 197 28 954 C1 under

Example 31h), of the 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triacetic acid and 0.37 g of anhydrous lithium chloride (8.8 mmol) are dissolved at 40°C in 60 ml of absolute dimethyl sulfoxide while being stirred, and it is mixed "at this temperature with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.78 g (4.0 mmol) of the title compound of Example 46e), dissolved in 40 ml of absolute dimethyl sulfoxide.

After cooling to room temperature, the reaction solution is mixed with 1.82 g (8.8 mmol) of

N,N'-dicyclohexylcarbodiimide, and it is stirred for 12 hours at room temperature. The suspension that is obtained is then mixed with sufficient acetone until the above-mentioned title compound is completely precipitated, the precipitate is suctioned off, taken up in water, insoluble dicyclohexylurea is filtered out, and the filtrate is desalinated with an AMICON® YM-3

® yiiiration membrane (cut-off 3,000 Da), and low-molecular components are removed. The retentate is then freeze-dried.

Yield: 5.17 g (83.0% of theory) as a colorless lyophilizate.

H,0 content (Karl-Fischer): 4.43%.

Elementary analysis (relative to anhydrous substance):

Cld: C 35.45 H4.07 N8.09 F20.72 Gd 10.09 S 4.11

Fnd: C35.50 H4.01 N8.12 F20.6 Gd 10.13 S4.14

Example 47 a) 6-N-Benzyloxycarbonyl-2-N-(1-O-3-D-carbonylmethyl-2,3,4,6-tetra-O- benzylglucopyranose)-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide 8.02 g (13.4 mmol) of the title compound [1-carboxymethyloxy-2,3,4,6-tetra-O-benzyl-f-

D-gluocopyranoside], described in Patent Application DE 197 28 954 C1 under Example 46a), and 3.24 g (28.14 mmol) of N-hydroxysuccinimide are dissolved in 100 ml of dimethylformamide and mixed in portions at 0°C with a total of 5.80 g (28.14 mmol) of N,N'- dicyclohexylcarbodiimide. It is stirred for 3 more hours at this temperature. A solution, cooled to 0°C, of 11.13 g (13.4 mmol) of the title compound of Example 21c), dissolved in 50 ml] of dimethylformamide, is added drop by drop to the thus produced active ester solution, and it is stirred for 2 hours at 0°C and for 12 hours at room temperature. For working-up, precipitated dicyclohexylurea is filtered out, and the solvent is then drawn off until a dry state is reached.

The thus obtained residue is then chromatographed on silica gel (mobile solvent: dichloromethane/ethanol, 20:1; chromatography was carried out with use of a solvent gradient with continuous increase of the ethanol content).

Yield: 12.67 2 (67.0% of theory) of the title compound in the form of a colorless and strongly viscous oil.

Elementary analysis: :

Cld: C52.77 H4.50 N3.97 F22.89 S2.27

® @ Fnd: C 352.75 H4.61 N3.98 F22.94 S226 b) 2-N-(1-O-B-D-Carbonylmethyl-glucopyranose)-L-lvsine-[ 1-(4-perfluorooctylsulfonyl)- piperazine]-amide 11.52 g (8.17 mmol) of the compound that is produced under 47a) is dissolved in 100 ml of ethanol, mixed with 0.5 g of Pearlman's catalyst (Pd 20%, C), and hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen absorption can be observed. Catalyst is suctioned out, it is thoroughly rewashed with ethanol (three times with about 40 ml in each case), and evaporated to the dry state in a vacuum. The title compound is obtained as a strongly viscous and colorless oil.

Yield: 7.36 g (98.4% of theory).

Elementary analysis:

Cld: C34.07 H3.63 N6.11 F 35.24 S3.50

Fnd: C 34.11 H3.59 N6.08 F35.23 S3.52 c) 2-N-(1-O-B-D-Carbonylmethyl- glucopyranose)-6-N-[ 1,4,7-tris(carboxylatomethyl)-10- (aza-4-ox0-5-methyl-5-yl-pentanoyl)-1,4,7,10-tetraazacyclododecane]-L-lysine-[ 1-(4- perfluorooctylsulfonyl)-piperazine}-amide, Gd complex 9.98 g [(15.84 mmol; 2.2 molar equivalents relative to the amine component of Example 47b) that is used] of the Gd complex, described in Patent Application DE 197 28 954 C1 under

Example 31h), of 10-(4-carboxy-1-methyl-2-ox0-3-azabutyl)-1 4.7,10-tetraazacyclododecane- ] 1,4,7-triacetic acid and 0.67 g (15.84 mmol) of anhydrous lithium chloride are dissolved at 40°C in 80 ml of absolute dimethyl sulfoxide while being stirred, and it is mixed at this temperature with a total of 1.82 g (15.84 mmol) of N-hydroxysuccinimide and 7.25 g (7.19 mmol) of the title compound of Example 47D), dissolved in 30 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 3.27 g (15.84 mmol) of N,N'- dicyclohexylcarbodiimide, and it is stirred for 12 hours at room temperature. The suspension

® @s obtained is then mixed with sufficient acetone until the above-mentioned title compound is completely precipitated, the precipitate is suctioned off, taken up in water, insoluble dicyclohexylurea is filtered out, and the filtrate is desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off 3,000 Da), and low-molecular components are removed. The retentate is then freeze-dried.

Yield: 9.11 g (83.0% of theory) as a colorless lyophilizate.

H,O content (according to Karl-Fischer): 4.02%.

Elementary analysis (relative to anhydrous substance):

Cld: C3537 H4.02 N825 F21.13 S2.10 Gd 10.29

Fnd: C3542 H4.07 N 8.18 F21.09 S2.06 Gd10.34

Example 48 a) 2-N-Trifluoroacetyl-L-lysine-[ 1-(4-perfluorooctylsulfonyl)-piperazine]-amide 10.0 g (11.46 mmol) of the compound, produced under 21b), is dissolved in 100 ml of ethanol, mixed with 1.0 g of Pearlman's catalyst (Pd 20%/C) and hydrogenated until quantitative hydrogen uptake is reached. Catalyst is suctioned out, it is rewashed with ethanol and evaporated to the dry state in a vacuum. The title compound is obtained as a viscous and colorless oil.

Yield: 8.85 g (97.5% of theory).

Elementary analysis:

Cld: C3031 H2.54 N7.07 F47.95 S4.05

Fnd: C30.36 H2.50 N7.11 F47.99 S 4.00 b) 2-N-Trifluoroacetyl-6-N-[1-O-a-D-(5-carbonyl)-pentyl-2,3,4,6-tetra-O-benzyl- mannopyranose]-L-lysine-[1 _(4-perfluorooctylsul fonyl)-piperazine] -amide

A solution of 27.51 g (36.6 mmol) of the title compound of Example 37¢) in 150 ml of dimethylformamide is added in drops to a solution, cooled to 0°C, that consists of 29.0 g (36.6

® @° of the title compound of Example 48a) and 4.05 g (40.26 mmol) of triethylamine in 100 ml of dimethylformamide. After addition is completed, it is stirred for one more hour at 0°C and then overnight at room temperature. It is evaporated to the dry state in a vacuum, and the residue is taken up in 300 ml of ethyl acetate. Insoluble components are filtered out, and the filtrate is washed twice with 100 ml each of 5% aqueous soda solution. The organic phase is dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/isopropanol 25:1). 42.05 g (80.4% of theory) of the title compound is obtained in the form of a colorless oil.

Elementary analysis:

Cid: C50.42 H4.51 N7.96 F26.59 S§2.24

Fnd: C 50.38 H4.50 N 7.91 F26.62 S2.20 c) 6-N-[1-O-a-D-(5-Carbonyl)-pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose]-L-lysine-[ 1- (4-perfluorooctylsulfonyl)-piperazine]-amide 20.0 g (14.0 mmol) of the compound that is produced under Example 48D) is dissolved in 150 ml of ethanol. The solution of 2.8 g (70.0 mmol) of sodium hydroxide in 25 ml of distilled water is then added to it, and it is stirred for 0.5 hour at 50°C. According to the thin-layer chromatogram, the protective group cleavage is already carried out quantitatively at this time. It 1s evaporated to the dry state in a vacuum, and traces of water are removed by repeated co- distillation with ethanol. The residue is chromatographed on silica gel (mobile solvent: n- hexane/isopropanol 20:1). 16.66 g (89.3% of theory) of the title compound is obtained in the form of a colorless oil.

Elementary analysis:

Cld: C52.25 H4.91 N4.20 F2422 S241

Fnd: C 52.30 H4.90 N 4.18 F 24.22 S2.38

® ® 6-N-[1-O-a-D-(5-Carbonyl)-pentyl-mannopyranose]-L-lysine-[ 1-(4- perfluorooctylsulfonyl)-piperazine]-amide 15.0 g (11.25 mmol) of the compound that is produced under 48c) is dissolved in 150 ml of a 10:1 mixture that consists of ethanol and water, and it is mixed with 1.0 g of Pearlman's catalyst (Pd 20%/C). Then, it is hydrogenated until quantitative hydrogen uptake is reached at room temperature and under one atmosphere of hydrogen pressure. Catalyst is suctioned out, it is rewashed with ethanol/water (10:1) and evaporated to the dry state in a vacuum. The title compound is obtained as a viscous and colorless oil.

Yield: 10.77 g (98.4% of theory).

Elementary analysis:

Cld: C37.04 H4.25 N5.76 F 33.20 S3.30

Fnd: C37.06 H4.20 N 5.81 F33.19 S3.30 e) 6-N-[1-0-a-D-(5-Carbonyl)-pentyl-mannopyranose]-2-N-[1,4,7-tris(carboxylatomethyl)- 1 0-(3-aza-4-ox0-5-methyl-5-yl-pentanoyl)- 1,4,7,10-tetraazacyclododecane]-L-lysine-[1- (4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex 5.54 g [(8.8 mmol; 2.2 molar equivalents relative to the amine component of Example 48d) that is used] of the Gd complex, described in Patent Application DE 197 28 954 C1 under

Example 31h), of 10-(4-carboxy-1-methyl-2-0x0-3-azabutyl)-1,4,7,1 0-tetraazacyclododecane- 1,4,7-triacetic acid and 0.37 g (8.8 mmol) of anhydrous lithium chloride are dissolved at 40°C in 60 ml of absolute dimethyl sulfoxide while being stirred and mixed at this temperature with a total of 1.01 g (8.8 mmol) of N-fydrenysucoinimide and 3.89 g (4.0 mmol) of the title compound of Example 48d), dissolved mn 60 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 1.82 g (8.8 mmol) of N,N'- dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The suspension that is obtained is then mixed with sufficient acetone until the above-mentioned title compound is completely precipitated, the precipitate is suctioned off, taken up in water, insoluble

® @iohexylurea is filtered out, and the filtrate is desalinated with an AMICON™ YM-3 ultrafiltration membrane (cut-off: 3,000 Da), and low-molecular components are removed. The retentate is then freeze-dried.

Yield: 4.81 g (75.9% of theory) as a colorless lyophilizate.

H,O content (Karl-Fischer): 8.98%.

Elementary analysis (relative to anhydrous substance):

Cld: C37.15 H4.39 N7.96 F20.38 Gd 9.92 S2.02

Fnd: C 37.27 H4.40 N 8.02 F20.31 Gd 10.00 S 1.98

Example 49 a) 1,7-Bis(benzyloxycarbonyl)-4-(1-O-B-D-carbonylmethyi-2,3,4,6-tetra-O-benzyl- galactopyranose)-10- {3-oxa-pentane-1,5-dicarboxylic acid-1-oyl-5-[1-(4- : perfluorooctylsulfonyl)-piperazine}-amide]-1,4,7,10-tetraazacyclododecane 35.80 g (25.0 mmol) of the title compound of Example 37e), dissolved in 250 ml of tetrahydrofuran, is added at 0°C and under nitrogen atmosphere to a solution that consists of 27.0 g (24.4 mmol) of the sec-amine that 1s produced under Example 35a), in a mixture that consists of 150 ml of tetrahydrofuran and 15 ml of chloroform. Then, a total of 18.0 g (36.6 mmol) of

EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is added in portions at 0°C, and it is allowed to stir overnight at room temperature. It is then evaporated to the dry state in a vacuum, and the remaining oil is chromatographed on silica gel (mobile solvent: n-hexane/isopropanol 20:1). 32.11 g (78.0% of theory, relative to the sec-amine that is used) of the title compound is obtained in the form of a colorless oil.

Elementary analysis: :

Cld: C54.09 H4.72 F 19.14 N 4.98 S 1.90

Fnd: C54.12 H4.77 F 19.17 N5.03 S1.90

C @ 1-(1-O-B-D-Carbonylmethyl-galactopyranose)-7-{3-oxa-pentane-1,5-dicarboxylic acid-1- oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-1,4,7,10-tetraazacyclododecane

In 250 ml of ethanol, 30.0 g (17.77 mmol) of the title compound that is produced under

Example 49a) is dissolved, and it is mixed with 3.0 g of Pearlman's catalyst (Pd 20%,/C). Itis hydrogenated until quantitative hydrogen uptake is reached, catalyst is then suctioned out, it is thoroughly rewashed with ethanol and evaporated to the dry state in a vacuum. The product is yellowish in color, and extremely viscous oil is obtained.

Yield: 17.89 g (95.1% of theory)

Elementary analysis:

Cld: C36.30 H4.09 F30.50 N7.94 $3.03

Fnd: C36.26 H4.12 F 30.46 N 7.90 S3.04 c) 1-(1-0O-B-D-Carbonylmethyl-galactopyranose)-7- {3-oxa-pentane-1,5-dicarboxylic acid-1- oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-4,10-bis[1,4,7- tris(carboxylatomethyl)-10-(3-aza-4-oxo0-5-methyl-5-yl-pentanoyl)-1,4,7,10- tetraazacyclododecane]-1,4,7,10-tetraazacyclododecane, di-gadolinium complex 5.54 g [8.8 mmol; 4.4 molar equivalents relative to the amine component of Example 49b) that 1s used] of the Gd complex, described in Patent Application DE 197 28 954 C1 under

Example 31h), of 10-(4-carboxy-1-methyl-2-0x0-3-azabutyl)-1,4,7,10-tetraazacyclododecane- 1,4,7-triacetic acid and 0.37 g (8.8 mmol) of anhydrous lithium chloride are dissolved at 40°C in 60 ml of absolute dimethyl sulfoxide while being stirred and mixed at this temperature with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 2.11 g (2.0 mmol) of the title compound of Example 49b), dissolved in 25 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 1.82 g (8.8 mmol) of N,N'- dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The suspension that is obtained is then mixed with sufficient acetone until the above-mentioned title compound is completely precipitated, the precipitate is suctioned off, dried, taken up in water, insoluble

C @ciobexylurea is filtered out, and the filtrate is desalinated with an AMICON® YM-3 ultrafiltration membrane (cut-off 3,000 Da), and low-molecular components are removed. The retentate is then freeze-dried.

Yield: 3.29 g (72.2% of theory; relative to the amine component that is used) as a colorless lyophilizate.

H,O content (Karl-Fischer): 5.99%.

Elementary analysis (relative to anhydrous substance):

Cid: C36.84 H4.37 N9.82 F 14.15 Gd 19.63 S 1.40

Fnd: C 36.87 H4.40 N9.82 F 14.09 Gd 19.59 S 1.38

Example 50 a) 3-(1-0-a-D-2,3,4,6-Tetra-O-benzyl-mannopyranose)-2-N-benz yloxycarbonyl-L-serine- methyl ester 21.42 g (39.61 mmol) of 2,3,4,6-tetra-O-benzyl-a-D-mannopyranose (production according to: F. Kong et al, J. Carbohydr. Chem.; 16; 6; 1997; 877-890) is dissolved in 500 ml of dry acetonitrile. After the reaction solution is cooled to 5°C, a solution of 13.23 g (59.52 mmol) of trifluoromethanesulfonic acid trimethyl silyl ester in 30 ml of acetonitrile, followed by a solution that consists of 20.06 g (79.21 mmol) of N-benzyloxycarbonyl-L-serine methyl ester (commercially available from the Bachem Company) in 50 ml of acetonitrile, are slowly added in drops at this temperature while being stirred, whereby the rate of addition by drops can be selected in such a way that an internal temperature of 10°C is not exceeded. After a reaction time of 15 hours at room temperature, the reaction solution is evaporated to the dry state in a vacuum. The remaining residue is taken up in 250 ml of ethyl acetate and washed twice with 100 ml each of saturated sodium bicarbonate solution and once with 200 ml of water. After the organic phase is dried on sodium sulfate, salt is suctioned out, and the ethyl acetate is drawn off in a vacuum. The remaining oily residue is purified on silica gel with use of ethyl acetate/n- hexane (1:5) as an eluant.

os - Be003/1949 ® ) Yield: 23.60 g (76.8% of theory) of the above-mentioned title compound as a colorless oil.

Elementary analysis:

Cld: C71.21 H6.37 N 1.81

Fnd: C71.19 H6.41 N 1.79 b) 3-(1-0-a-D-2,3,4,6-Tetra-O-benzyl-mannopyranose)-2-N-benzyloxycarbonyl-L-serine 10.0 g (12.90 mmol) of the compound that is produced under Example 50a) is dissolved in a mixture that consists of 20 ml of methanol, 20 ml of water and 50 ml of tetrahydrofuran. 0.47 g (19.35 mmol) of lithium hydroxide, dissolved in 25 ml of distilled water, is then added at room temperature, and it is then stirred for 6 hours at 60°C. After the course of the reaction is checked by means of thin-layer chromatography (eluant: methylene chloride/methanol 10:1), saponification of the methyl ester of Example 30a) has already taken place quantitatively according to the above-mentioned reaction time. For the purpose of working-up, the product solution is evaporated to the dry state in a vacuum, and the remaining residue is taken up in 250 ml of ethyl acetate in heat (about 60°C). Then, the thus obtained ethyl acetate phase is washed twice with 50 ml each of a 15% aqueous hydrochloric acid, and once with 100 ml of distilled water. The organic phase is dried on magnesium sulfate, filtered and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/ethyl acetate 5:1). 8.40 g (85.7% of theory) of the title compound is obtained in the form of a colorless oil.

Elementary analysis: . Cid: C7094 H6.22 N 1.84

Fond: C70.97 H6.30 N1.78

® @ 3-(1-0-a-D-2,3,4,6-Tetra-O-benzyl-mannopyranose-2-N-benzyloxycarbonyl-L-serine-[ 1- (4-perfluorooctylsulfonyl)piperazine}-amide 20.57 g (27.0 mmol) of the carboxylic acid, produced according to Example 50b) and dissolved in 50 ml of tetrahydrofuran, is added drop by drop at 0°C and under nitrogen atmosphere to 13.86 g (24.40 mmol) of 1-perfluorooctylsulfonyl-piperazine (produced according to DE 19603033), dissolved in a mixture that consists of 150 ml of tetrahydrofuran and 15 ml of chloroform. Then, a total of 18.0 g (36.60 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2- dihydroquinoline] is added in portions at 0°C, and it is allowed to stir overnight at room temperature. For the purpose of working-up, the reaction solution is concentrated by evaporation in a vacuum, and the remaining, extremely viscous oil is chromatographed on silica gel with use of an n-hexane/isopropanol (15:1) mixture as an eluant system. 17.0 g (79.6% of theory, relative to the primary amine that is used) of the title compound is obtained in the form of a colorless and viscous oil.

Elementary analysis:

Cld: C51.53 H4.23 N3.15 F25.65 S 2.41

Fnd: C51.48 H4.27 N3.10 F25.71 S2.35 d) 3-(1-O-a-D-Mannopyranose)-L-serine-[ 1-(4-perfluorooctylsulfonyl)piperazine]-amide 15.0 g (11.41 mmol) of the compound that is produced according to Example 50c) is dissolved in 200 ml of ethanol, and it is mixed with 1.5 g of Pearlman's catalyst (Pd 20%, C).

Then, the reaction solution is hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen absorption can be observed (about 8 hours). For the purpose of working-up, catalyst is suctioned out, it is thoroughly rewashed with ethanol (twice with about 100 ml each), and the product-containing ethanolic filtrate is evaporated to the dry state in a vacuum. The title compound is obtained as a strongly viscous and colorless oil.

Yield: 8.79 g (94.0% of theory).

® ® Elementary analysis:

Cid: C30.78 H3.20 N5.13 F 39.41 S3.91

Fnd: C 30.87 H3.14 N5.19 F 39.50 S 3.88 e) 3-(1-O-a-D-Mannopyranose)-2-N-[ 1 ;4,7-tris(carboxylatomethyl)- 10-(3-aza-4-0x0-5- methyl-5-yl-pentanoyl)-1,4,7,10-tetraazacyclododecane]-L-serine-[ 1-(4- perfluorooctylsulfonyl)-piperazine]-amide, Gd complex

A stirred suspension of 5.7 g [9.06 mmol; corresponding to 1.5 molar equivalents relative to the title compound (primary amine) of Example 50d) that is used] of the Gd complex, described in Patent Application DE 197 28 954 C1 under Example 31h), of 10-(4-carboxy-1- methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid in 75 ml of absolute dimethyl sulfoxide is mixed at 70°C with 0.68 g (15.9 mmol) of lithium chloride. After minutes of stirring at 70°C, the now clear reaction solution is mixed in portions with a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide, and the reaction mixture is kept for 1 more hour at 70°C. After the reaction solution is cooled to 10°C, it is mixed with 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide, and the reaction solution is stirred for another hour at 0°C, followed by 12 hours at 22°C. The thus obtained solution of N-hydroxysuccinimide ester of the Gd complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid is now mixed at 22°C drop by drop with a solution of 4.94 g (6.03 mmol) of the title compound of Example 30d), in 15 ml of absolute dimethyl sulfoxide, and it is stirred for another 12 hours at room temperature. For working-up, the reaction solution is slowly added in drops at 22°C in a solvent mixture that consists of 250 ml of acetone and 250 m! of 2-propanol, whereby the title compound has settled completely as a light yellowish-colored oil after 12 hours at 10°C. Supernatant eluant mixture is carefully decanted out, and the oily product is taken up in 200 ml of distilled water, whereby the latter goes completely into solution in such a way that a light yellowish-colored aqueous solution of the above-mentioned title compound is obtained.

Subsequently, the aqueous product solution is first filtered with a membrane filter and then, for

® gure of desalination and separation of low-molecular components, it is ultrafiltered three times with a YM3-ultrafiltration membrane (AMICON®): cut-off: 3,000 Da). The thus obtained retentate is then freeze-dried.

Yield: 8.63 g (80.2% of theory, relative to the title compound of Example 30d) that is used) as a colorless lyophilizate with a water content of 7.65%.

Elementary analysis (relative to anhydrous substance):

Cld: C33.57 H3.80 N7.83 F22.57 Gd10.99 S 2.24

Fnd: C 33.57 H3.76 N7.82 F22.63 Gd 11.06 S2.18

Example 51 a) 6-N-Benzyloxycarbonyl-2-N-[O-B-D-galactopyranosyl (1 — 4)-gluconosyl]-L-lysine-[1- (4-perfluorooctylsulfonyl)-piperazine]-amide

A solution of 13.3 g (37.2 mmol) of O-B-D-galactopyranosyl-(1->4)-D-glucono-1,5- lactone [lactobionolactone; production according to: (a) Williams, T. J.; Plessas, N. R.;

Goldstein, I. J. Carbohydr. Res. 1978, 67, Cl. (b) Kobayashi, K.; Sumitomo, H.; Ina, Y. Polym. J. 1985, 17, 567, (c) Hiromi Kitano, Katsuko Sohda, and Ayako Kosaka, Bioconjugate Chem. 1995, 6 131-134] in 40 ml of absolute dimethyl sulfoxide is added drop by drop at room temperature to a stirred solution of 4.98 g (6.0 mmol) of the title compound of Example 21¢) in 40 ml of absolute dimethyl sulfoxide. The thus obtained reaction solution is then stirred for 14 hours at 40°C. For working-up, it is mixed at room temperature with 500 ml of absolute 2- propanol, and the resulting colorless precipitate is suctioned off by means of a G4 frit and thoroughly rewashed with a total of 250 ml of absolute 2-propanol. The thus obtained solid is : now dissolved in 300 ml of distilled water and ultrafiltered a total of three times with a YM3- ultrafiltration membrane (AMICON®: cut-off: 3,000 Da). By the third time of the ultrafiltration process, both the excess lactobionolactone and also possibly still present low- molecular components are separated from the desired product. The residue that remains in the

183 oo ® filtration membrane is subsequently dissolved completely in 300 ml of distilled water and freeze-dried.

Yield: 6.51 g (92.7% of theory) as a colorless lyophilizate

Water content: 10.03%

Elementary analysis (relative to anhydrous substance):

Cld: C 38.98 H4.05 N4.79 F 27.58 §2.74

Fnd: C 39.04 H4.09 N 4.82 F27.61 S2.71 b) 2-N-[O-B-D-Galactopyranosyl (1—>4)-gluoconosyl}-L-lysine-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide 5.0 g (4.27 mmol) of the compound that is produced under 51a) is dissolved in 100 ml of ethanol, mixed with 0.5 g of Pearlman's catalyst (Pd 20%, C) and hydrogenated until quantitative hydrogen uptake is reached at 1 atmosphere of hydrogen pressure. Catalyst is suctioned out, rewashed with ethanol and evaporated to the dry state in a vacuum. The title compound is obtained as a colorless and viscous oil.

Yield: 4.36 g (98.5% of theory).

Elementary analysis:

Cld: C34.76 H3.99 N540 F31.51 S3.09

Fnd: C34.78. H4.04 N 5.34 F31.51 S3.15 c) | 2-N-[O-B-D-Galactopyranosyl(1—4)-gluoconosyl]-6-N-[ 1,4, 7-tris(carboxylatomethyl)- 10-(3 _aza-4-0x0-5-methyl-5-yl-pentanoyl)-1 ,4,7,10-tetraazacyclododecane]-L-lysine-[ 1- (4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex 5.54 g [(8.8 mmol; 2.2 molar equivalents relative to the amine component of Example 51b) that is used] of the Gd complex, described in Patent Application DE 197 28 954 C1 under

Example 31h), of 10-(4-carboxy-1-methyl-2-ox0-3-azabutyl)-1,4,7,10-tetraazacyclododecane-

® acetic acid and 0.37 g (8.8 mmol) of anhydrous lithium chloride are dissolved at 40°C in 60 ml of absolute dimethyl sulfoxide while being stirred and mixed at this temperature with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.85 g (4.0 mmol) of the title compound of Example 31Ab), dissolved in 60 ml of absolute dimethyl sulfoxide. After cooling to room temperature, the reaction solution is mixed with 1.82 g (8.8 mmol) of N,N'- dicyclohexylcarbodiimide and stirred for 12 hours at room temperature. The suspension that is obtained is then mixed with sufficient acetone/2-propanol (1:1) until the above-mentioned title compound is completely precipitated, and the precipitate is suctioned off. The thus obtained precipitate is subsequently taken up in 300 ml of water, and insoluble dicyclohexylurea is filtered out. The filtrate is ultrafiltered three times with an AMICON® YM-3 ultrafiltration membrane (cut-off: 3,000 Da). By the third time that the ultrafiltration process is performed, both the excess Gd complex and possibly still present, low-molecular components are separated from the desired product. The residue that remains in the ultrafiltration membrane is subsequently completely dissolved in 500 ml of distilled water and freeze-dried.

Yield: 4.64 g (70.4% of theory) as a colorless lyophilizate.

H,O0 content (Karl-Fischer): 10.08%.

Elementary analysis (relative to anhydrous substance):

Cld: C35.70 H4.22 N7.65 F19.59 Gd 9.54 S 1.95

Fnd: C3577 H4.17 N7.71 F19.61 Gd 9.60 S 1.99

Example 52 a) 2-N-Trifluoroacetyl-6-N-benzylox ycarbonyl-lysine 100 g (356.7 mmol) of 6-N-benzyloxycarbonyl-lysine is dissolved in a mixture that consists of 1000 ml of trifluoroacetic acid ethyl ester/500 ml of ethanol, and it is stirred for 24 hours at room temperature. It is evaporated to the dry state, and the residue is crystallized from diisopropyl ether.

Yield: 128.9 g (96% of theory) of a colorless, crystalline powder.

[ [ Elementary analysis:

Cld: C51.07 H5.09 F 15.14 N 7.44

Fnd: C51.25 H5.18 F 15.03 N 7.58 b) 2-N-Trifluoroacetyl-6-N-benzyloxycarbonyl-lysine-[ 1 -(4-perfluorooctylsulfonyl)- piperazine]-amide 164.2 g (0.664 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) is added at 0°C to 125 g (332 mmol) of the title compound of Example 52a) and 188.7 g (332 mmol) of 1-perfluorooctylsulfonyl-piperazine (produced according to DE 19603033) in 800 ml of tetrahydrofuran, and it is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

Yield: 286 g (93% of theory) of a colorless solid.

Elementary analysis:

Cld: C36.30 H2.83 F41.01 N 6.05 S3.46

Fnd: C36.18 H2.94 F 40.87 N 5.98 S3.40 c) 6-N-Benzyloxycarbonyl-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide

Ammonia gas is introduced at 0°C for one hour into a solution that consists of 280 g (302.2 mmol) of the title compound of Example 52b) in 2000 ml of ethanol. It is then stirred for 4 hours at 0°C. It is evaporated to the dry state, and the residue is absorptively precipitated from water. The solid is filtered off and dried in a vacuum (50°C).

Yield: 243.5 g (97% of theory) of an amorphous solid.

Elementary analysis:

Cld: C37.60 H3.28 F38.89 N6.75 S3.86

Fnd: C37.15 H3.33 F38.78 N 6.68 S 3.81

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

A solution that consists of 19.93 g (70 mmol) of 3,6,9,12,15 pentaoxahexadecanoic acid chloride {produced according to Liebigs Ann. Chem. (1980), (6), 852-62] in 50 ml of dichloromethane is added in drops at 0°C to 50 g (60.20 mmol) of the title compound of Example 52c) and 7.10 g (70 mmol) of triethylamine, dissolved in 350 ml of dichloromethane, and it is stirred for 3 hours at 0°C. 200 ml of 5% aqueous hydrochloric acid is added, and it is stirred for minutes at room temperature. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 15:1).

Yield: 53.7 g2 (93% of theory) of a colorless, viscous oil.

Elementary analysis:

Cld: C33.83 H4.94 F3.34 N5.84 S 33.69

Fnd: C 33.75 H5.05 F3.29 N5.78 S 33.75 e) 2-N-(3,6,9,12,15-Pentaox ahexadecanoyl)-lysine| 1-(4-perfluorooctylsulfonyl)- piperazine]-amide 50 g (52.15 mmol) of the title compound of Example 52d) is dissolved in 500 ml of ethanol, and 6 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 43.0 g (quantitative) of a colorless solid.

Elementary analysis:

Cld: C27.68 H5.01 F39.17 N 6.79 S 3.89

Fnd: C 27.60 H5.13 F 39.09 N 6.68 S 3.81

~~ ¢ BE00S/ 1949

C @® 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3- aza-4-oxo-5-methyl-5-y1)]-2-N-(3,6,9,12,15-pentaoxahexadecanoyl)-lysine [1-(4- perfluorooctylsulfonyl)-piperazine]-amide, Gd complex g (24.25 mmol) of the title compound of Example 52¢), 2.79 g{24.25 mmol) of N- hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 2 (24.25 mmol) of 1,4,7- tris(carboxylatomethyl)- 10-[(3-aza-4-ox0-5-methyl-5-yl)]-pentanoic acid]-1,4,7,10- tetraazacyclododecane, Gd complex are dissolved in 200 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is added, and it is then stirred overnight at room temperature. | The solution is poured into 3000 ml of acetone, and it 1s stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: eradient that consists of water/ethanol/acetonitrile).

Yield: 28.21 g (81% of theory) of a colorless solid.

Water content: 11.0%

Elementary analysis (relative to anhydrous substance):

Cld: C31.78 H4.84 F 22.49 N 8.78 S2.23 Gd 10.95

Fnd: C31.74 H4.98 F22.39 N8.69 S2.15 Gd 10.87

Example 53 a) 6-N-[3,9-Bis(t-butyloxycarbonylmethyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid bis (t butylester)-6-carbonylmethyl]-2-N-[3 ,6,9,12,15-pentaoxahexadecanoyl)-lysine-{1-(4- perfluorooctylsulfonyl)-piperazine}-amide 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is added at 0°C to a solution that consists of 20 g (24.08 mmol) of the title compound of Example 52¢), 14.88 g (24.08 mmol) of 3,9-bis(t butyloxycarbonylmethyl-3,6,9-triazaundecane-1,1 1-dicarboxylic acid-bis(t butylester) and 2.77 g (24.08 mmol) of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide.

It is stirred for 3 hours at 0°C, then overnight at room temperature. Precipitated urea is filtered

C C the filtrate is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: =dichloromethane/ethanol = 20:1).

Yield: 31.61 g (91% of theory) of a viscous oil.

Elementary analysis: oo Cld: C40.80 H6.71 F22.39 N6.80 S222

Fnd: C40.72 H6.82 F22.30 N6.75 S2.14 b) 6-N-[6-Carbonylmethyl-3,9-bis(carboxylatomethyl)-3 6.9-triazaundecanedicarboxylic acid-1-carboxy-11-carboxylato-]-2-N-(3,6,9,12,1 5-pentaoxahexadecanoyl)-lysine-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide, Gd complex, sodium salt g (20.8 mmol) of the title compound of Example 53a) is dissolved in 300 ml of trifluoroacetic acid, and it is stirred for 5 hours at room temperature. It is evaporated to the dry state, the residue is taken up in 300 ml of water, and it is set at a pH of 2.5 with 10% aqueous

NaOH. Then, 3.77 g (10.4 mmol) of gadolinium oxide is added, and it is stirred for 3 hours at 60°C. It is allowed to reach room temperature, and it is set at a pH of 7.4 with sodium hydroxide solution. It is evaporated to the dry state, and the residue is purified on silica gel RP-18 (mobile solvent: gradient that consists of water/acetonitrile).

Yield: 19.18 g (67% of theory) of a colorless, amorphous solid.

Water content: 9.8%

Elementary analysis (relative to anhydrous substance):

Cld: C28.80H4.25F23.47N7.1252.33 Gd 11.48 Na 1.67

Fnd: C28.67H4.34F2338N7.03S2.27Gd 11.37 Na 1.74

® got 54 a) Lysine-[1-(4-perfluorooctylsulfonyl-piperazine]-amide 20 g (24.08 mmol) of the title compound of Example 52c¢) is dissolved in 300 ml of ethanol, and 4 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 16.77 g (quantitative) of a colorless solid.

Elementary analysis:

Cld: C31.04 H3.04 F46.38 N 8.04 S4.60

Fnd: C30.97 H3.15 F46.31 N7.98 S4.51 b) 2,6-N,N'-Bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-lysine-[ 1-(4-perfluorooctylsulfonyl-piperazine]-amide,

Gd complex (metal complex XVI) oo g (14.36 mmol) of the title compound of Example 54a), 3.34 g (29 mmol) of N- hydroxysuccinimide, 2.54 g (mmol) of lithium chloride and 18.26 g (29 mmol) of 1,4,7- tris(carboxylatomethyl)-10-(3-aza-4-0xo0-5-methyl-5yl) 1,4,7,10-tetraazacyclododecane-Gd complex are dissolved in 200 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 12.38 g (60 mmol) of N,N-dicyclohexylcarbodiimide is added, and it is then stirred overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes.

The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 19.02 g (69% of theory) of a colorless solid

Water content: 11.3%

Elementary analysis (relative to anhydrous substance):

Cld: C35.03 H4.04 F 16.82 N 10.21 S1.67 Gd 16.38

Fnd: C3496 H4.13 F 16.74 N 10.16 S 1.61 Gd 16.33

® got 55 a) 2-[4-(3-Oxapropionic acid ethyl ester)]-phenylacetic acid methyl ester 233.8 g (1.4 mol) of 2-bromoacetic acid-ethyl ester is added to 200 g (1.204 mol) of 4- hydroxyphenylacetic acid methyl ester, 212 g (2 mol) of sodium carbonate in 2000 ml of acetone, and it is refluxed for 5 hours. The solid is filtered off, and it is evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: -n- hexane/ethyl acetate = 15:1).

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

Elementary analysis:

Cld: C61.90 H 6.39

Fnd: C 61.75 H6.51 b) 2-[4-(3-Oxapropionic acid ethyl ester) -phenyl-2-bromoacetic acid methyl ester 201 g (1.13 mol) of N-bromosuccinimide and 100 mg of dibenzylperoxide are added to 285 g (1.13 mol) of the title compound of Example 55a), dissolved, in 2000 ml of carbon tetrachloride, and it is refluxed for 8 hours. It is cooled in an ice bath, the precipitated succinimide is filtered off, and the filtrate is evaporated to the dry state in a vacuum. The residue is purified on silica gel (mobile solvent: n-hexane/acetone = 15: 1).

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

Elementary analysis:

Cld: C 47.28 H4.57 Br24.16

Fnd: C 47.19 H4.71 Br24.05 c) 2-[4-(3-Oxapropionic acid ethyl ester)]-phenyl-2-[1-(1,4,7,10-tetraazacyclododecan-7- vl]-acetic acid methyl ester 350 g (1.057 mol) of the title compound of Example 55b) is added to 603 g (3.5 mol) of 1,4,7,10-tetraazacyclododecane in 6000 ml of chloroform, and it is stirred overnight at room o © 0200371949 ® @ It is extracted 3 times with 3000 ml of water, the organic phase is dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is used without further purification in the next reaction (3d).

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

Elementary analysis:

Cld: C59.70 H8.11 N 13.26

Fnd: C 59.58 H 8.20 N 13.18 d) 2-[4-(3-Oxapropionic acid)]-phenyl-2-[1 ,4,7-tris(carboxymethyl)- 1,4,7,10-tetraaza- cyclododecan-10-yl]-acetic acid 445 g (1.053 mol) of the title compound of Example 55¢) and 496 g (5.27 mol) of chloroacetic acid are dissolved in 4000 ml of water. It is set with 30% aqueous sodium hydroxide solution to a pH of 10. It is heated to 70°C, and the pH is kept at 10 by adding 30% aqueous sodium hydroxide solution. It is stirred for 8 hours at 70°C. It is then setat a pH of 13 and refluxed for 30 minutes. The solution is cooled in an ice bath and set at a pH of 1 by adding concentrated hydrochloric acid. It is evaporated to the dry state in a vacuum. The residue is taken up in 4000 ml of methanol and absorptively precipitated for one hour at room temperature.

Precipitated common salt is filtered out, the filtrate is evaporated to the dry state, and the residue is purified on silica gel.

RP-18 (mobile solvent: gradient that consists of water/ethanol/acetonitrile).

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

Water content: 10.2%

Elementary analysis (relative to anhydrous substance):

Cld: C51.98 H6.18 N 10.10

Fnd: C 51.80 H 6.31 N 10.01

® ® 2-[4-(3-Oxapropionic acid)]-phenyl-2-[1,4,7-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecan-10-yl]-acetic acid, Gd complex 130.73 g (360.65 mmol) of gadolinium oxide is added to 400 g (721.3 mmol) of the title compound of Example 55d) in 2000 ml of water, and it is stirred for 5 hours at 80°C. The solution is filtered, and the filtrate is freeze-dried.

Yield: 511 g (quantitative) of an amorphous solid.

Water content: 11.0%

Elementary analysis (relative to anhydrous substance):

Cid: C40.67 H4.41 Gd 22.19 N 7.98

Fnd: C 40.51 H4.52 Gd 22.05 N 8.03 f) 2,6-N,N'-Bis{2-[4-(3-oxapropionyl)-phenyl]-2-[1,4,7-tris(carboxylatomethyl)-1,4,7,10- tetraazacyclododecan-10-yl]-acetic acid]-lysine-[4-perfluorooctylsulfonyl)-piperazine]- amide, digadolinium complex, disodium salt g (14.36 mmol) of the title compound of Example 54a), 3.45 g (30 mmol) of N- hydroxysuccinimide, 2.54 g (60 mmol) of lithium chloride and 21.26 g (30 mmol) of the title compound of Example 4Be are dissolved in 250 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 16.51 g (80 mmol) of N,N-dicyclohexylcarbodiimide is added, and it is then stirred overnight at room temperature. The solution is poured into 2000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient that consists of water/ethanol/-acetonitrile). It is dissolved in a little water, set at a pH of 7.4 with sodium hydroxide solution and freeze-dried.

Yield: 21.02 g (69% of theory) of a colorless solid.

Water content: 11.2%

Elementary analysis (relative to anhydrous substance): ~~ Cld: C3736 H3.66F 1522 Gd 14.82 N 7.92 Na2.71S 1.51

Fnd: C3728 H3.74F 15.14 Gd 14.75 N 8.03 Na 2.23 S 1.46

® ® S56 a) 2,6-N,N'-Bis[6-carbonylmethyl-3,9-bis(t butyloxycarbonylmethyvl)3,6,9-triazaundecane- 1,11-dicarboxylic acid-bis(t butylester)]-lysine-[ 1-(4-perfluorooctylsulfonyl)-piperazine]- amide 10.32 g (50 mmol) of N,N-dicyclohexylcarbodiimide is added at 0°C to a solution that consists of 10 g (14.36 mmol) of the title compound of Example 54a), 18.53 g (30 mmol) of 3,9- bis(t butyloxycarbonylmethyl)-6-carboxymethyl-3,6,9-triazaundecane-1,1 1-dicarboxylic acid- bis(t butylester), and 3.45 g (30 mol) of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide. It is stirred for 3 hours at 0°C, then overnight at room temperature.

Precipitated urea is filtered out, the filtrate is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/ethanol = 20:1).

Yield: 19.60 g (72% of theory) of a viscous oil.

Elementary analysis:

Cld: C49.41 H6.75 F17.03 N 7.39 S 1.69

Fnd: C4935 H6.82 F16.92 N7.32 S1.62 b) 2,6-N,N-Bis[6-carbonylmethyl-3,9-bis(carboxylatomethyl)-3,6,9- triazaundecanedicarboxylic acid-1-carboxy-11-carboxylato-lysine-[ 1-(4-perfluorooctylsulfonyl)- piperazine]-amide, Gd complex, sodium salt] g (7.91 mol) of the title compound of Example 56a) is dissolved in 50 ml of chloroform, and 200 ml of trifluoroacetic acid is added. Itis stirred for 10 minutes at room temperature. It is evaporated to the dry state in a vacuum, and the residue is dissolved in 150 ml of water. 2.87 g (7.91 mmol) of gadolinium oxide is added, and it is stirred for 5 hours at 80°C.

It is allowed to cool to room temperature and set at pH 7.4 with 2N sodium hydroxide solution.

The solution is evaporated to the dry state in a vacuum and purified on RP-18 (mobile solvent: gradient that consists of water/ethanol/acetonitrile).

® C Yield: 8.11 g (57% of theory) of a colorless, amorphous solid.

Water content: 9.6%

Elementary analysis (relative to anhydrous substance):

Cid: C30.70 H3.08 Gd 17.48 N 7.78 Na2.56 S 1.78

Fnd: C3058 H3.19 Gd 17.42 N 7.71 Na2.68 S1.72

Example 57 a) 6-N-Benzyloxycarbonyl-2-N-[6-carboxymethyl-3,9-bis(t-butyloxycarbonylmethyl)-3,6,9- triazaundecane-1,11-dicarboxylic acid-bis(t butylester)]-lysine-[1(4- : perfluorooctylsulfonyl)-piperazine]-amide 8.25 g (40 mol) of N,N-dicyclohexylcarbodiimide is added at 0°C to a solution that consists of 20 g (24.08 mmol) of the title compound of Example 52c), 14.88 g (24.08 mmol) of 3,9-bis(t butyloxycarbonylmethyl)-6-carboxymethyl-3,6,9-triazaun-decane-1,11 -dicarboxylic acid-bis(t butylester) and 2.88 g (25 mol) of N-hydroxysuccinimide, dissolved in 100 ml of dimethylformamide. It is stirred for 3 hours at 0°C, then overnight at room temperature.

Yield: 27.21 g (79% of theory) of a viscous oil

Elementary analysis:

Cld: C47.03 H5.64 F22.58 N6.85 S2.24

Fnd: C46.94 H5.58 F22.65 N6.84 S2.31

® ® 2-N-[Carbonylmethyl-3,9-bis(t butyloxycarbonylmethyl)-3,6,9-triazaundecane-1,11- dicarboxylic acid-bis(t butylester)]-lysine-[ 1-(4-perfluorooctylsulfonyl)-piperazine]- amide 25 ¢ (17.48 mmol) of the title compound of Example 57a) is dissolved in 350 ml of ethanol, and 5 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 22.66 g (quantitative) of a colorless solid.

Elementary analysis:

Cld: C4448 HS5.75 F24.92 N7.56 S2.47

Fnd: C44.59 HS.81 F25.03 N7.46 S2.52

Cc) 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3- aza-4-oxo-5-methyl-5yl)]-2-N-[6-carbonylmethyl-3,9-bis(t butyloxycarbonylmethyl) 3,6,9-triazaundecane-1,11-dicarboxylic acid bis (t butylester)]-lysine-[1-(4- perfluorooctylsulfonyl)-piperazine-]-amide, Gd complex g (15.43 mmol) of the title compound of Example 57b), 1.78 g (15.43 mmol) of N- hydroxysuccinimide, 1.48 g (35 mmol) of lithium chloride and 9.72 g (15.43 mmol) of 1,4,7- tris(carboxylatomethyl)-10-(3-aza-40x0-5methyl-5yl)-pentanoic acid-1,4,7,10- tetraazacyclododecane, Gd complex, are dissolved in 150 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 5.16 g (25 mmol) of N,N-dicyclohexylcarbodiimide is added, and then it is stirred overnight at room temperature. The solution is poured into 2500 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 22.94 g (78% of theory) of a colorless solid.

Water content: 7.9%

Elementary analysis (relative to anhydrous substance):

Cld: C42.22H5.29 F16.95 Gd 8.25 N 8.82 S1.68

® ® Fnd: C42.15H 5.41 F 16.87 Gd&8&.13 N&.70 S 1.60 d) 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1 0-(3-aza-4-o0x0-5- methyl-5-yl-pentanoyl)]-2-N-[6-carbonylmethyl-3,9-bis(carboxylatomethyl) 3,6,9- triazaundecanedicarboxylic acid-carboxy-11-carboxylato-z]-lysine-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide, digadolinium complex, sodium salt g (10.49 mmol) of the title compound of Example 57¢) is dissolved in 200 ml of trifluoroacetic acid. It is stirred for 60 minutes at room temperature. It is evaporated to the dry state in a vacuum, and the residue is dissolved in 150 ml of water. 1.90 g (5.25 mmol) of gadolinium oxide is added, and it is stirred for 5 hours at 80°C. It is allowed to cool to room temperature and set at a pH of 7.4 with sodium hydroxide solution. The solution is evaporated to the dry state in a vacuum and purified on silica gel RP-18 (mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 11.89 g (61% of theory) of a colorless, amorphous solid.

Water content: 10.2%

Elementary analysis (relative to anhydrous substance):

Cld: C3297H347F17.39Gd 16.93N9.05Na1.24S5 1.73

Fnd: C3290H3.53F 17.31 Gd 16.87 N8.92Na 1.33 S 1.67

Example 58 a) 5,6-Bis(benzyloxy)-3oxa-hexanoic acid-t butylester 100 g (376.2 mmol) of 1,2-di-O-benzyl-glycerol [produced according to Chem. Phys.

Lipids (1987), 43(2), 113-277] and 5 g of tetrabutylammonium hydrogen sulfate are dissolved in a mixture that consists of 400 ml of toluene and 200 ml of 50% aqueous sodium hydroxide solution. At 0°C, 78 g (400 mmol) of 2-bromoacetic acid-t butyl ester is added in drops over 30 minutes, and then it is stirred for 3 hours at 0°C. The organic phase is separated, dried on

@ mgpesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/acetone = 20:1).

Yield: 133.4 g (94% of theory) of a colorless oil.

Elementary analysis:

Cld: C 71.48 H 7.82

Fnd: C 71.61 H7.92 b) 5,6-Bis(benzyloxy)-3-oxa-hexanoic acid 130 g (336.4 mmol) of the title compound of Example 58a) is dissolved in 200 ml of dichloromethane, and 100 ml of trifluoroacetic acid is added at 0°C. It is stirred for 4 hours at room temperature, and then it is evaporated to the dry state. The residue is crystallized from pentane/diethyl ether.

Yield: 102.2 g (92% of theory) of a waxy solid

Elementary analysis:

Cld: C 69.07 H6.71

Fnd: C 69.19 H 6.82 c) 6-N-Benzyloxycarbonyl-2-N-[1,4,7-tris(carboxylatomethyl) 1,4,7,10-tetraazacyclo- dodecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-lysine-[ 1-(4- perfluorooctylsulfonyl)-piperazine]-amide, Gd complex 50 g (60.20 mmol) of the title compound of Example 52¢), 6.93 g (60.20 mmol) of N- hydroxysuccinimide, 5.09 g (120 mmol) of lithium chloride, and 37.91 g (60.20 mmol) of 1,4,7- tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane- 10-pentanoyl-3-aza-4-0x0-5 -methyl- 5y1), Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 20.63 g (100 mmol) of N,N-dicyclohexylcarbodiimide is added, and then it is stirred overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10

’ 198 3200371949 ® {| A The precipitated solid is filtered off and then purified by chromatography (silica gel

RP-18, mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 75.53 g (87% of theory) of a colorless solid.

Water content: 10.1%

Elementary analysis (relative to anhydrous substance):

Cld: C37.48 H3.84 F22.39 Gd 10.90 N 8.74 § 2.22

Fnd: C 37.39 H4.02 F22.29 Gd 10.75 N 8.70 S2.22 d) 2-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3aza- 4-0x0-5methyl-5yl]-lysine-[ 1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex 70 g (48.53 mmol) of the title compound of Example 58c) is dissolved in 500 ml of water/100 ml of ethanol, and 5 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 63.5 g (quantitative) of a colorless solid.

Water content: 9.8% :

Elementary analysis (relative to anhydrous substance):

Cld: C37.48 H3.84 F2239 Gd 10.90 N 8.74 S2.22

Fnd: C 37.39 H4.03 F2231 Gd 10.78 N 8.65 S2.20 e) 6-N-[5,6-Bis(benzyloxy)-3-oxahexanoyl]-2-N-[1,4,7-tris(carbox ylatomethyl)-1,4,7,10- tetraazacyclododecane-10-(pentanoyl-3 aza-4-0x0-5-methyl-5 y1)]-lysine-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide, Gd complex g (7.64 mmol) of the title compound of Example 58d), 3.30 g (10 mmol) of the title compound of Example 7b, 0.85 g (20 mmol) of lithium chloride and 1.15 g (10 mmol) of N- hydroxysuccinimide are dissolved in 150 ml of dimethyl sulfoxide while being heated slightly.

At 10°C, 3.10 g (15 mmol) of N,N'-dicyclohexylcarbodiimide is added, and it is stirred for 8

® @: at room temperature. The reaction solution is poured into 2000 ml of acetone, and the deposited precipitate is isolated. The title compound is purified on silica gel RP-18 (mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 11.14 g (90% of theory) of a colorless, amorphous solid.

Water content: 4.3%

Elementary analysis (relative to anhydrous substance):

Cld: C41.51 H429 F19.93 N7.78 Gd 9.70 S1.98

Fnd: C41.45 H4.38 F19.84 N7.70 Gd 9.58 S1.90 fH 6-N-(5,6,-Dihydroxy-3-oxahexanoyl)-2-N-[1,4,7-tris carboxylatomethyl)-1,4,7,1 0- tetraazacyclododecane-10-pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-lysine [1-(4- perfluorooctylsulfonyl)-piperazine]-amide, Gd complex g (6.17 mmol) of the title compound of Example 58e) is dissolved in 200 ml of ethanol, and 3 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 8.89 g (quantitative) of a colorless solid.

Water content: 3.1%

Elementary analysis (relative to anhydrous substance):

Cld: C35.03 H3.99 F22.42 Gd 10.92 N8.75 S2.23

Fnd: C 34.95 H4.12 F22.30 Gd 10.78 N&.71 S2.18

Example 59 a) 6-N-Benzyloxycarbonyl-2-N[-5,6-bis(benzyloxy)-3-oxa-hexanoyl]-lysine-[ 1-(4- perfluorooctylsulfonyl)-piperazine]-amide 9.28 g (45 mmol) of N,N-dicyclohexylcarbodiimide is added at 0°C to a solution that consists of 20 g (24.08 mmol) of the title compound of Example 52c), 9.91 g (30 mmol) of the title compound of Example 7b and 3.45 g (30 mmol) of N-hydroxysuccinimide, dissolved in 100

® dB dimethylformamide. It is stirred for 3 hours at 0°C and then overnight at room temperature. Precipitated urea is filtered out, the filtrate is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/ethanol = 20:1).

Yield: 24.50 g (89% of theory) of a viscous oil.

Elementary analysis:

Cld: C47.29 H4.14 F 28.26 N4.90 S 2.81

Fnd: C47.14 H4.26 F 28.17 N491 S 2.69 b) 2-N-(5,6-Dihydroxy-3-oxahexanoyl)-lysine-{ 1-(4-perfluorooctylsulfonyl)-piperazine]- amide 20 g (17.5 mmol) of the title compound of Example 52d) is dissolved in 300 ml of ethanol, and 5 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 17.65 g (quantitative) of a colorless solid.

Elementary analysis:

Cld: C 44.05 H4.10 F32.02 N'5.55 S3.18

Fnd: C 43.96 H4.21 F31.94 N548 S3.24 c) 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3- aza-4-oxo-5-methyl-5yl)]-lysine-| 1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex g (14.87 mmol) of the title compound of Example 59b), 1.73 g (15 mmol) of N- hydroxysuccinimide, 1.27 g (30 mmol) of lithium chloride and 9.48 g (15 mmol) of 1,4,7- tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl)-pentanoic acid-1,4,7,10- tetraazacyclododecane, Gd complex, are dissolved in 100 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 5.16 g (25 mol) of N,N-dicyclohexylcarbodiimide is added, and then it is stirred overnight at room temperature. The solution is poured into 1500 ml of acetone and

® Le for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18 mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 19.28 g (80% of theory) of a colorless solid.

Water content: 10.3%

Elementary analysis (relative to anhydrous substance):

Cld: C41.51 H4.29 F19.93 Gd 9.70 N7.78 S 1.98

Fnd: C 41.37 H4.40 F 19.88 Gd 9.58 N 7.67 S 1.85

Example 60 a) 6-N-Benzyloxycarbonyl-2-N-[2,6-N,N'-bis(benzyloxycarbonyl)-lysyl]-lysine-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide g (24.08 mmol) of the title compound of Example 52c) and 2.53 g (25 mmol) of triethylamine are dissolved in 200 ml of tetrahydrofuran (THF), and 14.46 g (27 mmol) of di-

N,N'-Z-lysine paranitrophenylester is added. It is stirred for 5 hours at 50°C. It is evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel. Mobile solvent: dichloromethane/methanol = 20:1).

Yield: 28.07 g (95% of theory) of a colorless solid.

Elementary analysis:

Cld: C46.99 H4.19 F 26.32 N 6.85 S2.61

Fnd: C47.08 H4.32 F2621 N6.75 S2.54 b) 2-N-(Lysyl)-lysine-[ 1-(4-perfluorooctylsulfonyl)-piperazine]-amide, trihydrobromide 100 ml of hydrobromic acid in glacial acetic acid (48%) is added to 25 g (20.37 mmol) of the title compound of Example 60a) and stirred for 2 hours at 40°C. It is cooled to 0°C, 1500 ml of diethyl ester is added in drops, and the precipitated solid is filtered off. After dryingina vacuum (60°C), 21.52 g (99% of theory) of a slightly yellow-colored, crystalline solid is obtained.

C ® Elementary analysis:

Cld: C 27.01 H3.40 Br22.46 F30.26 N7.87 §3.00

Fnd: C 26.92 H3.53 Br22.15 F 30.14 N7.69 S2.87 c) 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3- aza-4-0x0-5-methyl-5y1)]-2-N-]2,6-N,N'-bis[ 1,4, 7-tris carboxylatomethyl)-1,4,7,10- tetraazacyclododecane-10-(pentanoyl-3-aza-4-o0xo-5-methyl-5 y1)]-lysyl]-lysine-{1-(4- perfluorooctylsulfonyl)-piperazine]-amide, trigadolinium complex 31.49 g (50 mmol) of 1,4,7-tris(carboxylatomethyl)- 10-(3-aza-4-0xo-5-methyl-)-5-y1)- pentanoic acid, Gd complex 6.91 g (60 mmol) of N-hydroxysuccinimide and 4.24 g (100 mmol) of lithium chloride are dissolved in 350 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 16.51 g (80 mmol) of N,N-dicyclohexylcarbodiimide is added, and it is stirred for 5 hours at 10°C. 10g (9.37 mmol) of the title compound of Example 60b) and 3.03 g (30 mmol) of triethylamine are added to this mixture, and it is stirred for 12 hours at 60°C. It is allowed to cool to room temperature, and the mixture is poured into 3000 ml of acetone. The deposited precipitate is filtered off and purified on silica gel RP-18 (mobile solvent: gradient that consists of water/ethanol/acetonitrile). | :

Yield: 16.7 g (67% of theory) of a colorless solid.

Water content: 7.9%

Elementary analysis (relative to anhydrous substance):

Cld: C36.58 H4.43 F12.14 Gd 17.74 N11.06 S 1.14

Fnd: C 36.47 H4.54 F12.03 Gd 17.65 N 10.95 S 1.21 o Egunle 61 a) 1,7-Bis(benzyloxycarbonyl)-4-(3,6,9,12,15-pentaoxahexadecanoyl)-1,4,7,10- tetraazacyclododecane 24.73 g (100 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) is added at 0°C to 18.13 g (68.1 mmol) of 3,6,9,12,15-pentaoxahexadecanoic acid and 30 g : (68.1 mmol) of 1,7 di-Z-cyclene, produced according to Z. Kovacs and A. D. Sherry, J. Chem.

Soc. Chem. Commun. (1995), 2, 185, in 300 ml of tetrahydrofuran, and it is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromato graphed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

Yield: 19.13 g (42% of theory) of a colorless solid

Elementary analysis:

Cid: C61.03 H7.61 N&.13

Fnd: C 60.92 H7.75 N 8.04 b) 1,7-Bis(benzyloxycarbonyl)-4-(3,6,9,12,15-pentaoxahexadecanoyl)-10- (2H,2H,4H,5H,5H-3-oxa-perfluorotridecanoyl)- 1,4,7,10-tetraazacyclododecane 12.36 g (50 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline- 1-carboxylic acid ethyl ester) is added at 0°C to 18 g (26.91 mmol) of the title compound of Example 612) and 14.05 g (26.91 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid, produced according to

DE 19603033, in 300 ml of tetrahydrofuran, and it is stirred overnight at room temperature. Itis evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

Yield: 21.51 g (67% of theory) of a colorless solid

Elementary analysis:

Cld: C 47.32 H4.82 F27.07 N4.70

Fnd: C47.26 H5.01 F26.94 N4.59

204 ~ 3200371949 ® © 1-(3,6,9,12,15-Pentaoxahexadecanoyl)-7-(2H,2H,4H,4H,5H,5H-3- oxaperfluorotridecanoyl)-1,4,7,10-tetraazacyclododecane 20 g (16.77 mmol) of the title compound of Example 52d) is dissolved in 200 ml of ethanol, and 2.5 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 15.5 g (quantitative) of a colorless solid.

Elementary analysis:

Cld: C 40.27 H4.90 F 34.93 N 6.06

Fnd: C 40.15 H4.99 F 34.87 N5.94 d) 1,7-Bis(1,4,7-tris(carboxylatomethyl)-1,4,7,1 0-tetraazacyclododecane-1 0-(pentanoyl-3- aza-4-oxo-5-methyl-5-yl)]-4-(3,6,9,12,15-pentaoxahexadecanoyl)-10- (2H,2H,4H,4H,5H,5 H,-3-oxaperfluorotridecanoyl)-1,4,7,1 0-tetraazacyclododecane, Gd complex g (16.22 mmol) of the title compound of Example 61¢), 4.60 g (40 mmol) of N- hydroxysuccinimide, 3.39 g (80 mmol) of lithium chloride and 25.19 g (40 mmol) of 1,4,7- tris(carboxylatomethyl)-10-(3-aza-4-0xo-5-methyl-5-yl)-pentanoic acid, Gd complex, are dissolved in 300 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 24.73 g (100 mmol) of EEDQ is added, and then it is stirred overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes.

The precipitated solid is filtered off and then purified by chromatography (silica gel RP- 18, mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 19.86 g (57% of theory) of a colorless solid

Water content: 11.3%

Elementary analysis (relative to anhydrous substance):

Cld: C 38.58 H4.74 F 15.04 Gd 14.64 N9.13

Fnd: C 38.47 H491 F1495 Gd 14.57 N9.04

® e. 62 a) 3,5-Dinitrobenzoic acid-1-[(4-perfluorooctylsulfonyl)-piperazine]-amide

A solution that consists of 8.76 g (38 mmol) of 3,5-dinitrobenzoyl chioride in 55 ml of dichloromethane is added in drops at 0°C to 20 g (35.2 mmol) and 8.1 g (80 mmol) of triethylamine, dissolved in 200 ml of dichloromethane, and it is stirred for 3 hours at 0°C. 200 ml of 5% aqueous hydrochloric acid is added, and it is stirred for 5 minutes at room temperature.

The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/ acetone = 15:1).

Yield: 24.96 g (93% of theory) of a colorless solid.

Elementary analysis: - Cid: C29.35 H1.45 F42.37 N 7.35 S4.21 :

Fnd: C29.28 H 1.61 F42.15 N7.25 S4.15 b) 3,5 Diaminobenzoic acid-{1-(4-perfluorooctylsulfonyl)-piperazine]-amide g (26.23 mmol) of the title compound of Example 62a) is dissolved in 400 ml of ethanol, and 6 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 18.43 g (quantitative) of a cream-colored solid.

Elementary analysis:

Cld: C32.49 H2.15 F4598 N 798 S4.57

Fnd: C32.29 H2.35 F45.69 N7.81 S4.40

® y 3,5-N,N'-Bis[1,4,7-tris(carboxylatomethyl)-1,4,7,1 0-tetraazacyclododecane- 10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl-)]-benzoic acid-[1-(4-perfluorooctyl-sulfonyl)- piperazine]-amide, Gd complex g (14.24 mmol) of the title compound of Example 62b), 3.45 g (30 mmol) of N- hydroxysuccinimide, 2.54 g (60 mol) of lithium chloride and 18.89 g (30 mmol) of 1,4,7- tris(carboxylatomethyl)-10-(3-aza-4-0x0-5-methyl-5yl)-pentanoic acid, Gd complex, are dissolved in 200 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 10.32 g (50 mmol) of N,N-dicyclohexylcarbodiimide is added, and then it is stirred overnight at room temperature. The solution is poured into 2000 ml of acetone, and it is stirred for 10 minutes.

Yield: 19.74 g (72% of theory) of a colorless solid.

Water content: 11.8%

Elementary analysis (relative to anhydrous substance):

Cld: C35.55 H3.72 F16.77 Gd 16.33 N 10.18 S 1.67

Fnd: C3548 H3.84 F 16.58 Gd 16.24 N 10.07 S1.58

Example 63 a) 3-Oxa-2H,2H,4H,4H, 5H, 5H-perfluorotridecanecarboxylic acid-t-butylester 25.0 g (53.8 mmol) of 1H,1H,2H,2H-perfluoro-1-decanol [commercially available from : the Lancaster Company] is dissolved in 250 ml of absolute toluene and mixed at room temperature with a catalytic amount (about 0.75 g) of tetra-n-butyl-ammonium hydrogen sulfate.

Then, a total of 7.55 g (134.6 mmol; 2.5 equivalents relative to the alcohol component that is used) of fine-powder potassium hydroxide powder is added at 0°C, followed by 15.73 g (80.7 mmol; 1.5 equivalents relative to the alcohol component that is used) of bromoacetic acid-tert- butylester, and it is allowed to stir for 2 more hours at 0°C. The thus obtained reaction solution is stirred for 12 more hours at room temperature, and for the purpose of working-up, it is mixed

® @ a total of 500 ml of ethyl acetate and 250 ml of water. The organic phase is separated and washed twice with water. After the organic phase is dried on sodium sulfate, salt is suctioned out, and the solvent is drawn off in a vacuum. The remaining oily residue is purified on silica gel with use of ethyl acetate/hexane (1:10) as an eluant.

Elementary analysis:

Cld: C33.23 H2.61 F55.85

Fnd: C33.29 H2.61 F 55.90 b) 3-Oxa-2H,2H,4H,4H, 5H, 5H-perfluorotridecanecarboxylic acid 20.0 g (34.58 mmol) of the title compound of Example 63a) is suspended in 200 ml of a mixture that consists of methanol and 0.5 molar sodium hydroxide solution at a ratio of 2:1 while being stirred at room temperature, and then it is heated to 60°C. After a reaction time of 12 hours at 60°C, the now clear reaction mixture is neutralized for working-up by mixing with

Amberlite® IR 120 (H form)-cation-exchange resin, exchanger is suctioned out, and the thus obtained methanolic-aqueous filtrate is drawn off in a vacuum until a dry state is reached. The amorphous-oily residue that is obtained is purified on silica gel with use of ethyl acetate/n- hexane (1:3) as an eluant.

Elementary analysis:

Cld: C27.60 H1.35 F61.85

Fnd: C27.58 H1.36 F61.90

C ® 1,7-Bis{[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)}- 1,4,7,10-tetraazacyclododecane} -diethylenetriamine, digadolinium complex 2.48 g [(3.94 mmol); 2.05 molar equivalents relative to the diethylenetriamine that is used] of the Gd complex, described in Patent Application DE 197 28 954 C1 under Example 31h), of 10-(4-carboxy-1-methyl-2-0x0-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid and 167 mg of anhydrous lithium chloride (3.94 mmol) are dissolved at 40°C in 40 mi of absolute dimethyl sulfoxide while being stirred and mixed at this temperature with a total of 453 mg (3.94 mmol) of N-hydroxysuccinimide. After cooling to room temperature, the thus obtained reaction solution is mixed with 814 mg (3.946 mmol) of N,N'- dicyclohexylcarbodiimide and stirred for 2 hours at room temperature. The suspension of active ester that is obtained is then mixed with 198.3 mg (1.92 mmol) of diethylenetriamine, dissolved in 5 ml of absolute dimethyl sulfoxide, and it is stirred for 12 hours at room temperature. For the purpose of working-up, the reaction mixture is mixed with sufficient acetone until the above- mentioned title compound is completely precipitated, the precipitate is suctioned off, dried, taken up in water, insoluble dicyclohexylurea is filtered out, and the filtrate is desalinated with an

AMICON® YM-3 ultrafiltration membrane (cut-off 3,000 Da), and low-molecular components are removed. The retentate is then freeze-dried.

Yield: 1.85 g (72.7% of theory) as a colorless lyophilizate.

H,O0 content (Karl-Fischer): 3.89%.

Elementary analysis (relative to anhydrous substance):

Cld: C 38.03 H5.24 N13.73 Gd 23.71 :

Fnd: C 37.98 H5.20 N 13.69 Gd 23.78 i BEUUVI/ 1949 ® @® 1,7-Bis{[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-0x0-5-methyl-5-yl-pentanoyl)]- 1,4,7,10-tetraazacyclododecane} -4-(3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoyl)- diethylenetriamine, digadolinium complex 1.27 g (2.44 mmol) of the title compound of Example 63b), dissolved in a mixture that consists of 15 ml of tetrahydrofuran and 15 ml of dimethyl sulfoxide, is added drop by drop at 50°C and under nitrogen atmosphere to a solution of 3.23 g (2.44 mmol) of the title compound of

Example 63c¢), in a mixture that consists of 30 ml of dimethyl sulfoxide and 3 ml of tetrahydrofuran. Then, a total of 1.80 g (3.66 mmol) of EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2- dihydroquinoline] is added in portions at 0°C and allowed to stir overnight at room temperature.

The reaction solution that is obtained is then mixed with sufficient acetone until the above- mentioned title compound is completely precipitated, the precipitate is suctioned off, dried, taken up in water, insoluble components are filtered out, and the filtrate is ultrafiltered with an

AMICON®™ YM-3 ultrafiltration membrane (cut-off 3,000 Da), which is used both for complete desalination and for removing low-molecular components from the title compound. The retentate is then freeze-dried.

Yield: 3.54 g (79.4% of theory) as a colorless lyophilizate.

H,O content (Karl-Fischer): 5.87%.

Elementary analysis (relative to anhydrous substance):

Cid: C35.43 H4.07 N9.95 F 17.64 Gd 17.18

Fnd: C3542 H4.01 N9.89 F 17.67 Gd 17.18

Example 64 a) 2-N-Trifluoroacetyl-6-N-benzyloxycarbonyl-L-lysine 100.0 g (356.7 mmol) of 6-N-benzyloxycarbonyl-L-lysine is dissolved in a mixture that consists of 1000 ml of trifluoroacetic acid ethyl ester and 500 ml of ethanol, and it is stirred for 24 hours at room temperature. lt is evaporated to the dry state, and the residue is crystallized from diisopropyl! ether.

® ( Yield: 128.9 g (96% of theory) of a colorless crystalline powder.

Melting point: 98.5°C.

Elementary analysis:

Cld: C51.07 H5.09 N7.44 F 15.14

Fnd: C 51.25 HS5.18 N7.58 F 15.03 b) 2-N-Trifluoroacetyl-6-N-benzyloxycarbonyl-L-lysine [1-(4-perfluorooctylsulfonyl)- piperazine]-amide 164.2 g (0.664 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) is added at 0°C to 125.0 g (332.0 mmol) of the title compound of Example 52a) and 188.7 g (332.0 mmol) of 1-perfluorooctylsulfonylpiperazine (produced according to DE 19603033) in 750 ml of tetrahydrofuran, and it is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/ methanol = 20:1).

Yield: 286.0 g (93% of theory) of a colorless solid.

Melting point: 92°C.

Elementary analysis:

Cld: C36.30 H2.83 N6.05 F41.01 S3.46

Fnd: C36.18 H2.94 N5.98 F 40.87 S3.40 €) 6-N-Benzyloxycarbonyl-L-lysine-{1 -(4-perfluorooctylsulfonyl)-piperazine}-amide

Ammonia gas is introduced at 0°C for one hour into a solution that consists of 280.0 g (302.2 mol) of the title compound of Example 52b) in 2000 ml of ethanol. It is then stirred for 4 hours at 0°C. It is evaporated to the dry state, and the residue is absorptively precipitated from water. The solid is filtered off and dried in a vacuum at 50°C.

Yield: 243.5 g (97.0% of theory) of an amorphous solid.

@ ® Elementary analysis:

Cld: C37.60 H3.28 N6.75 F 38.89 S3.86

Fnd: C 37.55 H3.33 N6.68 F38.78 S3.81 d) L-Lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide 200.0 g (240.8 mmol) of the compound that is produced under 64c) is dissolved in 1000 ml of ethanol, mixed with 5.0 g of Pearlman's catalyst (Pd 20%, C) and hydrogenated at room temperature under a hydrogen atmosphere (1 atm) until no more hydrogen absorption can be observed. Catalyst is suctioned out, it is thoroughly rewashed with ethanol (three times with about 100 ml each) and evaporated to the dry state in a vacuum. The title compound is obtained as a strongly viscous and yellowish-colored oil.

Yield: 162.5 g (96.9% of theory)

Elementary analysis:

Cld: C 31.04 H 3.04 N8.05 F46.38 S 4.60

Fnd: C31.11 H3.09 N8.08 F 46.33 S 4.62 e) 6N-2N-Bis- {4-[2,3-bis-(N,N-bis(t-butyloxycarbonylmethyl)-amino)-propyl]-phenyl}-3- oxa-propionyl-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide 5.25 g (7.72 mmol) of the 4-[2,3-bis-(N,N-bis(t-butyloxycarbonylmethyl)-amino)- propyl]-phenyl}-3-oxa-propionic acid and 781.0 mg (7.72 mmol) of triethylamine are dissolved in 50 ml of methylene chloride. At -15°C, a solution that consists of 1.16 g (8.5 mmol) of isobutyl chloroformate in 10 ml of methylene chloride is added in drops within 5 minutes, and it is stirred for another 20 minutes at -15°C. Then, the solution is cooled to -25°C, and a solution, consisting of 2.68 g (3.86 mmol) of the title compound of Example 64d) and 2.12 g (21.0 mmol) of triethylamine, in 70 ml of tetrahydrofuran is added in drops within 30 minutes and subsequently stirred for another 30 minutes at -15°C, and then stirring is continued overnight at room temperature. For working-up, the solvent is drawn off in a vacuum, and the remaining oily

® rue is taken up in 250 ml of chloroform. The chloroform phase is extracted twice with 100 ml each of a 10% aqueous ammonium chloride solution, the organic phase is dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol = 20:1).

Yield: 5.37 g (68.8% of theory) of a colorless and very viscous oil.

Elementary analysis:

Cld: C5227 H6.43 N5.54 F15.97 S 1.39

Fnd: C 52.22 H6.51 N549 F15.99 S 1.63 f) (6N-2N-Bis- {4-[2,3-bis-(N,N-bis(carboxylatomethyl)-amino)-propyl]-phenyl}-3-oxa- propionyl-L-lysine-[ 1-(4-perfluorooctylsulfonyl)-piperazine}-amide, octa-sodium salt 5.0 g (2.47 mmol) of the title compound of Example 64e) is dissolved in 60 ml of absolute dichloromethane. Then, it is mixed drop by drop at 0°C with a total of 75 ml of trifluoroacetic acid. After a reaction time of 12 hours at room temperature, it is evaporated to the dry state in a vacuum. The remaining residue is mixed with 100 ml of water and drawn off again in a vacuum until a dry state is reached. The thus obtained residue is dissolved in 200 ml of distilled water, and the aqueous product solution of the above-mentioned title compound is extracted twice with 60 ml of diethyl ether in each case. The resulting aqueous product solution is made up to a total volume of 300 ml by mixing with water, insoluble components are filtered out, and the filtrate is ultrafiltered with an AMICON® YM-3 ultrafiltration membrane (cut-off 3,000 Da), which is used both for complete desalination and for removing low-molecular components from the title compound. The retentate is made up to a total volume of 200 ml by mixing with water, and the pH of this solution is then set at 10.0 with 15% sodium hydroxide solution. The basic, aqueous product solution is subsequently freeze-dried. 4.0 g (92.8% of theory) of the title compound is obtained in the form of the octa-sodium salt as an amorphous lyophilizate.

Water content: 5.37%

@® ( Elementary analysis (relative to anhydrous substance):

Cld: C 38.46 H3.28 N6.41 F 18.47 S1.83 Nal10.52

Fnd: C 38.42 H3.31 N6.39 F18.51 S1.87 Na10.38 2) 6N-2N-Bis- {4-[2,3-bis-(N,N-bis(carboxymethyl)-amino)-propyl]-phenyl} -3-oxa- propionyl-L-lysine-[ 1-(4-perfluorooctylsulfonyl)-piperazine]-amide, di-manganese complex, tetra-sodium salt 1.94 g (1.11 mmol) of the title compound of Example 64f) is dissolved in 100 ml of distilled water, and the resulting solution is brought to a pH of 4.0 by mixing with 1 molar aqueous hydrochloric acid. At 80°C, it is now mixed in portions with 0.25 g (2.22 mmol) of manganese(ll) carbonate. Then, the thus obtained reaction solution is refluxed for 5 hours. After cooling to room temperature, the pH of the aqueous product solution is set at 7.2 by mixing with

IN sodium hydroxide solution while being stirred vigorously, and it is desalinated with an

AMICON®™ YM-3 ultrafiltration membrane (cut-off 3,000 Da), and low-molecular components are removed. The retentate is then freeze-dried.

Yield: 1.80 g (92.0% of theory) of the title compound as a colorless lyophilizate.

H,O content (Karl-Fischer): 7.28%.

Elementary analysis (relative to anhydrous substance):

Cld: C38.07H3.25F 18.28 Mn 6.22 N 6.34 Na 5.20 S 1.81

Fnd: C3801 H3.29F 18.29 Mn 6.21 N 6.36 Na 5.28 S 1.78

Example 65 a) 6-N-(Benzyloxycarbonyl)-2-N-[(N-pteroyl)-L-glutaminyl]-lysine-[ 1-(4- perfluorooctylsulfonyl)-piperazine}-amide g (45.31 mmol) of folic acid is dissolved in 300 ml of dimethyl sulfoxide, and 9.49 g (46 mmol) of N,N-dicyclohexylcarbodiimide is added at 10°C. It is stirred overnight at room temperature. 29.1 g (35 mmol) of the title compound of Example 52c) and 20 ml of pyridine are

[ LA to this mixture, and it is stirred for 3 hours at 50°C. It is cooled to room temperature, and a mixture that consists of 1500 ml of diethyl ether/1500 m! of acetone is added. The deposited precipitate is filtered off and purified on (RP-18) (mobile solvent = gradient that consists of water/ethanol/tetrahydrofuran).

Yield: 21.59 g (38% of theory) of a yellow solid.

Water content: 2.1%

Elementary analysis (relative to anhydrous substance):

Cld: C43.10 H3.54 F25.76 N 11.29 S2.56

Fnd: C43.02 H3.62 F25.68 N 11.21 S2.48 b) 2-N-[(N-Pteroyl)-L-glutaminyl]-lysine-[ 1-(4-perfluorooctylsulfonyl)-piperazine]-amide 200 ml of hydrobromic acid in glacial acetic acid (48%) is added to 20 g (15.95 mmol) of the title compound of Example 65a), and it is stirred for 2 hours at 40°C. It is cooled to 0°C, 2000 ml of diethyl ether is added in drops, and the precipitated solid is filtered off. After drying in a vacuum (60°C), 18.96 g (99% of theory) of a yellow-colored, crystalline solid is obtained.

Elementary analysis:

Cld: C37.01 H3.27 Br6.65 F 26.90 N 12.83 S 2.67

Fnd: C3691 H3.42 Br6.31 F29.75 N 12.72 S2.56 c) 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane- 1 0-(pentanoyl-3- aza-4oxo-5-methyl-5yl]-2-N-[(N-pteroyl]-L-glutaminyl}-lysine-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide, Gd complex : 0.92 g (8 mmol) of N-hydroxysuccinimide, 0.68 g (16 mol) of lithium chloride and 5.04 g (8 mmol) of 1,4,7-tris(carboxylatomethyl-10-(3-aza-4-oxo-5-methyl-5yl)- 1,4,7-10- tetraazacyclododecane, Gd complex, are dissolved in 80 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 2.06 g (10 mol) of N,N-dicyclohexylcarbodiimide is added, and then it is stirred for 3 hours at room temperature. 5 g (4.16 mmol) of the title compound of Example

( oad 10 ml of pyridine are added to this reaction solution. It is stirred overnight at room temperature. The solution is poured into 1000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient that consists of water/ethanol/acetonitrile). It is dissolved in some water, the pH is set at 7.4 with sodium hydroxide solution, and it is freeze-dried.

Yield: 3.87 g (53% of theory) of a yellow solid.

Water content: 5.8%

Elementary analysis (relative to anhydrous substance):

Cld: C3836 H3.74F 18.42 Gd897N 12.78 Na1.31S 1.83

Fnd: C 38.28 H3.85F 18.33 Gd 8.85 N 12.69 Na 1.425 1.75

Example 66 a) 2H,2H,4H,4H,5H,5H-3-0xa)-perfluorotridecanoic acid-N-(2,3-dihydroxypropyl)-amide 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, and it is stirred for 12 hours at room temperature. It is evaporated to the dry state in a vacuum. The residue is dissolved in 100 ml of dichloromethane, and at 0°C, it is added in drops to a solution that consists of 5.47 g (60 mmol) of 2,3-dihydroxypropylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It is stirred for 3 hours at 0°C, then for 6 : hours at room temperature. 300 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred for 15 minutes. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/ethanol = 15:1).

Yield: 29.70 g (87% of theory) of a colorless solid

Elementary analysis:

Cld: C 30.32 H2.20 N2.36 F 54.35

Fnd: C 30.12 H2.41 N2.18 F 54.15

' 216 ~ B2003/1949 ® © b) N-(2,3-Dihydroxypropyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)- amine 30 g (48.8 mmol) of the title compound of Example 66a is dissolved in 300 ml of tetrahydrofuran, and 50 ml of 10 M boranedimethyl sulfide (in tetrahydrofuran) is added. It is refluxed for 16 hours. It is cooled to 0°C, and 300 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is stirred for 8 hours at 60°C. Itis evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous sodium hydroxide solution, and it is extracted 3 times with 300 ml each of dichloromethane. The organic phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 15:1).

Yield: 24.07 g (85% of theory) of a colorless solid

Elementary analysis:

Cld: C31.05 H2.61 N2.41 F 55.66

Fnd: C3191 H2.78 N233 F 55.47 c) 1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(2,3- dihydroxypropyl)-N-(1H,1H,2H,2H,4H,4H,5H,5 H-3-oxa)-perfluorotridecyl)-amide]- 1.4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 9.21 g (15.88 mmol) of the title compound of Example 66b is added. It is stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 mi of diethyl ether, and it is stirred for 2 hours at room temperature. The

Qo d@sited precipitate is filtered off, it is dissolved in a mixture that consists of a little ethanol/water and chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water). :

Yield: 16.09 g (85% of theory) of a colorless, amorphous powder

Water content: 6.3%

Elementary analysis (relative to anhydrous substance):

Cld: C 34.26 H3.64 N7.05 F27.10 Gd 13.19

Fnd: C 34.12 H3.83 N6.91 F 26.88 Gd 12.93

Example 67 1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N- (1H, 1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amide]-1,4,7,1 O-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride and 3.66 g (31.76 mmol) of N-hydroxysuccinimide are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, 3.51 g (17 mmol) of N,N'-dicyclohexylcarbodiimide is added, and it is stirred for 5 hours at 15°C. To separate the urea, the solution is filtered. 8.63 g (15.88 mmol) of the title compound of Example 68b and 5.06 g (50 mmol) of triethylamine are added to the filtrate, and it is stirred for 12 hours at room temperature. The solution is poured into 1500 ml of diethyl ether/100 ml of acetone, and it is stirred for 30 minutes. The precipitated solid is filtered off and chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/ acetonitrile/water).

Yield: 13.86 g (78% of theory) of a colorless, amorphous powder

Water content: 9.3%

Elementary analysis (relative to anhydrous substance):

Cld: C 33.28 H3.42 N7.51 F 28.87 Gd 14.05

@ [ Fnd: C 33.12 H3.61 N7.37 F28.69 Gd 13.89

Example 68 a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid amide 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, and it is stirred for 12 hours at room temperature. It is evaporated to the dry state in a vacuum. The residue is dissolved in 200 ml of dichloromethane. Ammonia gas is then directed into the solution for about 2 hours at 0°C. It is stirred for 4 more hours at 0°C, then for 2 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred for minutes. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 20:1).

Yield: 27.85 g (93% of theory)

Elementary analysis:

Cld: C27.66 H 1.55 N2.69 F 61.97

Fnd: C27.49 H1.72 N 2.54 F 61.81 b) 1H,1H,2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecylamine, hydrochloride 27 g (51.8 mmol) of the title compound of Example 68a is dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M boranedimethyl sulfide (in tetrahydrofuran) is added. Itis refluxed for 16 hours. It is cooled to 0°C, and 200 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 400 ml of ethanol/100 ml of 10% aqueous hydrochloric acid, and it is stirred for 8 hours at 60°C. Itis evaporated to the dry state in a vacuum, and the residue is crystallized from a little ethanol/diethyl ether.

Yield: 26.75 g (95% of theory) of a colorless, crystalline solid

219 | B2003/1949 o o Elementary analysis:

Cld: C 26.51 H2.04 N2.58 F 59.41 Cl16.52

Fnd: C2637 H2.21 N2.46 F 59.25 C16.38 c) 3,6,9,12,15-Pentaoxahexadecanoic acid-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-o0xa)- perfluorotridecyl)-amide 14.24 g (50 mmol) of 3,6,9,12,15-pentaoxahexadecanoic acid chloride is added at 0°C to 26.5 g (48.74 mmol) of the title compound of Example 68b, and 14.8 g (146.2 mmol) of triethylamine, dissolved in 300 ml of dichloromethane, is added in drops, and it is stirred for 3 hours at 0°C. 300 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred for minutes. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone: 20:1). :

Yield: 32.03 g (87% of theory) of a colorless oil

Elementary analysis:

Cld: C36.57 H4.00 N 1.85 F42.75

Fnd: C36.46 H4.12 N 1.76 F 42.53 d) N-(3,6,9,12,15-Pentaoxahexadecyl)-N-(1H,1H,2H,2H 4H,4H-3-oxa)-perfluorotridecyl)- amide 31 g (41.03 mmol) of the title compound of Example 68c¢ is dissolved in 300 m] of tetrahydrofuran, and 25 ml of 10 M boranedimethyl sulfide (in tetrahydrofuran) is added. It is refluxed for 16 hours. It is cooled to 0°C, and 200 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is stirred for 8 hours at 40°C. It is evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous sodium hydroxide solution, and it is extracted 3 times with 300 ml each of dichloromethane. The

® Pc phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/2-propanol = 15:1).

Yield: 27.68 g (91% of theory)

Elementary analysis:

Cld: C37.26 H4.35 N 1.89 F 43.56

Fnd: C 37.11 H4.51 N 1.73 F434] e) 1,4,7-Tris(carboxylatomethyl)-10- {(3-aza-4-oxo-hexan-5-ylic)-acid-[N-3,6,9,12,15- pentaoxa)-hexadexyl)-N-(1H,1H,2H,2H,4H,4H,5H,SH-3-oxa)-perfluorotridecyl]-amide} - 1,4,7,10-tetraazacyclododecane, gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 11.77 g (15.88 mmol) of the title compound of Example 68d is added. It is stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little ethanol/water and chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 18.05 g (84% of theory) of a colorless, amorphous powder

Water content: 6.2%

Elementary analysis (relative to anhydrous substance):

Cld: C3728 H4.47 N6.21 F23.87 Gd 11.62

Fnd: C37.11 H4.61 N6.03 F23.64 Gd 11.42 o ou a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-(5-hydroxy-3-oxa-pentyl)- amide 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300 ml of dichloromethane, and it is stirred for 12 hours at room temperature. It is evaporated to the dry state in a vacuum. The residue is dissolved in 100 ml of dichloromethane and added in drops at 0°C to a solution that consists of 6.25 g (60 mmol) of 5-hydroxy-3-oxa-pentylamine and 6.07 g (60 mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It is stirred for 3 hours at 0°C, then for 6 hours at room temperature. 300 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred for 15 minutes. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 15:1).

Yield: 32.20 g (92% of theory) of a colorless solid

Elementary analysis:

Cld: C31.54 H2.65 N2.30 F 53.01

Fnd: C31.61 H2.84 N2.14 F 52.85 b) N-(5-Hydroxy-3-oxa-pentyl)-N-(1H,1 H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)- amine g (49.24 mmol) of the title compound of Example 69a is dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M boranedimethyl sulfide (in tetrahydrofuran) is added. It is refluxed for 16 hours. It is cooled to 0°C, and 200 ml of methanol is added in drops, then it is evaporated to the dry state in a vacuum. The residue is taken up in a mixture that consists of 300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is stirred for 10 hours at 50°C. It is evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of 5% aqueous sodium hydroxide solution, and it is extracted 3 times with 300 ml each of dichloromethane. The

( ofric phases are dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/2-propanol = 20:1).

Yield: 26.09 g (89% of theory) of a colorless solid

Elementary analysis:

Cld: C 32.28 H3.05 N2.35 F 354.25

Fnd: C 32.12 H3.21 N2.18 F 54.09 c) 1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(5-hydroxy-3-oxa- pentyl)-N-(1H,1 H,2H,2H,4H,4H,5H,5H-3-0xa)-perfluorotridecyl)-amide]-1,4,7,10- tetraazacyclododecane, gadolinium complex g (15.88 mmol) of the gadolinium complex of 10-[1-(carboxymethylcarboamoyl)- ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and 9.45 g (15.88 mmol) of the title compound of Example 69b is added. It is stirred for 10 minutes, and then 7.42 g (30 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is stirred for 12 hours at room temperature. The solution is poured into a mixture that consists of 200 ml of acetone/1300 ml of diethyl ether, and it is stirred for 2 hours at room temperature. The deposited precipitate is filtered off, it is dissolved in a mixture that consists of a little ethanol/water and chromatographed on silica gel RP-18 (mobile solvent: gradient that consists of tetrahydrofuran/acetonitrile/water).

Yield: 16.10 g (84% of theory) of a colorless, amorphous powder

Water content: 5.7%

Elementary analysis (relative to anhydrous substance):

Cld: C 34.83 H3.84 N6.96 F 26.76 Gd 13.03

Fnd: C 34.65 H3.96 N6.84 F 26.62 Gd 12.91

® TR 70 a) 1,2,3,4,6-Penta-O-acetyl-q,-D-mannopyranose

Analogously to what is described in the literature [M. L. Wolfrom and A. Thompson in

Methods in Carbohydrate Chemistry (R. L. Whistler, M. L. Wolfrom and J. N. BeMiller, Eds.),

Academic Press, New York, Vol. II, 53, pp. 211-215, (1963)], the reaction of 150 g (832.5 mmol) of a.B-D-mannopyranose with a mixture that consists of 1500 ml of absolute pyridine and 1500 ml of acetic acid anhydride yields, after working-up, 315 g (96.7%) of the above- mentioned title compound as a crude product in the form of a viscous and colorless oil. By 'H-

NMR spectroscopic study of the thus obtained title compound, it was possible to determine the a to B ratio of both anomers at 4:1. Separation of the a,B-anomers of the above-mentioned title compound can be eliminated to carry out the reaction steps below. :

Elementary analysis:

Cid: C49.21 HS5.68

Fnd: C49.12 H5.78 b) 6-(1-0-a-(2,3,4,6-Tetra-O-acetyl-D-mannopyranosyl)-hexanoic acid ethyl ester]

Analogously to what is described in the literature for the synthesis of aryl glycopyranosides [J. Conchie and G. A. Levvy in Methods in Carbohydrate Chemistry (R. L.

Whistler, M. L. Wolfrom and J. N. BeMiller, Eds.), Academic Press, New York, Vol. II, 90, pp. 345-347, (1963)], the reaction of 156.2 g (400 mmol) of the title compound of Example 70a as an o,B-anomer mixture with 67 ml (400 mmol) of 6-hydroxy-hexanoic acid ethyl ester and 60.8 ml (520 mmol) of tin(IV) chloride in a total of 600 ml of 1,2-dichloroethane after column- chromatographic purification (eluant: hexane/ethyl acetate 2:1) results in the formation of 100.05 g (51% of theory) of the above-mentioned title compound as a colorless and viscous oil.

By "H-NMR -spectroscopic study of the thus obtained title compound, it was possible to show that the above-mentioned title compound is only the pure a-anomer.

® ® Elementary analysis:

Cld: C5294 H6.77

Fnd: C 52.80 H 6.78 c) 6-[1-0-a-(2,3,4,6-Tetra-O-benzyl-D-mannopyranosyl)-hexanoic acid

A stirred suspension of 141.0 g (289 mmol) of the title compound of Example 70b in 200 ml of dioxane is mixed in portions with a total of 238.5 g (4.26 mol) of fine-powder potassium hydroxide powder at room temperature and with simultaneous vigorous stirring. To make it easier to stir, the reaction mixture is mixed with another 200 ml of dioxane, and the thus obtained suspension is subsequently heated to boiling and mixed at this temperature drop by drop with a total of 372 ml (3.128 mol) of benzyl bromide over a period of two hours. After a reaction time of 4 hours at 110°C followed by 12 hours at room temperature, the reaction mixture is slowly poured into a total of 2.5 liters of ice water for the purpose of working-up, and the aqueous phase is subsequently completely extracted with diethyl ether. After the thus obtained ether phase is washed, and after the subsequent drying of the same with sodium sulfate, salt is suctioned out, and the diethyl ether is drawn off in a vacuum. Excess benzyl bromide is then quantitatively distilled off from the reaction mixture in an oil pump vacuum at an oil bath temperature of 180°C. The thus obtained, resinous-oily residue is purified on silica gel with use of ethyl acetate/hexane (1:10) as an eluant.

Yield: 172.2 g (91.0% of theory) of the above-mentioned title compound in the form ofa colorless and extremely viscous oil.

Elementary analysis:

Cid: C75.68 H7.16

Fnd: C 75.79 H7.04

® @® 6-[1-0-a-(2,3,4,6-Tetra-O-benzyl-D-mannopyranosyl)-hexanoic acid-N-(3-oxa- 1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide 100 g (134 mmol) of the acid that is described in Example 70c and 13.5 g (134 mmol) of triethylamine are dissolved in 1200 ml of dry tetrahydrofuran. After cooling to -15°C, a solution of 18.45 g (135 mmol) of isobutyl chloroformate in 200 ml of dry tetrahydrofuran is slowly added in drops while being stirred, whereby the internal temperature does not exceed -10°C.

After a reaction time of 15 minutes at -15°C, a solution of 165.5 g (134 mmol) of 1-amino- 1H,1H,2H,2H-perfluorodecane and 13.5 g (134 mmol) of triethylamine in 250 ml of dry tetrahydrofuran is added in drops at -20°C. After a reaction time of one hour at -15°C and two hours at room temperature, the reaction solution is evaporated to the dry state in a vacuum. The remaining residue is taken up in 300 ml of ethyl acetate and washed twice with 400 ml each of saturated sodium bicarbonate solution and once with 500 ml of water. After the organic phase 1s dried on sodium sulfate, salt is suctioned out, and the ethyl acetate is drawn off in a vacuum.

The remaining oily residue is purified on silica gel with use of dichloromethane/hexane/2- propanol (10:5:1) as an eluant.

Yield: 143.8 g (86.9% of theory)

Elementary analysis:

Cld: C57.38 H4.98 N 1.13 F 26.15

Fnd: C57.30 H5.44 N 1.01 F26.25 e) 6-[ 1-O-a-D-Mannopyranosyl)-hexanoic acid N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H- ) perfluorotridecyl)-amide 40.0 g (32.38 mmol) of the title compound of Example 70d is dissolved in 750 ml of 2- propanol and mixed with 2.0 g of palladium catalyst (10% Pd/C). The reaction solution is hydrogenated for 12 hours at 22°C and 1 atmosphere of hydrogen pressure. Then, catalyst is filtered out, and the filtrate is evaporated to the dry state. The remaining residue is taken up in 300 ml of dimethyl sulfoxide, and 21.52 g (88.0% of theory) of the above-mentioned title

( o@pound is obtained as a colorless and crystalline powder with the decomposition melting point of 83.5°C from the thus obtained product solution by mixing with a total of 1000 ml of diethyl ether after the precipitated solid is suctioned off.

Elementary analysis:

Cld: C36.01 H5.92 N1.75 F40.34

Fnd: C 36.07 H 6.08 N 1.76 F 40.66 f) Production of a formulation that consists of metal complex I and 6-[1-O-a-D- mannopyranosyl)-hexanoic acid N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H- ~ perfluorotridecyl)-amide 3.17 g (4.2 mmol) of the title compound of Example 70e is added to 35 ml of a solution of metal complex I (280 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 98 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered with a 0.2 pm filter, and the filtrate is decanted into vials. A solution that is produced in such a way can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.)

Example 71 a) 1-O-a-D-[(1-Perfluorooctylsulfonylpiperazine-4-carbonyl)-pentyl-5]-2,3,4,6-tetra-O- benzyl-mannopyranose 74.59 g (100 mmol) of the acid that is described in Example 71c and 10.11 g (100 mmol) of triethylamine are dissolved in 800 ml of a mixture that consists of tetrahydrofuran/ acetonitrile (mixing ratio 7:3). Then, it is mixed drop by drop at room temperature with 500 ml ofa tetrahydrofuran solution of 58.0 g (102.0 mmol) of 1-perfluorooctylsulfonylpiperazine, 10.11 g (100 mmol) of triethylamine and 16.84 g (110 mmol) of 1-hydroxybenzotriazole. The thus obtained reaction solution is mixed at -5°C with a solution of 22.7 g (110 mmol) of

C oy ohexylearbodiimide, dissolved in 100 ml of tetrahydrofuran, and then it is stirred at -5°C for another two hours. After the reaction solution has thawed, it is stirred at room temperature for another 12 hours, precipitated dicyclohexylurea is filtered out, and the filtrate that is obtained is evaporated to the dry state in a vacuum. The remaining residue is taken up in 600 ml of ethyl acetate and washed twice with 300 ml each of saturated sodium bicarbonate solution and twice with 300 ml each of water. After the organic phase is dried on sodium sulfate, salt is suctioned out, and the ethyl acetate is drawn off in a vacuum. The remaining oily residue is purified on silica gel with use of dichloromethane/acetone/2-propanol (16:2:1) as an eluant.

Yield: 113.01 g (79.8% of theory) of a colorless and viscous oil

Elementary analysis:

Cld: C 58.52 H4.27 N 1.98 S226 F22.80

Fnd: C 58.42 H4.41 N 1.80 S2.28 F 23.02 b) 1-O-a-D-[(1 -Perfluorooctylsulfonyl-piperazine-4-carbonyl)-pentyl-5]-mannopyranose 50 g (35.30 mmol) of the title compound of Example 71a is dissolved in a mixture that consists of 500 ml of 2-propanol and 50 ml of water, and 2 g of palladium catalyst (10% Pd on activated carbon) is added. It is hydrogenated for 12 hours at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is dissolved in 200 m1 of methanol, and the reaction product is precipitated by mixing with a total of 800 ml of diethyl ether. After the thus obtained solid is suctioned off, the latter 1s dried in a vacuum at 50°C.

Yield: 29.51 g (99% of theory) of an amorphous solid

Elementary analysis:

Cld: C 34.13 H3.46 N3.32 S3.80 F 38.23

Fnd: C 34.28 H 3.81 N 3.25 S3.80 F 38.01

@® ‘QP Production of a formulation that consists of metal complex II and 1-O-a-D-[(1- perfluorooctylsulfonyl-piperazine-4-carbonyl)-pentyl-5 ]-mannopyranose 9.92 g (11.75 mmol) of the title compound of Example 71b is added to 47 ml of a solution of metal complex II (250 mmol/L), dissolved in 0.45% aqueous sodium chloride solution, and it is heated for 10 minutes in the microwave. The solution is cooled to room temperature, filtered with a 0.2 um filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 250 mmol of

Gd/L.)

Example 72 a) 2-Acetamido-2-deoxy-1,3,4,6-(tetra-O-benzyl)-a,B-D-glucopyranose

A total of 24.0 g (108.5 mmol) of 2-acetamido-2-deoxy-a.,p-D-glucopyranose, dissolved in 500 ml of absolute dimethyl sulfoxide, is added drop by drop at room temperature to a stirred suspension of 20.16 g (700 mmol; 80% in mineral oil) of sodium hydride in 150 ml of dimethyl sulfoxide. Then, it is allowed to stir for another 120 minutes at room temperature, and then 159.5 g (1.26 mol) of benzyl chloride is added in drops. “The thus obtained reaction solution is subsequently stirred for another 12 hours at room temperature. For working-up, the reaction solution is slowly poured into 1.5 liters of ice water and then exhaustively extracted with diethyl ether. The combined diethyl ether phases are subsequently washed twice with 600 ml each of saturated sodium bicarbonate solution and twice with 800 ml each of water. After the organic phase is dried on sodium sulfate, salt is suctioned out, and the solvent is drawn off in a vacuum.

The remaining oily residue is purified on silica gel with use of ethyl acetate/hexane (1:5) as an eluant.

Yield: 48.68 g (73.6% of theory) of the above-mentioned title compound in the form of a viscous and colorless oil.

Elementary analysis:

Cld: C 70.92 H 6.45 N 6.89

@ @ C743 HE4NTOZ b) 1-O-Benzyl-3,4,6-tri-O-benzyl-2-amino-2-deoxy-a,p-D- glucopyranose 30.0 g (49.2 mmol) of the title compound of Example 72a is suspended in a mixture that consists of 750 ml of methanol and 215 ml of water, and it is mixed drop by drop at room temperature with a total of 440 ml (49.2 mmol) of a 0.112 molar aqueous perchloric acid solution. After the addition has been completed, the reaction solution is stirred for 10 more minutes at room temperature, and the thus obtained, now homogenous reaction solution is subsequently evaporated to the dry state in a vacuum. By mixing the remaining oily residue with a mixture that consists of equal parts of hexane and dichloromethane, the latter is brought to crystallization. The crystalline reaction product is suctioned off, washed with hexane and dried in a vacuum at room temperature.

Yield: 27.08 g (86% of theory) of the above-mentioned title compound in the form of its perchlorate, which is present as a colorless, crystalline compound.

Melting point: 180.5-181.5°C

Elementary analysis:

Cld: C 63.68 H5.98 N2.19 Cl15.54

Fnd: C 63.43 H6.04 N2.02 C15.71 c) 1,3,4,6-Tetra-O-benzyl-2-deoxy-2-[acetyl-(2-amino-N-ethyl-N-perfluorooctylsulfonyl)- - amino]-1-a,p-D-glucopyranose 20.8 g (35.6 mmol) of the 2-[N-ethyl-N-perfluorooctylsulfonyl)-aminoacetic acid and 3.60 g (35.6 mmol) of triethylamine are dissolved in 350 ml of dry tetrahydrofuran. After the reaction solution is cooled to -15°C to -20°C, a solution of 4.92 g (35.6 mmol) of isobutyl chloroformate in 75 ml of dry tetrahydrofuran is slowly added in drops at this temperature while being stirred, whereby the rate of addition by drops can be selected in such a way that an internal temperature of -10°C is not exceeded. After a reaction time of 15 minutes at -15°C, a solution of o ¥: g (35.6 mmol) of the perchlorate (title compound of Example 72b) and 3.60 g (35.6 mmol) of triethylamine, in 100 m] of dry tetrahydrofuran at -20°C is then slowly added in drops. After a reaction time of one hour at -15°C and two hours at room temperature, the reaction solution is evaporated to the dry state in a vacuum. The remaining residue is taken up in 250 ml of ethyl acetate and washed twice with 100 ml each of saturated sodium bicarbonate solution and once with 200 ml of water. After the organic phase is dried on sodium sulfate, salt is suctioned out, and the ethyl acetate is drawn off in a vacuum. The remaining oily residue is purified on silica gel with use of ethyl acetate/hexane (1:5) as an eluant. | :

Yield: 333 ¢g (84.6% of theory) of the above-mentioned title compound as a colorless and strongly viscous oil.

Elementary analysis:

Cld: C49.92 H3.92 N2.53 F29.18 S290

Fnd: C 49.99 H4.11 N2.69 F 29.22 §3.01 d) 2-Deoxy-2-[acetyl-(2-amino-N-ethyl-N-perfluorooctylsulfonyl)-amino]-1-a,B-D- glucopyranose ) 20.0 g (18.06 mmol) of the title compound of Example 72¢ is dissolved in 250 ml of 2- propanol and mixed with 1.5 g of palladium catalyst (10% Pd/C). The reaction solution is hydrogenated for 12 hours at 22°C and 1 atmosphere of hydrogen pressure. Then, catalyst is filtered out, and the filtrate is evaporated to the dry state. The remaining residue is taken up in 300 ml of dimethyl sulfoxide, and 12.65 g (93.8% of theory) of the above-mentioned title compound is obtained as a colorless and crystalline powder from the thus obtained product solution by mixing with 750 ml of a mixture that consists of equal parts of diethyl ether and ethyl acetate after the precipitated solid is suctioned off. The above-mentioned title compound is present as an o/B-anomer mixture, whereby the ratio relative to the two possible anomers was determined at about 1:1.2 by '"H-NMR-spectroscopic studies. The title compound is accordingly an almost approximately evenly distributed a/B-anomer mixture.

@ @ eine point 132.5-133°C.

Elementary analysis:

Cld: C 28.97 N2.57 N3.75 F43.27 §4.30

Fnd: C 29.09 N 2.56 N3.84 F43.36 S 4.42 €) Production of a formulation that consists of metal complex XIV and 2-deoxy-2-[acetyl- (2-amino-N-ethyl-N-perfluorooctylsulfonyl)-amino]-1-a,B-D-glucopyranose

A solution that consists of 4.90 g (6.57 mmol) of the title compound of Example 3d, dissolved in 200 ml of ethanol, is added to 51 ml of a solution of metal complex XIV (300 mmol/L), dissolved in 0.45% sodium chloride solution (pH 7.4/0.25 mg/L of CaNa;DTPA), and it is stirred for 2 hours at 50°C. The solution is evaporated to the dry state in a vacuum, and the residue is made up with distilled water to a total of 153 ml. It is stirred for 10 minutes at 40°C and filtered with a 0.2 um filter. The filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.)

Example 73 a) 1,2,3,4,6-Penta-O-acetyl-a-D-glucopyranose

Analogously to what is described for the synthesis of title compound 70a, the reaction of 100 g (555.0 mmol) of a-D-glucopyranose with a mixture that consists of 1000 ml of absolute pyridine and 1000 ml of acetic acid anhydride after working-up and recrystallization from 95% aqueous ethanol yields 190.6 g (88.0%) of the above-mentioned title compound as a colorless and crystalline compound. By "H-NMR -spectroscopic study of the thus obtained title compound, it was possible to determine the a to P ratio of two possible anomers at > 98:2. The title compound accordingly is the exclusively a-configured anomer.

Melting point: 110.5°C

Elementary analysis:

Cld: C49.21 H5.68

¢ . 232 " W2003/71949 ® C Fnd: C 49.24 H 5.68 : b) 5-(Ethoxycarbonyl)pentyl-2,3,4,6-tetra-O-acetyl-a-D-glucopyranoside :

Analogously to what is described in the synthesis of the title compound of Example 70b, the reaction of 130.0 g (332.8 mmol) of the title compound of Example 4a) with 55.8 ml (332.8 mmol) of 6-hydroxy-hexanoic acid ethyl ester and 50.6 ml (520 mmol) of tin(IV) chloride in 500 ml of 1,2-dichloroethane after column-chromatographic purification (eluant: hexane/ethyl acetate 2:1) yields 101.85 g (62.4% of theory) of the above-mentioned title compound as a colorless and viscous oil. After 'H-NMR-spectroscopic study of the title compound, the presence of the B-configuration at the anomeric center was definitively established based on the size of the coupling constant of J; » = 8.8 Hz; moreover, said configuration represents the sole existing configuration at the anomeric center. The above-mentioned title compound thus could be shown only in the form of the B-configured anomer.

Elementary analysis:

Cld: C 52.94 H6.77

Fnd: C 52.77 H6.70 c) 5-(Carboxy)pentyl-2,3,4,6-tetra-O-benzyl-a-D-glucopyranoside

A stirred suspension of 100.0 g (204.96 mmol) of the title compound of Example 73b in 150 ml of dioxane is mixed in portions at room temperature and with simultaneous, vigorous stirring with- a total of 169.14 g (3.02 mol) of fine-powder potassium hydroxide powder. To make it easier to stir, the reaction mixture is mixed with another 150 ml of dioxane, and the thus obtained suspension is subsequently heated to boiling and mixed drop by drop at this temperature with a total of 264 m] (2.218 mol) of benzyl bromide over a period of two hours. After a reaction time of 4 hours at 110°C followed by 12 hours at room temperature, the reaction mixture is slowly poured into a total of 2.0 liters of ice water for the purpose of working-up, and the aqueous phase is subsequently completely extracted with diethyl ether. After the thus obtained

) & phase is washed and after the subsequent drying of the organic phase on sodium sulfate, salt is suctioned out, and the diethyl ether is drawn off in a vacuum. Excess benzyl bromide is then quantitatively distilled off from the reaction mixture in an oil pump vacuum at an oil bath temperature of 180°C. The thus obtained, remaining oily residue is purified on silica gel with use of ethyl acetate/hexane (1:10) as an eluant.

Yield: 128.8 g (84.3% of theory) of the above-mentioned title compound in the form of a colorless and extremely viscous oil

Elementary analysis:

Cld: C 75.68 H7.16

Fnd: C 75.66 H 7.23 d) 2,3,4,6-Tetra-O-benzyl-1-O-B-D-[6-hexanoic acid-N-(3-oxa- 1H,1H,2H,2H,4H,4H,5H, 5H-perfluorotridecyl)-amide]-glucopyranose 68.5 g (91.79 mmol) of the acid that is described in Example 73c and 9.25 g (91.79 mmol) of triethylamine are dissolved in 825 ml of dry tetrahydrofuran. After the reaction solution is cooled to -15°C to -20°C, a solution of 12.64 g (92.5 mmol) of isobutyl chloroformate in 150 ml of dry tetrahydrofuran is slowly added in drops at this temperature while being stirred, whereby the rate of addition by drops can be selected in such a way that an internal temperature of -10°C is not exceeded. After a reaction time of 15 minutes at -15°C, a solution 0f 46.40 g (91.79 mmol) of 1H,1H,2H,2H-heptadecafluoro-1-(2-aminoethoxy)-decane and 9.25 g (91.79 mmol) of triethylamine is then slowly added in drops as a solution to 200 ml of dry tetrahydrofuran at -20°C. After a reaction time of one hour at -15°C and two hours at room temperature, the reaction solution is evaporated to the dry state in a vacuum. The remaining residue is taken up in 250 ml of ethyl acetate and washed twice with 300 ml each of saturated sodium bicarbonate solution and once with 400 ml of water. After the organic phase is dried on sodium sulfate, salt is suctioned out, and the ethyl acetate is drawn off in a vacuum. The

® @pinine oily residue is purified on silica gel with use of dichloromethane/hexane/2-propanol (10:5:1) as an eluant.

Yield: 104.7 g (92.4% of theory) of the above-mentioned title compound as a colorless and strongly viscous oil

Elementary analysis:

Cld: C57.38 H4.98 N1.13 F 26.15

Fnd: C 57.27 H5.09 N 1.11 F 26.08 e) 1-O-B-D-[6-Hexanoic acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H, SH-perfluorotridecyl)- amide]-glucopyranose 40.0 g (32.38 mmol) of the title compound of Example 73d is dissolved in 750 ml of 2- propanol and mixed with 2.0 g of palladium catalyst (10% Pd/C). The reaction solution is hydrogenated for 12 hours at 22°C and 1 atmosphere of hydrogen pressure. Then, catalyst is filtered out, and the filtrate is evaporated to the dry state. The remaining residue is taken up in 300 ml of dimethyl sulfoxide, and 22.05 g (90.2% of theory) of the title compound is obtained as a colorless and crystalline powder with a decomposition melting point of 122-124°C from the thus obtained product solution by mixing with a total of 1000 ml of diethyl ether and subsequent suctioning-off of the precipitated solid.

Elementary analysis:

Cld: C36.01 H5.92 N 1.75 F 40.34

Fnd: C 36.07 H6.08 N 1.76 F 40.66 o ‘QP " Production of a formulation that consists of the title compound of Example 12 from WO 99/01161 (1,4,7-tris {1,4,7-tris(N-carboxylatomethyl)-10-(N-1-methyl-3-aza-2,5-dioxo- pentane-1,5-diyl]-1,4,7,10-tetraazacyclododecane, Gd complex } -10-[2-(N-ethyl-N- perfluorooctylsulfonyl)-amino]-acetyl-1,4,7,10-tetraazacyclododecane) and 1-O-B-D-[6- hexanoic acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide]- glucopyranose 20.29 g (25.9 mmol) of the title compound of Example 73¢ is added to 37 ml of a solution of 1,4,7-tris{1,4,7-tris(N-carboxylatomethyl)-10-(N-1-methyl-3-aza-2,5-dioxo-pentane- 1,5-diyl]-1,4,7,10-tetraazacyclododecane, Gd complex }-10-[2-(N-ethyl-N- perfluorooctylsulfonyl)-amino]-acetyl-1,4,7,10-tetraazacyclododecane (300 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 111 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered with a 0.2 pm filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.)

Example 74 a) 1-O-(1H,1H,2H,2H-Perfluorodecyl)-(2,3,4,6-tetra-O-acetyl)-a-D-mannopyranose

The reaction of 50 g (128.09 mmol) of the title compound of Example 70a, which is used as a 4:1 mixture relative to the a,B-anomers, with a solution of 75.84 g (128.1 mmol) of 1- hydroxy-1H,1H,2H,2H-perfluorodecane in 150 ml of 1,2-dichloroethane and a total of 19.47 g (166.53 mmol) of tin(IV) chloride, analogously to what is described for the syntheses of the title compounds of Examples 1b) and 4b), results, after working-up and column-chromatographic purification (eluant: hexane/ethyl acetate, 2:1), in the formation of 74.2 g (63.4% of theory) of the above-mentioned title compound in the form of a viscous and colorless oil. After 'H-NMR- spectroscopic study of the title compound, the presence of the a-configuration at the anomeric

[ @r was definitively established based on the size of the coupling constant of Ji» = 1.3 Hz; moreover, said configuration represents the sole existing configuration at the anomeric center, so that the above-mentioned title compound accordingly could be represented only in the form of the pure a-configured anomer.

Elementary analysis:

Cld: C 44.65 H2.53 F35.32

Fnd: C 44.77 H 2.61 F 35.09 b) 1-O-(1H,1H,2H,2H-Perfluorodecyl)-a-D-mannopyranose g (27.33 mmol) of the title compound of Example 74a is suspended in 400 ml of absolute methanol and mixed at 5°C with a catalytic amount of sodium methanolate. After a reaction time of 3 hours at room temperature, even thin-layer chromatographic checking (eluant: chloroform/methanol 9:1) of the course of the reaction indicates quantitative reaction. For the purpose of working-up, the now clear reaction solution is neutralized by mixing with Amberlite

IR 120 (H form)-cation-exchange resin, exchanger is suctioned out, and the thus obtained methanolic filtrate is drawn off in a vacuum until a dry state is reached. The crystalline residue that is obtained is purified by twice-repeated recrystallization of ethanol. After 'H-NMR- spectroscopic study of the title compound, the presence of the a-configuration at the anomeric center was definitively established based on the size of the coupling constant of J; 2 = 1.0 Hz.

The existing a-configuration is the sole existing configuration at the anomeric center, i.e., the amount of B-configured anomer of the title compound that can possibly be formed lies below the 'H-NMR-spectroscopic detection limit. The above-mentioned title compound was accordingly represented only in the form of the pure a-configured anomer.

Yield: 16.2 g (94.6% of theory) of a colorless and crystalline solid

Melting point: 172-174°C while decomposing.

Elementary analysis:

Cld: C30.69 H2.41 F51.57

® ® Fnd: C 30.57 H 2.48 F 51.65 c) Production of a formulation that consists of metal complex II and 1-O-(1H,1H,2H,2H- perfluorodecyl)-a-D-mannopyranose

A solution that consists of 2.01 g (3.21 mmol) of the title compound of Example 74b, dissolved in 200 ml of ethanol, is added to 50 ml of a solution of metal complex II (150 mmol/L), dissolved in 0.45% sodium chloride solution (pH 7.4/0.25 mg/L of CaNa;DTPA), and it is stirred for 2 hours at 50°C. The solution is evaporated to the dry state in a vacuum, and the residue is made up with distilled water to a total of 75 ml. It is stirred for 10 minutes at 40°C and filtered with a 0.2 um filter. The filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.)

Example 75 a) 1-O-(1H,1H,2H,2H-Perfluorododecyl)-2,3,4,6-tetra-O-acetyl-a-D-mannopyranose

The reaction of 35 g (89.66 mmol) of the title compound of Example 70a, which is used as a 4:1 mixture relative to the a,B-anomers, with a solution of 50.60 g (89.7 mmol) of 1- hydroxy-1H,1H,2H,2H-perfluorododecane in 100 ml of 1,2-dichloroethane and a total of 13.63 g (16.61 mmol) of tin(IV) chloride, analogously to what is described for the syntheses of the title compounds of Examples 1b), 4b) and 5b), results, after working-up and column-chromatographic purification (eluant: hexane/ethyl acetate = 2:1), in the formation of 62.49 g (68.7% of theory) of the above-mentioned title compound in the form of a viscous and colorless oil. After 'H-

NMR-spectroscopic study of the title compound, the presence of the a-configuration at the anomeric center was definitively established based on the size of the coupling constant of J; > = 1.4 Hz; moreover, said a-configuration represents the sole existing configuration at the anomeric center, so that accordingly the above-mentioned title compound can be represented only in the form of the pure a-configured anomer.

[ ® Elementary analysis: © Cld: C42.62 H2.28 F39.32

Fnd: C 42.55 H2.38 F 39.40 b) 1-O-(1H,1H,2H,2H-Perfluorododecyl)-a-D-mannopyranose g (24.64 mmol) of the title compound of Example 75a is suspended in 400 ml of absolute methanol and mixed at 5°C with a catalytic amount of sodium methanolate. After a reaction time of 3 hours at room temperature, even thin-layer chromatographic checking (eluant: chloroform/methanol = 9:1) of the course of the reaction indicates quantitative reaction. For the purpose of working-up, the now clear reaction solution is neutralized by mixing with Amberlite

IR 120 (H" form)-cation-exchange resin, exchanger is suctioned out, and the thus obtained methanolic filtrate is drawn off in a vacuum until a dry state is reached. The crystallization residue that is obtained is purified by twice-repeated recrystallization of a mixture that consists of 2-propanoVethanol (1:1). After 'H-NMR-spectroscopic study of the title compound, the presence of the a-configuration at the anomeric center was definitively established based on the size of the coupling constant of J; 2 = 0.9 Hz. The existing a-configuration is the sole existing configuration at the anomeric center, i.e., the amount of B-configured anomer of the title compound that can possibly be formed lies below the 'H-NMR-spectroscopic detection limit.

The above-mentioned title compound was accordingly represented only in the form of the pure a-configured anomer.

Yield: 16.96 g (90.8% of theory) of a colorless and crystalline solid

Melting point: 187-188°C while decomposing.

Elementary analysis:

Cld: C29.77 H2.08 F 54.93

Fnd: C 29.70 H 2.28 F 54.83

® ‘@ Production of a formulation that consists of metal complex VI and 1-O-(1H,1H,2H,2H- perfluorodecyl)-a-D-mannopyranose 1.70 g (2.34 mmol) of the title compound of Example 75b is added to 52 ml of a solution of metal complex VI (180 mmol/L), dissolved in 0.45% aqueous sodium chloride solution, and it is heated for 10 minutes in the microwave. The solution is cooled to room temperature, filtered with a 0.2 um filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 180 mmol of Gd/L.)

Example 76 a) 2,3,4,6-Tetra-O-acetyl)-1-0-a-D-[3,6,9-trioxa-(C12-C, o-heptadecafluoro)-nonadecyl]- mannopyranose

The reaction of 20 g (51.23 mmol) of the title compound of Example 70a, which is used as a 4:1 mixture relative to the a,B-anomers, with a solution of 30.54 g (51.23 mmol) of 1- hydroxy-tris-(1H,1H,2H,2H-0)-1H,1H,2H,2H-perfluorodecane in 100 ml of 1,2-dichloroethane and a total of 5.98 g (51.23 mmol) of tin(IV) chloride, analogously to what is described for the syntheses of the title compounds of Examples 1b), 4b) and 5b), results, after working-up and column-chromatographic purification (eluant: hexane/ethyl acetate = 1:1), in the formation of 34.22 g (72.1% of theory) of the above-mentioned title compound in the form of a viscous and colorless oil. After 'H-NMR-spectroscopic study of the title compound, the presence of the o- configuration at the anomeric center was definitively established based on the size of the coupling constant of J; » = 1.1 Hz; moreover, said a-configuration represents the sole existing configuration at the anomeric center, so that accordingly the above-mentioned title compound can be represented only in the form of the pure a-configured anomer.

Elementary analysis:

Cld: C 38.89 H3.81 F34.86

Fnd: C 39.02 H3.77 F 34.90

® @ 1-0-0-D-[3,6,9-Trioxa-(C,2-C o-heptadecafluoro)-nonadecyl]-mannopyranose g (21.58 mmol) of the title compound of Example 76a is suspended in 350 ml of absolute methanol and mixed at 5°C with a catalytic amount of sodium methanolate. After a reaction time of 3 hours at room temperature, even thin-layer chromatographic checking (eluant: chloroform/methanol = 6:1) of the course of the reaction indicates quantitative reaction. For working-up, the now clear reaction solution is neutralized by mixing with Amberlite IR 120 (H" form)-cation-exchange resin, exchanger is suctioned out, and the thus obtained methanolic filtrate is drawn off in a vacuum until a dry state is reached. The crystalline residue that is obtained is purified by twice-repeated recrystallization from a mixture that consists of ethyl acetate/2-propanol/ethanol (1:0.5:1). After '"H-NMR-spectroscopic study of the title compound, the presence of the a-configuration at the anomeric center was definitively established based on the size of the coupling constant of J; ; = 1.0 Hz. The existing a-configuration is the sole existing configuration at the anomeric center, i.e., the amount of B-configured anomer of the title compound that can possibly be formed lies below the 'H-NMR-spectroscopic detection limit.

The above-mentioned title compound was accordingly represented only in the form of the pure a-configured anomer. '

Yield: 15.20 g (92.9% of theory) of a colorless, crystalline solid

Melting point: 141°C.

Elementary analysis:

Cld: C 34.84 H3.59 F42.58

Fnd: C 34.72 H3.66 F 4267 c) Production of a formulation that consists of the title compound of Example 68 and 1-O-a-

D-[3,6,9-trioxa-(C,,-C s-heptadecafluoro)-nonadecyl]-mannopyranose 3.71 g (4.89 mmol) of the title compound of Example 76b is added to 38 ml of a solution of the title compound of Example 68 (300 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa;DTPA), and it is made up with a 0.9% aqueous common

' 241 * W2003/1949 (1) yoiution to a total of 114 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered with a 0.2 um filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of

Gd/L.)

Example 77 a) 2,3,4,6-Tetra-O-acetyl-1-a-D-[3-thiopropionic acid-N-(3-oxa- 1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide]-mannopyranose 25.0 g (57.28 mmol) [production according to: Ponpipom, Mitree M.; Bugianesi, Robert

L.; Robbins, James C.; Doebber, T. W.; Shen, T. Y.; J. Med. Chem.; 24; 12; 1981; 1388-1395] of 3-(tetra-O-acetyl-a-D-mannopyranosylmercapto)-propionic acid and 5.77 g (57.28 mmol) of triethylamine are dissolved in 500 ml of dry tetrahydrofuran. After the reaction solution is cooled to -15°C to -20°C, a solution of 7.82 g (57.28 mmol) of isobutyl chloroformate in 100 ml of dry tetrahydrofuran is slowly added in drops at this temperature while being stirred, whereby the rate of addition by drops can be selected in such a way that an internal temperature of -10°C is not exceeded. After a reaction time of 15 minutes at -15°C, a solution of 29.05 g (57.28 mmol) of 1H,1H,2H,2H-heptadecafluoro-1-(2-aminoethyoxy)-decane and 5.77 g (57.28 mmol) of triethylamine is subsequently slowly added in drops as a solution to 200 ml of dry tetrahydrofuran at -20°C. After a reaction time of one hour at -15°C and two hours at room temperature, the reaction solution is evaporated to the dry state in a vacuum. The remaining residue is taken up in 250 ml of ethyl acetate, and it is washed twice with 200 ml each of saturated sodium bicarbonate solution and once with 300 ml of water. After the organic phase is dried on sodium sulfate, salt is suctioned out, and the ethyl acetate is drawn off in a vacuum.

The remaining oily residue is purified on silica gel with use of dichloromethane/hexane/2- propanol (8:5:1) as an eluant.

® @ Yield: 44.90 g (84.7% of theory) of the above-mentioned title compound as a colorless and strongly viscous oil.

Elementary analysis:

Cld: C37.63 H3.48 N1.51 S3.46 F 34.89

Fnd: C 37.77 H3.37 N 1.61 $3.57 F35.21 b) 1-a-D-[3-Thiopropionic acid-N-(3-oxa-1H, 1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)- amide ]-mannopyranose g (32.41 mmol) of the title compound of Example 77a is suspended in 400 ml of absolute methanol and mixed at 5°C with a catalytic amount of sodium methanolate. After a reaction time of 3 hours at room temperature, even thin-layer chromatographic checking (eluant: chloroform/methanol = 9:1) of the course of the reaction indicates quantitative reaction. For working-up, the now clear reaction solution is neutralized by mixing with Amberlite IR 120 (H' form)-cation-exchange resin, exchanger is suctioned out, and the thus obtained methanolic filtrate is drawn off in a vacuum until a dry state is reached. The crystalline residue that is obtained is purified by recrystallization from a mixture that consists of ethyl acetate/methanol (0.5:1). After 'H-NMR-spectroscopic study of the title compound, the presence of the a- configuration at the anomeric center was definitively established based on the size of the coupling constant of J; ; = 1.1 Hz. The existing a-configuration is the sole existing configuration at the anomeric center, i.e., the amount of p-configured anomer of the title compound that can possibly be formed lies below the 'H-NMR-spectroscopic detection limit. The above-mentioned title compound was accordingly represented only in the form of the pure a-configured anomer.

Yield: 23.76 g (96.8% of theory) of a colorless and crystalline solid

Melting point: 113-114.5°C

Elementary analysis:

Cld: C 33.30 H3.19 N1.85 S423 F42.64

Fnd: C 33.21 H3.26 N 1.96 S4.08 F 42.77

® o Production of a formulation that consists of the title compound of Example 66 and 1-a-D- [3-thiopropionic acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H, SH-perfluorotridecyl)-amide]- mannopyranose

A solution that consists of 27.41 g (36.19 mmol) of the title compound of Example 77b, dissolved in 200 ml of ethanol, is added to 47 ml of a solution of the title compound of Example 66 (330 mmol/L), dissolved in 0.45% sodium chloride solution (pH 7.4/0.25 mg/L of

CaNa;DTPA), and it is stirred for 2 hours at 50°C. The solution is evaporated to the dry state in a vacuum, and the residue is made up with distilled water to a total of 155 ml. It is stirred for 10 minutes at 40°C and filtered with a 0.2 pm filter. The filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.)

Example 78 a) 2,3,4,6-Tetra-O-acetyl-1-B-D-[3,6,9-trioxa-(C 12-C 19-heptadecafluoro)-nonadecyl}- glucopyranosyluronic acid 20.2 g (50.85 mmol) of methyl ( 1-bromo-2,3,4-tri-O-acety-a-D-glucopyranoside)uronate [production according to: Pelzer; Hoppe-Seyler's Z. Physiol. Chem.; 314; 1949; 234, 237 and

Goebel; Babers; J. Biol. Chem; 111; 1935; 347, 350 and Bollenback et al.; J. Amer. Chem. Soc; 77, 1955; 3310, 3313] and 60.64 g (101.7 mmol) of 3,6,9-trioxa-(C,2-C,o-heptadecafluoro)- nonadecan-1-ol are dissolved in 250 ml of anhydrous acetonitrile and mixed at room temperature with 13.0 g of freshly precipitated silver oxide. After a reaction time of 12 hours at room temperature, insoluble silver salts are filtered out, the salts are thoroughly rewashed with dichloromethane, and the thus obtained filtrate is drawn off in a vacuum until a dry state is reached. The remaining residue is purified by column chromatography (eluant: hexane/ethyl acetate = 3:1).

@® ® Yield: 22.99 g (53.3% of theory) of the above-mentioned title compound as a colorless, highly viscous oil.

Elementary analysis:

Cld: C 41.05 H3.92 F 38.06

Fnd: C41.20 H3.76 F 38.22 b) 1-O-B-D-[3,6,9-Trioxa-(Ci2-Co-heptadecafluoro)-nonadecyl]- glucopyranosyluronic acid 10.0 g (11.78 mmol) of the title compound of Example 78a is suspended in 200 ml of a mixture that consists of methanol and 0.5 molar sodium hydroxide solution at a ratio of 2:1 while being stirred at room temperature. After a reaction time of 12 hours at room temperature, the now clear reaction mixture is neutralized for working-up by mixing with Amberlite IR 120 (H* form)-cation-exchange resin, exchanger is suctioned out, and the thus obtained methanolic- aqueous filtrate is drawn off in a vacuum until a dry state is reached. The crystalline residue that is obtained is purified by recrystallization from a mixture that consists of ethyl acetate/methanol (0.25:1). After '"H-NMR-spectroscopic study of the title compound, the presence of the B- configuration at the anomeric center was definitively established based on the size of the coupling constant of Ji, = 9.2 Hz. The existing B-configuration is the sole existing configuration at the anomeric center, i.e., the amount of B-configured anomer of the title compound that can possibly be formed lies below the "H-NMR -spectroscopic detection limit. The above-mentioned title compound was accordingly represented only in the form of the pure B-configured anomer.

Melting point: 78.5°C

Elementary analysis:

Cld: C34.21 H3.26 F 41.81]

Fnd: C 34.38 H3.26 F41.90

¢® ‘@ Production of a formulation that consists of metal complex I and [-O-B-D-[3,6,9-trioxa- (C12-Cyo-heptadecafluoro)-nonadecyl]-glucopyranosyluronic acid 19.18 g (24.83 mmol) of the title compound of Example 78b is added to 38 ml ofa solution of metal complex I (280 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 53.2 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered with a 0.2 um filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 200 mmol of Gd/L.)

Example 79 a) 6-(2-Oxa-1H, 1H,3H,3H,4H,4H-perfluorodecyl)-O',0°,0°,0"-diisopropylidene-a-D- galactopyranose

A total of 12.15 g (46.66 mmol) of 0',0%,0°,0*-diisopropylidene-a-galactopyranose [production according to: Levene; Meyer; J. Biol. Chem.; 64; 1925; 473 and McCreath; Smith;

J. Chem. Soc.; 1939; 387, 389 and Freudenberg; Hixon; Chem. Ber.; 56; 1923; 2119, 2122], dissolved in 200 ml of absolute dimethylformamide, is added drop by drop at room temperature to a stirred suspension of 2.01 g (70.0 mmol; 80% in mineral oil) of sodium hydride in 25 ml of dimethylformamide. It is then allowed to stir for 120 more minutes at room temperature, and subsequently a total of 30.09 g (48.0 mmol) of 1-bromo-1H,1H,2H,2H-perfluorododecane, dissolved in 150 ml of absolute dimethylformamide, is slowly added in drops. The thus obtained reaction solution is subsequently stirred for another 12 hours at room temperature. For working- up, the reaction solution is slowly poured into 1 liter of ice water and then exhaustively extracted with diethyl ether. The combined organic phases are subsequently washed twice with 200 ml each of saturated sodium bicarbonate solution and twice with 200 ml each of water. After the organic phase is dried on sodium sulfate, salt is suctioned out, and the solvent is drawn off in a

® vim. The remaining oily residue is purified on silica gel with use of ethyl acetate/hexane (1:10) as an eluant.

Yield: 29.8 g (79.3% of theory) of the above-mentioned title compound in the form ofa viscous, colorless oil

Elementary analysis:

Cld: C 35.75 H2.87 F49.47

Fnd: C 35.64 H2.98 F 49.54 b) 6-(2-Oxa-1H,1H,3H,3H,4H,4H-perfluorodecyl)-a-D-galactopyranose . 20 g (24.8 mmol) of the title compound of Example 79a is mixed with 300 ml of a 1% aqueous sulfuric acid solution and stirred for 3 hours at 80°C. After cooling to room temperature, it is neutralized by mixing with aqueous barium hydroxide solution, precipitated barium sulfate is subsequently filtered out, and the thus obtained clear aqueous product solution is freeze-dried. By '"H-NMR-spectroscopic study of the title compound, it was possible to show clearly the presence of two possible configurations at the anomeric center, whereby the existing o/B-configuration ratio according to 'H-NMR-spectroscopic study was determined with 1:1.4 (a:B) at the anomeric center. The above-mentioned title compound was accordingly isolated only in the form of 1:1.4 (a:B)-anomer mixture, i.e., an anomeric separation was eliminated.

Yield: 15.28 g (98.4% of theory) of the above-mentioned title compound as a colorless lyophilizate

Elementary analysis (relative to anhydrous substance):

Cld: C 35.75 H2.87 F 49.47

Fnd: C 35.64 H2.98 F 49.54

[ ® Production of a formulation that consists of the title compound of Example 67 and 6-(2- oxa-1H,1H,3H,3H,4H 4H-perfluorodecyl)-a-D-galactopyranose

A solution that consists of 1.68 g (2.69 mmol) of the title compound of Example 79b, dissolved in 200 ml of ethanol, is added to 43 ml of a solution of the title compound of Example 67 (250 mmol/L), dissolved in 0.45% sodium chloride solution (pH 7.4/0.25 mg/L of

CaNa;DTPA), and it is stirred for 2 hours at 50°C. The solution is evaporated to the dry state in a vacuum, and the residue is made up with distilled water to a total of 107.5 ml. It is stirred for minutes at 40°C and filtered with a 0.2 um filter. The filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.)

Example 80 a) 1-O-a-D-[(1-Perfluorooctylsulfonylpiperazine-4-carbonyl-)-methyl]-mannopyranose g (52.8 mmol) of 1-perfluorooctylsulfonylpiperazine (production described in DE 196 03 033) and 31.73 g (53 mmol) of 2,3,4,6-tetra-O-benzyl-a-D-carboxymethyl-mannopyranose (production described in DE 197 28 954) are dissolved in 300 ml of tetrahydrofuran. At 0°C, 24.73 g (100 mmol) of EEDQ (= 1,2-dihydro-2-ethoxyquinoline-1-carboxylic acid ethyl ester) is added, and it is stirred for 3 hours at 0°C, then for 6 hours at room temperature. The solution is evaporated to the dry state in a vacuum, and the residue is purified by flash chromatography on silica gel (mobile solvent: hexane/ethyl acetate = 10:1). The product-containing fractions are evaporated to the dry state, the residue is dissolved in a mixture that consists of 200 ml of methanol/150 ml of dichloromethane, and it is hydrogenated for 8 hours on palladium/carbon (10% Pd/C 2 g). Hydrogenating catalyst is filtered out, and the filtrate is evaporated to the dry state. The residue is recrystallized from acetone/diethyl ether.

Yield: 30.39 g (73% of theory) of a waxy, colorless solid

Elementary analysis:

Cld: C30.47 H2.68 F 40.96 N 3.55 S4.07

@® @ Fnd: C 30.61 H2.75 F41.10 N 3.46 S4.12 b) Production of a formulation that consists of metal complex I and 1-O-a-D-[(1- perfluorooctylsulfonylpiperazine-4-carbonyl-)-methyl]-mannopyranose 4.71 g (5.97 mmol) of the title compound of Example 80a is added to 32 ml of a solution of metal complex I (280 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 55 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered witha 0.2 um filter. and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 200 mmol of Gd/L.)

Example 81 a) 3-Oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid, sodium salt g (38.3 mmol) of 3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid (production described in DE 196 03 033) is dissolved in 300 ml of ethanol, and 7.7 ml of SN aqueous sodium hydroxide solution is added. It is evaporated to the dry state, and the residue is dried in a vacuum drying oven (8 hours, 60°C).

Yield: 20.85 g (quantitative) of a colorless, crystalline powder

Elementary analysis:

Cld: C2649 H1.11 F59.35 Na4.22

Fnd: C 26.60 H1.19 F 59.47 Na 4.30 b) Production of a formulation that consists of metal complex I and 3-oxa- 2H,2H,4H,4H,5H, SH-perfluorotridecanoic acid, sodium salt 2.09 g (3.84 mmol) of the title compound of Example 81a is added to 32 ml of a solution of metal complex I (280 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4;

C ® mg/L of CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 90 ml.

It is heated for 2 hours at 60°C in an ultrasound bath.

The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution.

It is filtered with a 0.2 um filter, and the filtrate is decanted into vials.

A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.) c) Production of a formulation that consists of metal complex I and 3-oxa-

2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid, sodium salt

1.00 g (1.84 mmol) of the title compound of Example 81a is added to 32 ml of a solution of metal complex I (280 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa3;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 90 ml.

It is heated for 2 hours at 60°C in an ultrasound bath.

It is filtered with a 0.2 pum filter, and the filtrate is decanted into vials.

A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.) d) Production of a formulation that consists of metal complex I and 3-oxa-

2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid, sodium salt

0.54 g (1.0 mmol) of the title compound of Example 81a is added to 32 ml of a solution of metal complex I (280 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 90 ml.

It is heated for 2 hours at 60°C in an ultrasound bath.

It is filtered with a 0.2 um filter, and the filtrate is decanted into vials.

A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.)

® ©

Example 82 a) 1-Perfluorooctylsulfonyl-4-(3,6,9,12,15-pentaox ahexadecanoyl)-piperazine g (35.2 mmol) of perfluorooctylsulfonylpiperazine (see Example 80a) is dissolved in 300 ml of dichloromethane, and 5.06 g (50 mmol) of triethylamine is added.

It is cooled to 0°C and 14.24 g (50 mmol) of 3,6,9,12,15-pentaoxahexanoic acid chloride is added in drops within 20 minutes, and it is stirred for 3 hours at 0°C. 400 ml of 5% aqueous hydrochloric acid is added, and it is thoroughly stirred. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent = dichloromethane/methanol: 15:1).

Yield: 26.44 (92% of theory) of a waxy solid

Elementary analysis:

Cld: C33.83 H3.58 N3.43 F39.55 S3.93

Fnd: C 33.96 H3.66 N3.50 F39.67 S 3.82 b) Production of a formulation that consists of metal complex I and 1- perfluorooctylsulfonyl-4-(3,6,9,12,15-pentaoxahexadecanoyl)-piperazine 4.61 g (5.64 mmol) of the title compound of Example 82a is added to 47 ml of a solution of metal complex I (280 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 66 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered with a 0.2 um filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 200 mmol of Gd/L.)

®o ©

Example 83 a) 1H,1H,2H,2H-Perfluorodecyl-p-toluenesulfonic acid ester g (43.1 mmol) of 1H,1H,2H,2H-perfluorodecanol is dissolved in 200 ml of pyridine, and 9.53 g (50 mmol) of p-toluenesulfonic acid chloride is added in portions at 0°C. It is stirred for 5 hours at room temperature. The solution is poured into 1000 ml of ice water and stirred for 10 minutes. The precipitate is filtered off, washed with a lot of water and then recrystallized from acetone.

Yield: 22.04 g (97% of theory) of a colorless, crystalline solid

Elementary analysis:

Cld: C22.78 H0.76 F 61.26 S 6.08 '

Fnd: C22.89 H0.70 F 61.39 S6.15 b) Cs-C,s-Heptadeca-fluoro-3,6,9,12,15-pentaoxa-pentacosan-1-ol 20 g (37.94 mmol) of the title compound of Example 83a, 35.74 g (150 mmol) of pentaethylene glycol and 1 g of 18-crown-6 are dissolved in 300 ml of tetrahydrofuran, and 10.1 g (180 mmol) of fine-powder potassium hydroxide is added. It is stirred for 10 hours at room temperature. Solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue 1s chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 15:1).

Yield: 5.45 g (21% of theory) of a colorless, viscous oil

Elementary analysis:

Cld: C35.10 H3.68 F 47.19

Fnd: C3522 H3.77 F 47.10

® o Production of a formulation that consists of the title compound of Example 69 and

C5-Cas-heptadeca-fluoro-3,6,9,12,15-pentaoxa-pentacosan- 1-ol 44.98 g (65.72 mmol) of the title compound of Example 83b) is added to 53 ml of a solution of the title compound of Example 69 (310 mmol/L), dissolved in 0.45% aqueous sodium chloride solution, and it is heated for 10 minutes in the microwave. The solution is cooled to room temperature, filtered with a 0.2 um filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 310 mmol of Gd/L.)

Example 84 a) N,N-Bis(8-hydroxy-3,6-dioxa-octyl)-perfluorooctylsulfonic acid amide g (29.23 mmol) of perfluorooctylsulfonic acid amide and 22.16 g (87.7 ml) of 9-(tetrahydropyran-2-yl)-3,6,9-trioxa-nonyl chloride are dissolved in 200 ml of acetonitrile. 41.46 g (300 mmol) of potassium carbonate and 1 g (6 mmol) of potassium iodide are added, and it is refluxed for 10 hours. The solid is filtered off, and the filtrate is evaporated to the dry state in a vacuum. The residue is dissolved in 400 ml of ethanol, and 30 ml of 10% aqueous hydrochloric acid is added. It is stirred for 2 hours at room temperature. [tis set at pH 7 with sodium hydroxide solution, and the solution is concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 10:1).

Yield: 11.38 g (51% of theory) of a colorless, viscous oil

Elementary analysis:

Cld: C31.46 H343 N 1.83 F 42.30 $4.20

Fnd: C31.59 H3.50 N 1.90 F42.46 S 4.08

1g ® Production of a formulation that consists of metal complex I and N,N-bis(8- hydroxy-3.6,-dioxa-octyl)-perfluorooctylsulfonic acid amide 7.91 g (10.36 mmol) of the title compound of Example 84a is added to 37 ml of a solution of metal complex I (280 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 104 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered with a 0.2 um filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.)

Example 85 a) N,N-Bis(t-butyloxycarbonylmethyl)-perfluorooctylsulfonic acid amide g (38.97 mmol) of perfluorooctylsulfonic acid amide and 20.73 g (150 mol) of potassium carbonate are suspended in 200 ml of acetone, and 17.56 g (90 mmol) of bromoacetic acid-tert-butyl ester is added. It is refluxed for 3 hours. The solid 1s filtered off, and the filtrate is evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/ethyl acetate = 10:1).

Yield: 23.53 g (83% of theory) of a colorless, waxy solid .

Elementary analysis:

Cld: C 33.02 H3.05 F44.40 N 1.93 S441

Fnd: C 33.19 H3.11 F44.30 N 1.99 S 4.32 b) N,N-Bis(carboxymethyl)-perfluorooctylsulfonic acid amide, disodium salt 23 g (31.62 mmol) of the title compound of Example 85a is dissolved in 300 ml of trifluoroacetic acid and stirred for 5 hours at room temperature. It is evaporated to the

® ® state in a vacuum, and the residue is recrystallized from acetone. The crystals are suctioned off and dried at 50°C in a vacuum.

Yield: 17.7 g (91% of theory) of a colorless, crystalline powder 17 g (27.63 mmol) of the thus obtained dioic acid is dissolved in 100 ml of water/300 ml of ethanol, and 9.2 ml of 3N aqueous sodium hydroxide solution is added.

It is stirred for 20 minutes at room temperature and then evaporated to the dry state ina vacuum. The residue is dried in a vacuum (60°C/8 hours).

Yield: 18.2 g of colorless, crystalline powder

Elementary analysis:Cld: C21.87 HO0.61 N2.12 F49.00 S4.86 Na 6.98

Fnd: C22.00 H0.70 N 2.20 F 49.17 $4.93 Na 7.10 SE c) Production of a formulation that consists of metal complex II and N,N- bis(carboxymethyl)-perfluorooctylsulfonic acid amide, disodium salt 2.89 g (4.39 mmol) of the title compound of Example 85b 1s added to 41 ml of a solution of metal complex II (250 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa;DTPA, and it is made up with a 0.9% aqueous common salt solution to a total of 52 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution 1s cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered with a 0.2 pum filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 200 mmol of Gd/L.)

Example 86 a) 1H,1H,2H,2H-Perfluorododecyl-sulfuric acid monoester, sodium salt g (17.73 mmol) of 1H,1H,2H,2H-perfluorododecanol is dissolved in 300 ml of chloroform, and 2.82 ¢g (17.73 mmol) of sulfur trioxide-pyridine complex is added at 0°C.

® ©

Tt is stirred for one hour at 0°C and then evaporated to the dry state in a vacuum. The residue is dissolved in 300 ml of ethanol and mixed with 17.8 ml of 1N aqueous sodium hydroxide solution. The solution is evaporated to the dry state, and the residue is dried in a vacuum (60°C/2 hours).

Yield: 11.81 g (quantitative)

Elementary analysis:

Cld: C21.64 HO0.61 F39.89 Na3.45 S 4.81

Fnd: C21.70 H0.72 F 60.00 Na3.57 S4.92 b) Production of a formulation that consists of metal complex VI and 1H,1H,2H,2H- perfluorododecyl-sulfuric acid monoester, sodium salt 4.90 g (7.35 mmol) of the title compound of Example 86a is added to 38 ml of a solution of metal complex VI (290 mmol/L), dissolved in 0.45% aqueous sodium chloride solution), and it is heated for 10 minutes in the microwave. The solution is cooled to room temperature, filtered with a 0.2 pum filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 290 mmol of Gd/L.) -. Example 87 a) 2H,2H,4H,4H,5H,5H-3-0Oxa-perfluoropentadecanoic acid, sodium salt g (16.07 mmol) of 2H,2H,4H.4H,5H,5H-3-oxa-perfluoropentadecanoic acid is dissolved in 300 ml of ethanol, and it is mixed with 16.1 ml of IN aqueous sodium hydroxide solution. The solution is evaporated to the dry state, and the residue is dried in a vacuum (60°C/2 hours).

Yield: 10.35 g (quantitative) of a colorless, amorphous powder

Elementary analysis:

Cld: C26.10 H0.94 F 61.94 Na3.57

® ® Fnd: C2622 H 1.00 F 62.05 Na 3.66 b) Production of a formulation that consists of the title compound of Example 66 and 2H,2H,4H,4H,5H, 5H-3-oxa-perfluoropentadecanoic acid, sodium salt

A solution that consists of 3.36 g (5.21 mmol) of the title compound of Example 87a, dissolved in 200 ml of ethanol, is added to 45 ml of a solution of the title compound of Example 66 (270 mmol/L), dissolved in 0.45% sodium chloride solution (pH 7.4/0.25 mg/L of CaNa;DTPA), and it is stirred for 2 hours at 50°C. The solution is evaporated to the dry state in a vacuum, and the residue is made up with distilled water to a total of 122 ml. It is stirred for 10 minutes at 40°C and filtered with a 0.2 um filter. The filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.)

Example 88 a) Ethylenediamine-N,N-tetraacetic acid-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-0xa- perfluorotridecyl)-monoamide 10.14 g (20 mmol) of 1H,1H,2H,2H,4H,4H,5H,5H-3-0xa-perfluorotridecylamine is added in portions at 50°C to 30 g (117.1 mmol) of EDTA-bisanhydride, suspended in 200 ml of dimethylformamide, and 50 mi of pyridine, and it is stirred for 6 hours at 50°C. ml of water is added, it is stirred for 10 minutes at 50°C, and the residue is evaporated to the dry state. The residue is taken up in a little water and brought to pH 4 with glacial acetic acid. The insoluble precipitate is filtered off and chromatographed on RP-18 (mobile solvent: acetonitrile/water/gradient).

Yield: 9.58 g (61% of theory) of a colorless solid

Water content: 8%

Elementary analysis:

Cld: C33.64 H3.59 N535 F41.12

® ® Fnd: C 33.51 H3.69 N544 F41.24 b) Ethylenediamine-N,N-tetraacetic acid-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-o0xa- perfluorotridecyl)-monoamide, calcium salt, sodium salt 9.0 g (11.46 mmol) of the title substance of Example 88a is suspended in 300 ml of water, and 11.4 mi of IN aqueous sodium hydroxide solution is added. Then, 1.15 g (11.46 mmol) of calcium carbonate is added, and it is stirred for 5 hours at 50°C. The solution is filtered, and the filtrate is freeze-dried.

Yield: 9.7 g (100% of theory) of a colorless, amorphous solid

Water content: 7.5%

Elementary analysis:

Cld: C31.25 H2.98 N4.97 F38.20 Na2.72 Ca4.74

Fnd: C 31.40 H3.09 N5.10 F38.07 Na2.81 Ca4.82 c) Production of a formulation that consists of metal complex I and ethylenediamine-N,N-tetraacetic acid-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa- perfluorotridecyl)-monoamide, calcium salt, sodium salt 2.54 g (3.01 mmol) of the title compound of Example 88b is added to 43 ml of a solution of metal complex I (280 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa; DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 121 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered witha 0.2 um filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.)

® ® 89 a) 1H, 1H 2H,2H-Perfluorodecyl-(2,2-dimethyl-5-hydroxy-1,3-dioxepan-6-yi)-ether 30 g (64.64 mmol) of 1H,1H,2H,2H-perfluorodecanol is dissolved in 200 ml of tetrahydrofuran, and 1.68 g (70 mmol) of sodium hydride is added at 0°C. ltis stirred for 2 hours at room temperature, then for 4 hours at 60°C. The solution is added to a metal autoclave, then 9.31 g (64.64 mmol) of 2,2-dimethyl-1,3,6-trioxabicyclo[5.1.0]octane is added and then heated for 10 hours to 150°C. The reaction solution is poured onto ice water and extracted 2 times with diethyl ether. The combined organic phases are evaporated to the dry state, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 10:1.)

Yield: 16.12 g (41% of theory) of a colorless solid

Elementary analysis:

Cid: C33.57 H2.82 F53.10

Fnd: C33.69 H2.90 F 53.35

I) 1H,1H,2H,2H-Perfluorodecyl-(1-hydroxymethyl-2,3-dihydroxypropyl)-ether g (24.66 mmol) of the title compound of Example 89a is dissolved in 300 ml of ethanol, and 30 ml of 10% aqueous hydrochloric acid is added. tis refluxed for 5 hours. It is set at pH 7 with sodium hydroxide solution, then evaporated to the dry state, and the residue is chromatographed on RP-18 (mobile solvent: acetonitrile/water/ gradient).

Yield: 12.75 g (91% of theory) of a colorless solid

Water content: 4.5%

Elementary analysis:

Cld: C 29.59 H 231 F 56.84

Fnd: C 29.48 H2.37 F 56.99

® ® Production of a formulation that consists of the title compound of Example 12 of 2.5-dioxo-pentane-1,5-diyl]-1,4,7,10-tetraazacyclododecane, Gd complex }-10-[2- - (N-ethyl-N-perfluorooctylsulfonyl)-amino}-acetyl-1,4,7,10- tetraazacyclododecane) and 1H,1H,2H,2H-perfluorodecyl-(1 -hydroxymethyl-2,3- dihydroxypropyl)-ether 6.46 g (16.65 mmol) of the title compound of Example 89b is added to 37 ml of a solution of 1,4,7-tris{1,4,7-tris(N-carboxylatomethyl)-10-(N-1-methyl-3-aza-2,5-dioxo- pentane-1,5-diyl]-1.4,7,10-tetraazacyclodod=cane, Gd complex }-10-[2-(1N-ethyl-N- perfluorooctylsulfonyl)-amino}-acetyl-1.4,7,1 0-tetraazacyclododecane (300 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa;DIPA), and it is made up with a 0.9% aqueous common salt solution to a total of 111 mi. It 1s heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. Itis filtered with a 0.2 um filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The conceniration is 100 mmol of Gd/L.)

Example 90 a) 1H,1H,2H,2H-Perfluorodecyl-[1,2-bis(2,2-dimethyl-1,3-dioxolan-4-yl)-2- hydroxyethyl]-ether g (64.64 mmol) of 1H,1H,2H.2H-perfluorodecanol is dissolved in 200 ml of tetrahydrofuran, and 1.68 g (70 mmol) of sodium hydride is added at 0°C. It is stirred for 2 hours at room temperature, then for 4 heurs at 60°C. The solution is added to a metal autoclave, then 15.78 g (64.64 mmol) of 1,2-bis-(2,2-dimethyl-1,3-dioxolan-4-yl)-oxiran is added, and then it is heated for 10 hours to 150°C. The reaction solution is pcured onto ice water and extracted 2 times with diethyl ether. The combined organic phases are

® ® to the dry state, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 10:1).

Yield: 14.2 g (31% of theory) of a colorless solid

Elementary analysis: .

Cid: C 37.30 H3.56 F 45.39

Fnd: C 37.48 H3.66 F 4571 b) 1H,1H,2H,2H-Perfluorodecyl-[1,2-bis(1,2-dihydroxy-ethyl)-2-hydroxyethyl]- ether 14 g (19.76 mmol) of the title compound of Example 90a is dissolved in 300 ml of ethanol, and 30 ml of 10% aqueous hydrochloric acid is added. It is refluxed for 5 hours. It is set at pH 7 with sodium hydroxide solution, then it is evaporated to the dry state, and the residue is chromatographed on RP-18 (mobile solvent: acetonitrile/water/gradient).

Yield: 10.55 g (85% of theory) of a colorless solid

Water content: 3.2%

Elementary analysis:

Cld: C 30.59 H2.73 F 51.41 ~ Fnd: C30.73 H2.81 F51.58 c) Production of a formulation that consists of metal complex II and 1H,1H,2H,2H- perfluorodecyl-[1,2-bis(1,2-dihydroxy-ethyl)-2-hydroxyethyl]-ether 11.98 g (19.07 mmol) of the title compound of Example 90b is added to 41 ml of a solution of metal complex II (300 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 64 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N

® ® . hydroxide solution. It is filtered with a 0.2 um filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 200 mmol of Gd/L.)

Example 91 a) Perfluorooctylsulfonic acid-N,N-bis[(8-sulfuric acid-monoester, sodium salt)-3,6- dioxaoctyl]-amide 13.54 g (17.73 mmol) of the title compound of Example 84a is dissolved in 300 ml of chloroform, and 2.82 g (17.73 mmol) of sulfur trioxide-pyridine complex is added at 0°C. It is stirred for one hour at 0°C, and then it is evaporated to the dry state in a vacuum. The residue is dissolved in 300 ml of ethanol and mixed with 17.8 ml of IN aqueous sodium hydroxide solution. The solution is evaporated to the dry state, and the residue is dried in a vacuum (60°C/2 hours).

Yield: 17.15 g (quantitative)

Elementary analysis:

Cld: C24.83 H2.50 F33.83 N145 S 9.94 Na4.75

Fnd: C24.96 H2.62 F 33.97 N 1.53 S10.05 Na4.86 b) Production of a formulation that consists of metal complex I and perfluorooctylsulfonic acid-N,N-bis[(8-sulfuric acid-monoester, sodium salt)-3,6- dioxaoctyl]-amide 142.29 g (147.06 mmol) of the title compound of Example 91a is added to 43 ml of a solution of metal complex I (380 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 164 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered with a 0.2 pm filter, and the filtrate

® ® is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.)

Example 92 a) 2-(2H,2H,3H,3H.5,5H,6H,6H-1,4-Dioxaperfluorotetradec- 1-yl)-succinic acid- diethyl ester g (59.03 mmol) of |H,1H.2H,2H 4H 4H, 5H, 5H-3-oxa-perfluorotridecanol 1s added to 300 ml of tetrahydrofuran, and at 0°C, 1.68 g (70 mmol) of sodium hydride is added. Itis stirred for one hour at 0°C, then for 5 hours at 40°C. In this 40°C solution, 20.25 g (80 mmol) of bromosuccinic acid diethyl ester is added in drops within 10 minutes, and it is then stirred for 12 hours at this temperature. 500 ml of ice water is added, and it is extracted 2 times with 300 ml of diethyl ether. The combined organic phases are evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: n-hexane/ethanol = 20:1).

Yield: 12.05 g (30% of theory)

Elementary analysis:

Cld: C35.31 H3.11 F 47.47

Fond: C 35.19 H3.20 F 47.59 b) 2-(2H,2H,3H,3H,5H,5H,6H,6H-1,4-Dioxa-perfluorotetradec- 1-yl)-succinic acid, disodium salt 50 ml of 3N aqueous sodium hydroxide solution is added to 11.5 g (16.90 mmol) of the title compound of Example 92a, dissolved in 300 ml! of methanol, and it is refluxed for 8 hours. It is evaporated to the dry state, and the residue is taken up in 300 ml of water. The aqueous phase is extracted 2 times with 300 ml of diethyl ether. The aqueous phase is acidified with concentrated hydrochloric acid to pH 1 and extracted 2 times with 300 ml of chloroform. The combined chloroform phases are dried on magnesium sulfate

® ® evaporated to the dry state. The residue is dissolved in 300 ml of water and set at pH 7.4 with 5% aqueous sodium hydroxide solution. Then, it is freeze-dried.

Yield: 10.50 g (93% of theory) of a colorless, amorphous solid

Water content: 5.7%

Elementary analysis:

Cld: C28.76 H 1.66 F 48.33 Na 6.88

Fnd: C28.88 H 1.71 F 48.25 Na 6.95 c) Production of a formulation that consists of metal complex II and 2- (2H,2H,3H,3H,5H,5H,6H,6H-1,4-dioxa-perfluorotetradec-1-yl)-succinic acid, disodium salt 1.14 g (1.71 mmol) of the title compound of Example 92b is added to 57 ml ofa : "solution of metal complex II (300 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 154 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered with a 0.2 um filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.)

Example 93 a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-(succin-2-yl)-amide 16.51 g (80 mmol) of N,N'-dicyclohexylcarbodiimide is added at 0°C to 20 g (38.30 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid and 9.21 g (80 mmol) of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide, and it is stirred for 3 hours at this temperature. A solution, cooled to 0°C, of 5.10 g (38.30 mmol) of L-asparaginic acid, dissolved in 300 ml of 5% aqueous sodium carbonate solution, is

® ® to the thus produced active ester solution, and it is stirred for 2 hours at 0°C. It is poured onto 500 ml of ice water, precipitated dicyclohexylurea is filtered out, and it is set at pH 1 with concentrated hydrochloric acid. It is extracted 3 times with 300 ml of chloroform. The combined, organic phases are evaporated to the dry state, and the residue is chromatographed on RP-18 (mobile solvent: acetonitrile/ water/gradient). The thus obtained dioic acid is dissolved in 400 ml of water and set at pH 7.4 with IN aqueous sodium hydroxide solution. It is filtered, and the filtrate is freeze-dried.

Water content: 6.3%

Yield: 21.13 g (81% of theory) of a colorless, amorphous powder

Elementary analysis:

Cld: C28.21 H1.48 N2.06 F47.41 Na6.75

Fnd: C2830 H 1.53 N 2.11 F47.53 Na6.83 b) Production of a formulation that consists of metal complex XIV and 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid-N-(succin-2-yl)-amide 422 mg (0.62 mmol) of the title compound of Example 93a is added to 37 ml of a solution of metal complex XIV (300 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 111 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered with a 0.2 um filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.)

® ® 94

Production of a formulation that consists of the title compound of Example 67 and perfluorooctanesulfonic acid, sodium salt

A solution that consists of 1.34 g (2.69 mmol) of perfluorooctanesulfonic acid, sodium salt, dissolved in 200 ml of ethanol, is added to 43 ml of a solution of the title compound of Example 67 (250 mmol/L), dissolved in 0.45% sodium chloride solution (pH 7.4/0.25 mg/L of CaNa;DTPA), and it is stirred for 2 hours at 50°C. The solution is evaporated to the dry state in a vacuum, and the residue is made to up a total of 108 ml with distilled water. It is stirred for 10 minutes at 40°C and filtered with a 0.2 pm filter.

The filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.)

Example 95

Production of a formulation that consists of the title compound of Example 68 and perfluorodecanesulfonic acid, sodium salt 3.03 g (5.06 mmol) of perfluorodecanesulfonic acid, sodium salt, is added to 49 ml of a solution of the title compound of Example 68 (310 mmol/L), dissolved in 0.45% aqueous sodium chloride solution, and it is heated for 10 minutes in a microwave. The solution is cooled to room temperature, filtered with a 0.2 um filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 310 mmol of Gd/L.)

Example 96 a) (1H,1H,2H,2H-Perfluorodecyl)-5-{(1,3-dicarboxy, disodium salt)-phenyl]-ether 42.5 2 (80.62 mmol) of the title compound of Example 142 1s added to 20 g (80.62 mmol) of trisodium salt of 5-hydroxy-isophthalic acid in 300 ml of dimethylformamide, and it is stirred for 10 hours at 60°C. It is poured onto 1300 ml of

® ® water and set at pH 1 with concentrated hydrochloric acid. It is extracted 3 times with 300 ml of chloroform. The combined, organic phases are concentrated by evaporation, and the residue is chromatographed on RP-18 (mobile solvent: acetonitrile/water/ gradient). The dioic acid that is purified in such a way is dissolved in 400 ml of water, and the pH is brought to 7.4 with IN aqueous sodium hydroxide solution. It 1s filtered, and the filtrate is freeze-dried.

Yield: 20.05 g (37% of theory) of a colorless, amorphous solid

Water content: 5.0%

Elementary analysis:

Cld: C32.16 H1.05 F 48.05 Na 6.84

Fnd: C 32.30 H 1.15 F 48.20 Na 6.95 b) Production of a formulation that consists of the title compound of Example 12 of

WO 99/01161 (1,4,7-tris{1,4,7-tris(N-carboxylatomethyl)-10-(N-1-methyl-3-aza- 2,5-dioxo-pentane-1,5-diyl]-1,4,7,10-tetraazacyclododecane, Gd complex}-10-[2- (N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1,4,7,10- tetraazacyclododecane) and (1H,1H,2H,2H-perfluorodecyl)-5-[(1,3-dicarboxy, disodium salt)-phenyl}-ether 6.86 ¢ (10.2 mmol) of the title compound of Example 96a is added to 51 ml of a solution of 1,4,7-tris{1,4,7-tris(N-carboxylatomethyl)-10-(N-1-methyl-3-aza-2,5-dioxo- pentane-1,5-diyl]-1,4,7,10-tetraazacyclododecane, Gd complex }-10-[2-(N-ethyl-N- perfluorooctylsulfonyl)-amino]-acetyl-1,4,7,10-tetraazacyclododecane (300 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 153 ml. Itis heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered

® ®. a 0.2 um filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration is 100 mmol of Gd/L.)

Example 97

Production of a formulation that consists of metal complex XIV and 3-oxa- 2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid, sodium salt 434 mg (0.55 mmol) of the title compound of Example 80a is added to 4 ml of a solution of metal complex XIV (320 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 12.8 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered with a 0.2 pm filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The concentration 1s 100 mmol of Gd/L.)

Example 98 a) (Adamant-1-y1)-3-oxa-propionic acid-t-butylester 29.26 g (150 mmol) of bromoacetic acid-tert-butyl ester is added at 0°C to1522¢g (100 mmol) of 1-adamantanol in 300 ml of 50% aqueous potassium hydroxide solution, 200 ml of toluene, and it is vigorously and thoroughly stirred for 2 hours. It is poured onto 1500 ml of water and extracted 2 times with 300 ml of diethyl ether. The combined organic phases are dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: n-hexane/diethyl ether 20:1).

Yield: 21.58 g (81% of theory) of a viscous, colorless oil

Elementary analysis:

Cid: C72.14 H9.84

® ® Fnd: C 72.26 H9.95 b) (Adamant-1-yl)-3-oxa-propionic acid g (75 mmol) of the title compound of Example 98a is dissolved at 0°C in 200 ml of trifluoroacetic acid, and it is stirred for 8 hours at room temperature. Itis evaporated to the dry state, and the residue is recrystallized from diisopropyl ether.

Yield: 14.68 g (93% of theory) of colorless flakes

Elementary analysis:

Cld: C 68.55 H8.63

Fnd: C 68.41 H 8.74

C) 1-(Perfluorooctylsulfonyl)-4-[(adamant-1-yl)-oxapropionyl]-piperazine 14 g (66.6 mmol) of the title compound of Example 98b and 37.50 g (66.6 mmol) of 1-perfluorooctylsulfonyl-piperazine are dissolved in 300 ml of tetrahydrofuran, ed 32.15 g (130 mmol) of 1,2 dihydro-2-ethoxyquinoline-1-carboxylic acid ethyl ester (=EEDQ) is added at 0°C. lt is stirred for 5 hours at room temperature. The solution is evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/diethyl ether = 30:1).

Yield: 43.05 g (85% of theory) of a colorless solid

Elementary analysis:

Cld: C37.90 H331 N3.68 S422 F42.47

Fnd: C 38.04 H3.42 N3.49 S411 F42.30

® eo Preparation that consists of 0.5 part of metal complex I and 0.5 part of an inclusion compound of B-cyclodextrin-hydrate and I (perfluorooctylsulfonyl)-4- [(adamant-1-yl)-oxapropionyl]-piperazine 6.81 g (8.96 mmol) of the title compound of Example 98c and 10.33 g (8.96) of B- cyclodextrin monohydrate are added to 32 ml of a solution of metal complex I (280 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of

CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 98 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered with a 0.2 pm filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The Gd concentration is 100 mmol of Gd/L.)

Example 99 a) 3-Oxa-2H,2H,4H,4H, 5H, SH-perfluorotridecanoic acid-N-(1-adamantyl)-amide 30.95 g (150 mmol) of N,N-dicyclohexylcarbodiimide is added at 0°Cto 15.12 g (100 mmol) of 1-amino-adamantane, 52.21 (100 mmol) of 3-oxa-2H,2H,4H,4H,5H,5H- perfluorotridecanoic acid and 11.51 g (100 mmol) of N-hydroxysuccinimide, dissolved in 300 ml of tetrahydrofuran. It is stirred for 2 hours at 0°C, then for 6 hours at room temperature. Precipitated urea is filtered out, the filtrate is evaporated to the dry state, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 30:1).

Yield: 54.4 ¢ (83% of theory) of a waxy solid

Elementary analysis:

Cld: C40.32 H3.38 N2.14 F 49.28

Fnd: C 40.47 H3.49 N 2.03 F 49.09

" BR003/1949 ® ® Preparation that consists of 0.6 part of metal complex II and 0.4 part of an inclusion compound that consists of B-cyclodextrin-hydrate and 3-oxa- 2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid-N-(1-adamantyl)-amide 4.48 g (6.83 mmol) of the title compound of Example 99a and 7.87 g (6.83 mmol) of B-cyclodextrin monohydrate are added to 41 ml of a solution of metal complex IT (250 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of

CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 103 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered with a 0.2 um filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The Gd concentration is 100 mmol of Gd/L.)

Example 100 a) 2-[N-(Ethyl)-N-(perfluorooctylsulfonyl)-amino]-acetic acid-N-(adamantyl)-amide 30.95 g (150 mmol) of N,N-dicyclohexylcarbodiimide is added at 0°Cto 15.12 ¢ (100 mmol) of 1-aminoadamantane, 58.52 g (100 mmol) of N-(ethyl)-N- (perfluorooctylsulfonyl)-aminoacetic acid and 11.51 g (100 mmol) of N- hydroxysuccinimide, dissolved in 300 ml of tetrahydrofuran. It is stirred for 2 hours at 0°C, then for 6 hours at room temperature. Precipitated urea is filtered out, the filtrate 1S evaporated to the dry state, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 30:1).

Yield: 55.65 g (79% of theory) of an amorphous solid

Elementary analysis:

Cld: C37.51 H3.29 F45.85 N1.99 S455 :

Fnd: C37.64 H3.41 F4599 N2.12 S4.43.

® ® Preparation that consists of 0.6 part of metal complex I and 0.4 part of an inclusion compound that consists of B-cyclodextrin-hydrate and 2-[N-(ethyl)-N- (perfluoroac etylsulfonyl)-amino]-acetic acid-N-(1-adamantyl)-amide 4.20 g (5.97 mmol) of the title compound of Example 100a and 6.88 g (3.97 mmol) of B-cyclodextrin monohydrate are added to 32 ml of a solution of metal complex [ (280 mmol/L), dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of

CaNa;DTPA), and it is made up with a 0.9% aqueous common salt solution to a total of 90 ml. It is heated for 2 hours at 60°C in an ultrasound bath. The solution is cooled to room temperature and set at pH 7.4 with aqueous 2N sodium hydroxide solution. Itis filtered with a 0.2 um filter, and the filtrate is decanted into vials. A thus produced solution can be used directly for biological experiments. (The Gd concentration is 100 mmol of Gd/L.)

Example 101 a) 6-N- a)Benzyloxycarbonyl- 2-N- (3,6,9,12- tetraoxatridecanoyl)-lysine[ 1-(4- perfluorooctylsulfonyl)-piperazine]-amide

A solution that consists of 16.85 g (70 mmol) of 3,6,9,12 tetraoxatridecanoic acid chloride in 50 ml of dichloromethane is added in drops at 0°C to 50 g (60.20 mmol) of the title compound of Example 1c and 7.10 g (70 mmol) of triethylamine, dissolved in 350 ml of dichloromethane, and it is stirred for 3 hours at 0°C. 200 ml of 5% aqueous hydrochloric acid is added, and it is stirred for 5 minutes at room temperature. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 15:1).

Yield: 30.94 g (92% of theory) of a colorless, viscous oil.

@ ® Elementary analysis:

Cld.: C40.63 H4.19 F31.21 N5.41 S$3.10

Fnd.: C40.75 H4.08 F31.29 N5.58 §S3.25 b) 2-N-(3,6,9,12-Tetraoxatridecanoyl)-lysine[ 1-(4-perfluorooctylsulfonyl)- piperazine] 53.96 g (52.15 mmol) of the title compound of Example 101a is dissolved in 500 ml of ethanol, and 6 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum. :

Yield: 43.0 g (quantitative) of a colorless solid.

Elementary analysis:

Cld.: C36.01 H4.14 F35.86 N6.22 §3.56

Fnd.: C 36.20 H4.23 F35.99 N6.38 S3.71 c) 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1 0- (pentanoyl-3-aza-4-oxo-5-methyl-5-y1)}-2-N-(3,6,9,1 2-tetraoxatridecanoyl)- lysine[ 1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex 21.84 (24.25 mmol) of the title compound of Example 101b, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-0x0-5-methyl-5-yl)]- pentanoic acid]-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in 200 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 8.25 g (40 mmol) of N,N-

LJ ® dicyclohexylcarbodiimide is added and then stirred overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 28.21 g (81% of theory) of a colorless solid.

Water content: 11.0%

Elementary analysis (relative to anhydrous substance):

Cld.: C36.53 H4.33 F21.36 N 8.34 S2.12 Gd 10.40

Fnd.: C36.64 H4.48 F21.39 N8.29 S2.15 Gd 10.57

Example 102 a) 6-N-Benzyloxycarbonyl-2-N-(propyl-3-sulfonic acid)-lysine[1-(4-perfluorooctyl- sulfonyl)-piperazine]-amide

A solution that consists of 7.33 g (60 mol) of propanesultone in 50 ml of tetrahydrofuran is added in drops at 50°C to 50 g (60.20 mmol) of the title compound of

Example 1c and 7.10 g (70 mmol) of triethylamine, dissolved in 250 ml of dry tetrahydrofuran, and it is stirred for 3 hours at 60°C. 200 ml of 5% aqueous hydrochloric acid is added, and it is stirred for 5 minutes at room temperature. The organic phase is separated, dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 15:1).

Yield: 45.16 g (79% of theory) of a colorless, viscous oil.

® ® Elementary analysis:

Cld.: C 36.56 H3.49 F33.90 N588 S6.73

Fnd.: C36.72 H3.35 F 33.79 N5.78 §6.75 b) 2-N-(Propyl-3-sulfonic acid)-lysine[1-(4-perfluorooctylsulfonyl)-piperazine}- amide 49.68 g (52.15 mmol) of the title compound of Example 102a is dissolved in 500 m] of ethanol, and 6 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 42.69 g (quantitative) of a colorless solid.

Elementary analysis:

Cld.: C30.81 H3.32 F39.46 N6.84 S7.83

Fnd.: C30.64 H4.1 F 39.29 N6.68 S7.89 c) 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-y1)]-2-N-(propyl-3-sulfonic acid)-lysine[1-(4- perfluorooctylsulfonyl)-piperazine]-amide, Gd complex 19.85 g (24.25 mmol) of the title compound of Example 102b, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride, and 15.27 g ~ (24.25 mmol) of 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-0x0-5-methyl-5-yD)]- pentanoic acid]-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in 200 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 8.25 g (40 mmol) of N,N-

® ® dicyclohexylcarbodiimide is added, and then it is stirred overnight at room temperature.

The solution is poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 28.13 g (81% of theory) of a colorless solid.

Water content: 11.0%

Elementary analysis (relative to anhydrous substance):

Cld.: C3327 H3.70F 22.36 N 8.73 S4.44 Gd 10.89

Fnd.: C32.41 H3.88 F22.49 N 8.69 S4.35 Gd 10.97

Example 103 a) 6-N-Benzyloxycarbonyl-2-N,N-bis (propyl-3-sulfonic acid)-lysine[ 1-(4- perfluorooctylsulfonyl)-piperazine]-amide

A solution that consists of 14.65 g (120 mmol) of 1,3-propanesultone in 100 ml of tetrahydrofuran is added in drops at 50°C to 50 g (60.20 mmol) of the title compound of

Example lc and 12.14 g (120 mmol) of triethylamine, dissolved in 250 ml of dry tetrahydrofuran, and it is stirred for 3 hours at 60°C. 400 ml of 5% aqueous hydrochloric acid is added, it is stirred for 5 minutes at room temperature, mixed with sodium chloride, the organic phase is separated, it is dried on magnesium sulfate and evaporated to the dry sttate in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone = 15:1).

Yield: 52.24 g (81% of theory ) of a colorless, viscous oil.

® ® Elementary analysis:

Cld.: C35.76 H3.66 F30.05 N 521 S895

Fnd.: C 35.75 H3.55 F30.19 N 5.08 S9.04 b) 2-N,N Bis(propyl-3-sulfonic acid)-lysine{1-(4-perfluorooctylsulfonyl)- piperazine]-amide 53.74 ¢ (52.15 mmol) of the title compound of Example 103a is dissolved in 500 ml of ethanol, and 6 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 49.06 g (quantitative) of a colorless solid.

Elementary analysis:

Cld.: C30.64 H3.54 F34.33 N5.96 S 10.23

Fnd.: C 30.69 H3.71 F 34.19 N 6.08 S10.38 c) 6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-y1)}-2-N,N bis(propyl-3-sulfonic acid)- lysine[1-(4-perfluorooctylsulfonyl)-piperazine}-amide, Gd complex, disodium salt 38.76 ¢g (24.25 mmol) of the title compound of Example 103b, 2.79 g (24.25 mmol) of N-hvdroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of | 4.7-tris(carboxylatomethyl)-10-[(3-aza-4-0x0-5-methyl-5-y)]- pentanoic acid]-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in 200 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 8.25 g (40 mmol) of N,N-

® _ dicyclohexylcarbodiimide is added, and it then is stirred overnight at room temperature.

Yield: 31.63 g (81% of theory) of a colorless solid.

Water content: 11.0%

Elementary analysis (relative to anhydrous substance):

Cld.: C 32.07 H3.57 F20.06 N 7.83 S5.97 Gd 9.76 Na2.86

Fnd.: C31.94 H3.48 F20.19 N7.69 S5.85 Gd 9.87 Na2.99

Example 104 a) N-Trifluoroacetyl-L-glutamic acid-5-benzylester 100 g (421.5 mmol) of L-glutamic acid-5-benzylester is dissolved in a mixture that consists of 1000 ml of trifluoroacetic acid ethyl ester/500 ml of ethanol, and it is stirred for 24 hours at room temperature. It is evaporated to the dry state, and the residue is crystallized from diisopropyl! ether.

Yield: 140.47 g (96% of theory) of a colorless, crystalline powder.

Elementary analysis:

Cld.: C 50.46 H4.23 F 17.10 N4.20

Fnd.: C51.35 H4.18 F17.03 N 4.28

® @, 2-N-Trifluoroacetyl-L-glutamic acid-5-benzylester-N-bis(2-hydroxyethyl)- amide . 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is added at 0°C to a solution that consists of 24.9 g (24.08 mmol) of the title compound of Example 104a, 2.55 g (24.08 mmol) of diethanolamine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide. It is stirred for 3 hours at 0°C, then overnight at room temperature. Precipitated urea is filtered out, the filtrate is evaporated to the dry state in a vacuum, and it is chromatographed on silica gel (mobile solvent: = dichloromethane/ethanol = 20:1).

Yield: 9.11 g (90% of theory ) of a viscous oil.

Elementary analysis:

Cld.: C51.43 HS.51 F 13.56 N6.66

Fnd.: C51.22 H541 F 13.40 N6.75 c) N-Trifluoroacetyl-L-glutamic acid-N bis(2-hydroxyethyl)-monoamide 21.92 g (52.15 mmol) of the title compound of Example 104b is dissolved in 500 ml of ethanol, and 3 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 43.0 g (quantitative) of a colorless solid.

Elementary analysis:

Cld.: C40.01 H5.19 F17.26 N 8.48

Fnd.: C39.84 H5.13 F 17.09 N 8.68

® c) Trifluoroacetyl-L-glutamic acid-N-bis(2-hydroxyethyl)-amide-5-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) is added at 0°C to 10.96 g (33.2 mmol) of the title compound of Example 104a and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonyl-piperazine (produced according to DE 19603033) in 80 ml of tetrahydrofuran, and it is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum, and 1t is chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

Yield: 30.93 g (93% of theory) of a colorless solid.

Elementary analysis:

Cld.: C39.61 H2.89 F35.66 N6.19 S3.54

Fnd.: C 39.68 H2.74 F 35.81 N6.13 S3.40 e) L-Glutamic acid-N-bis(2-hydroxyethyl)-amide-5-[1-(4-perfluorooctylsulfonyl)- piperazine]-amide

Ammonia gas is introduced at 0°C for one hour into 200 ml of ethanol. It is then stirred for 4 hours at 0°C. It is evaporated to the dry state, and the residue is absorptively precipitated from water. The solid is filtered off and dried in a vacuum (50°C).

Yield: 26.55 g (97% of theory ) of an amorphous solid.

Elementary analysis:

Cld.: C41.12 H2.89 F35.66 N6.19 S3.54

Fnd.: C41.15H 2.83 F35.78 N6.28 S3.71

® | f) N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl- 3-aza-4-0x0-5-methyl-5-y1)]-L-glutamic acid-N-bis(2-hydroxyethyl)-amide-5-[1- (4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex 211.96 g (24.25 mmol) of the title compound of Example 104e, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-5-methyl-5-yl)]- pentanoic acid]-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in 200 m] of dimethyl sulfoxide while being heated slightly. At 10°C, 8.25 g (40 mmol) of N,N- dicyclohexylcarbodiimide is added, and it then is stirred overnight at room temperature.

The solution is poured into 3000 ml of acetone, and it is stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 27.43 g (81% of theory) of a colorless solid.

Water content: 11.0%

Elementary analysis (relative to anhydrous substance):

Cld.: C34.41 H3.83 F23.13 N9.03 $2.30 Gd 11.26

Fnd.: C34.34 H3.98 F23.29 N9.19 S2.15 Gd 11.07

Example 105 a) N-Trifluoroacetyl-L-glutamic acid-5-benzylester-N-dimethyl-bis(1,1- dihydroxymethyl)-amide 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is added at 0°C to a solution that consists of 8.03 g (24.08 mmol) of the title compound of Example 104a, 3.98 g

® @.. mmol) of dimethyl-bis(1,1-dihydroxymethyl)-amine and 2.77 g (24.08 mmol) of

N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide. It is stirred for 3 hours at 0°C, then overnight at room temperature. Precipitated urea is filtered out, the filtrate is evaporated to the dry state in a vacuum, and it is chromatographed on silica gel (mobile solvent: dichloromethane/ethanol = 20:1).

Yield: 110.53 g (91% of theory ) of a viscous oil.

Elementary analysis:

Cld C 50.00 H5.66 F 11.86 N7.18

Fnd.: C50.17 H5.82 F11.80N 7.15 b) N-Trifluoroacetyl-L-glutamic acid-5-benzylester-[ 1-(4-perfluorooctylsulfonyl)- piperazine]-amide 25.05 g (52.15 mmol) of the title compound of Example 105a is dissolved in 500 ml of ethanol, and 6 g of palladium catalyst (10% Pd/C) is added, hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum. :

Yield: 20.36 g (quantitative) of a colorless solid.

Elementary analysis:

Cld.: C40.00 H542 F 14.60 N7.18

Fnd.: C 40.10 H5.53 F 14.69 N 7.28

® QO. N-Trifluoroacetyl-L-glutamic acid-N-dimethyl-bis(1,1-dihydroxymethvl)-amide- 5-[1-(4-perfluorooctyisulfonyl)piperazine]-amide 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) is added at 0°C to 12.96 g (33.2 mmol) of the title compound of Example 105b and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonyl-piperazine (produced according to DE 19603033) in 800 ml of tetrahydrofuran, and it is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

Yield: 28.42 g (91% of theory ) of a colorless solid.

Elementary analysis:

Cld.: C3193 H3.00 F40.40 N5.96 S 3.41

Fnd.: C32.08 H294 F 40.57 N 5.88 S3.31 d) L-Glutamic acid-N-[dimethyl-bis(1,1-dihydroxymethyl)]-amide-5-[(1-4- perfluorooctylsulfonyl)-piperazine]-amide

Ammonia gas is introduced at 0°C for one hour into a solution that consists of 28.41 g (30.2 mmol) of the title compound of Example 105¢ in 200 ml of ethanol. It then is stirred for 4 hours at 0°C. It is evaporated to the dry state, and the residue is absorptively precipitated from water. The solid is filtered off and dried in a vacuum (50°C).

Yield: 24.74 g (97% of theory) of an amorphous solid.

Elementary analysis:

Cld.: C32.71 H3.46 F 38.24 N6.63 S3.80

® @® Fnd.: C32.75 H3.33 F 38.38 N6.68 S3.81 : e) 2-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo0-5-methyl-5-yl)]-L-glutamic acid-N-[dimethyl-bis(1,1- dihydroxymethyl)-amide]-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex 20.48 g (24.25 mmol) of the title compound of Example 105d, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo0-5-methyl-5-y1)]- pentanoic acid]-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in 200 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 8.25 g (40 mmol) of N,N- dicyclohexylcarbodiimide 1s added, and it then is stirred overnight at room temperature.

The solution is poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated filtrate is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 29.05 g (83% of theory) of a colorless solid.

Water content: 11.0%

Elementary analysis (relative to anhydrous substance):

Cld.: C34.12 H3.91 F2238 N8.73 S2.22 Gd 10.90

Fnd.: C3424 H3.98 F22.39 N869 S2.15 Gd 10.87

Qe 106 a) N-Trifluoromethylacetyl-L-glutamic acid-5-benzylester-[ 1-(4- perfluorooctylsulfonyl)-piperazine]-amide 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) is added at 0°C to 11.06 g (33.2 mmol) of the title compound of Example 104a and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonyl-piperazine (produced according to DE 19603033) in 80 ml of tetrahydrofuran, and it is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

Yield: 27.28 g (93% of theory) of a colorless solid.

Elementary analysis:

Cld.: C35.35 H2.40 F43.01 N4.76 S3.63

Fnd.: C3548 H2.51 F42.87 N4.73 S3.50 b) N-Trifluoroacetyl-L- glutamic acid-5-[1-[4-perfluorooctylsulfonyl)-piperazine]- amide 21.92 g (52.15 mmol) of the title compound of Example 106a is dissolved in 500 ml of ethanol, and 3 g of palladium catalyst (10% PU/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 41.37 g (quantitative) of a colorless solid.

Elementary analysis:

Cld.: C28.76 H1.91 F47.89 N5.30 S440

® _ Fnd.: C28.84 H2.03 F47.79 N 5.28 S4.19 c) N-Trifluoroacetyl-L-glutamic acid-N-bis(2-hydroxyethyl)-amide-5-{1-(4- perfluorooctylsulfonyl)-piperazine]-amide 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is added at 0°C to a solution that consists of 24.9 g (24.08 mmol) of the title compound of Example 106a, 2.53 g (24.08 mmol) of diethanolamine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide. It is stirred for 3 hours at 0°C, then overnight at room temperature. Precipitated urea is filtered out, the filtrate is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: = dichloromethane/ethanol = 20:1).

Yield: 9.11 g (90% of theory ) of a viscous oil.

Elementary analysis:

Cld.: C31.37 H2.75 F43.15 N 6.36 S 3.64

Fnd.: C3122 H2.61 F43.30 N6.25 S 3.81 d) L-Glutamic acid-N-bis(2-hydroxyethyl)-amide-5-[1-(4-perfluorooctylsulfonyl)- piperazine}-amide

Ammonia gas is introduced at 0°C for one hour into a solution that consists of 26.61 g (30.22 mmol) of the title compound of Example 106¢ in 200 ml of ethanol. It then is stirred for 4 hours at 0°C. It is evaporated to the dry state, and the residue is absorptively precipitated from water. The solid is filtered off and dried in a vacuum (50°C).

@ ® Yield: 23.93 g (97% of theory) of an amorphous solid.

Elementary analysis:

Cld.: C 30.89 H 3.09 F 39.56 N6.86 S 3.93

Fnd.: C30.75 H3.13 F 39.78 N6.75 S3.81 e) N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl- 3-aza-4-ox0-5-methyl-5-yl)]-L-glutamic acid-N-bis(2-hydroxyethyl)-amide-5-1- (4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex 16.43 g (24.25 mmol) of the title compound of Example 106d, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-5-methyl-5-yl)}- pentanoic acid]-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in 200 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 8.25 g (40 mmol) of N,N- dicyclohexylcarbodiimide is added, and 1t then 1s stirred overnight at room temperature.

Yield: 28.10 g (83% of theory) of a colorless solid.

Water content: 11.0%

Elementary analysis (relative to anhydrous substance):

Cld.: C3441 H3.83 F23.13 N9.03 S230 Gd 11.26

Fnd.: C3444 H4.98F 23.19 N889S2.15 Gd 11.17

® Q:..opic 107 a) N-Trifluoroacetyl-glutamic acid-5-benzylester-[ 1-(4-perfluorooctylsulfonyl)- piperazine]-amide 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) is added at 0°C to 11.06 g (33.2 mmol) of the title compound of Example 104a and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonyl-piperazine (produced according to DE 19603033) in 80 ml of tetrahydrofuran, and it is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

Yield: 27.28 g (93% of theory) of a colorless solid.

Elementary analysis:

Cld.: C 33.35 H2.40 F43.01 N4.76 S 3.63

Fnd.: C35.48 H2.54 F42.87 N 4.73 S3.40 b) N-Trifluoroacetyl-L- glutamic acid-5-[1-[4-perfluorooctylsulfonyl)-piperazine]- amide 21.92 g (52.15 mmol) of the title compound of Example 107a is dissolved in 500 ml of ethanol, and 3 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 41.37 g (quantitative) of a colorless solid.

Elementary analysis:

Cld.: C2876 H1.91 F47.89 N530 S4.04

® ® Fnd.: C28.84 H181 F47.79 N5.28 S4.16

Example 108 a) 6-N-Benzyloxycarbonyl-2-N-(2,3,4,5-pentahydroxy-hexanoyl)L-lysine-[ 1-(4- perfluorooctylsulfonyl)-piperazine]-amide

A solution that consists of 21.45 g (120.4 mol) of 5-gluoconolactone in 50 ml of tetrahydrofuran is added in drops at 50°C to a solution that consists of 100.0 g (120.4 mol) of the title compound of Example 21c¢), in 500 ml of dry tetrahydrofuran. It is stirred for 3 hours at 60°C and then overnight at room temperature. It is evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel. (Mobile solvent: dichloromethane/ethanol = 20:1).

Yield: 98.37 g (82% of theory of a viscous oil).

Elementary analysis:

Cld.: C38.10 H3.70 F32.02 N5.55 S3.18

Fnd.: C 38.22 H3.79 F32.02 N 5.42 S3.29 b) 2-N-(2,3,4,5-Pentahydroxy-hexanoyl)-L-lysine-1-[(4-perfluorooctylsulfony!)- piperazine]-amide 100.9 g (100.0 mmol) of the title compound of Example 108a) is dissolved in 2000 ml of ethanol, and 10.0 g of palladium catalyst (10% Pd/C) is added thereto. Itis hydrogenated for 12 hours at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 87.46 g (quantitative) of a colorless solid.

® ® Elementary analysis:

Cld.: C3296 H3.57 N6.41 S3.67 F36.93

Fnd.: C3291 H3.72 N6.34 S3.50 F 36.78 f) 6-N-[1,4, 7 Tris(carboxylatomethyl)]- 1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-0x0-5-methyl-5-v1)]-2-N-[1-O-a-D-carbonylmethyl- mannopyranose]-L-lysine-[ 1-(4-perfluorooctylsulfonyl)-piperazine}-amide, Gd complex 50.0 g (54.55 mmol) of the title compound of Example 21¢), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of lithium chloride and 34.35 g (54.55 mol) of 1,4,7-tris (carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5-methyl-pent-5-yl)- 1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 16.88 g (81.8 mol) of N,N- : dicyclohexylcarbodiimide is added, and it then is stirred overnight at room temperature.

The solution is poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18 mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 75.9 g (91.0% of theory) of a colorless solid. -

Water content: 8.6%.

Elementary analysis (relative to anhydrous substance):

Cld.: C3534 H4.09 N8.24 § 2.10 F21.12 Gd 10.28

Fnd.: C3528 H4.15 N 8.19 $2.15 F21.03 Gd 10.14

® [| F— 109 a) 6-N-Benzyloxycarbonyl-2-N-(2,3,4,5-pentahydroxy-hexanoyl)L-lysine-1-(4- perfluorooctylsulfonyl)-piperazine]-amide

A solution that consists of 21.45 g (120.4 mol) of 5-gluconolactone in 50 ml of tetrahydrofuran is added in drops at 50°C to a solution that consists of 100.0 g (120.4 mmol) of the title compound of Example 21c) and 12.18 g (120.4 mmol) of triethylamine in 500 ml of dry tetrahydrofuran. It is stirred for 3 hours at 60°C and then overnight at room temperature. Then, 400 ml of 5% aqueous hydrochloric acid is added thereto, it is stirred for 5 minutes at room temperature, mixed with sodium chloride, the organic phase is separated, it 1s dried on magnesium sulfate, evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel. (Mobile solvent: dichloromethane/ethanol = 20:1).

Yield: 100.97 g (82% of theory) of a viscous oil.

Elementary analysis:

Cld.: C37.58 H3.45 F31.58 N548 S3.14

Fnd.: C37.72 H3.59 F31.72 N542 S329 b) 2-N-(2,3,4,5-Pentahydroxy-hexanoyl)-L-lysine-1-[(4-perfluorooctylsulfonyl)- piperazine]-amide 100.9 g (100.0 mmol) of the title compound of Example 108a) is dissolved in 2000 ml of ethanol, and 10.0 g of palladium catalyst (10% Pd/C) is added thereto. It is hydrogenated for 12 hours at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

@® ® Yield: 87.46 g (quantitative) of a colorless solid.

Elementary analysis:

Cld.: C32.96 H3.57 N6.41 S3.67 F 36.93

Fnd.: C3291 H3.72 N6.34 S3.50 F 36.78 c) 6-N-[1,4,7-Tris(carboxylatomethyl)]-1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-0xo0-5-methyl-5-y1)]-2-N-[ 1-O-c-D-carbonylmethyl- mannopyranose]-L-lysine-[ 1 -(4-perfluorooctylsulfonyl)-piperazine}-amide, Gd complex 50.0 g (54.55 mmol) of the title compound of Example 21e), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54.55 mol) of 1,4,7-tris(carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5-methyl-pent-5-y1)-1,4,7,10- tetraazacyclododecane, Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 16.88 g (81.8 mol) of N,N-dicyclohexylcarbodiimide is added, and it then is stirred overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18 mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 75.9 g (91.0% of theory) of a colorless solid.

Water content: 8.6%.

Elementary analysis (relative to anhydrous substance):

Cld.: C3534 H4.09 N8.24 S2.10 F21.12 Gd 10.28

Fnd.: C3528 H4.15 N8.19 S2.15 F21.03 Gd 10.14

Example 110 a) 6-N-Benzyloxycarbonyl-2-N-{1-O-a-D-carbonylmethyl-(2,3,4,6-tetra-O-benzyl glucopyranose]-L-lysine-[ 1-(4-perfluorooctylsulfonyl)-piperazine]-amide 41.27 g (200.0 mmol) of N,N-dicyclohexylcarbodiimide is added at 0°C to a solution that consists of 100.0 g (120.4 mol) of the title compound of Example 21c), 72.1 g (120.4 mol) of 1-O-a-D-carboxymethyl-2.3.4,6-tetra-O-benz yl-glucopyranose and 13.86 g (120.4 mol) of N-hydroxysuccinimide, dissolved in 500 ml of dimethylformamide. It is stirred for 3 hours at 0°C and then overnight at room temperature. Precipitated urea is filtered out, the filtrate is evaporated to the dry state in a vacuum, and it is chromatographed on silica gel. (Mobile solvent: dichloromethane/ethanol = 20:1).

Yield: 136.1 g (87% of theory) of a viscous oil.

Elementary analysis:

Cld.: C57.32 H4.89 N4.31 F24.86 S247

Fnd.: C57.48 H5.04 N4.20 F 24.69 S2.38 b) 2-N-[1-O-a-D-Carbonylmethylglucopyranose]-L-lysine-1-[(4- perfluorooctylsulfonyl)-piperazine]-amide 130.0 g (100.0 mmol) of the title compound of Example 110a) is dissolved in 2000 ml of ethanol, and 10.0 g of palladium catalyst (10% Pd/C) is added thereto. Itis hydrogenated for 12 hours at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

® @ Yield: 9.17 g (quantitative) of a colorless solid.

Elementary analysis:

Cld.: C34.07 H3.63 N6.11 S3.50 F35.24

Fnd.: C33.92 H3.71 N6.02 S3.42 F 35.33 c) 6-N-[1,4,7-Tris(carboxylatomethyl)]-1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-y1)]-2-N-[1-O-a-D-carbonylmethyl- glucopyranose}-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex 50.0 g (54.55 mmol) of the title compound of Example 110b), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54.55 mol) of 1,4,7-tris(carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5-methyl-pent-5- yl)-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 16.88 g (81.8 mol) of N,N- dicyclohexylcarbodiimide is added and then stirred overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18 mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 75.9 g (91.0% of theory) of a colorless solid.

Water content: 8.6%

Elementary analysis (relative to anhydrous substance):

Cld.: C3534 H4.09 N824 S210 F21.12 Gd 10.28

Fnd.: C3526 H4.18 N8.14 S2.158 F21.01 Gd 10.13 oO

Example 111 a) 6-N-Benzyloxycarbonyl-2-N-[1-O-a-D-carbonylmethyl-(2,3,4,6-tetra-O-benzyl- galactopyranose]-L-lysine-[1 ~(4-perfluorooctylsulfonyl)-piperazine]-amide 20.64 g (100.0 mmol) of N,N-dicyclohexylcarbodiimide is added at 0°Ctoa solution that consists of 50.0 g (60.2 mol) of the title compound of Example 21c), 36.05 ¢ (60.2 mmol) of 1-O-a-D-carboxymethyl-2,3,4,6-tetra-O-benzyl-galactopyranose and 6.93 g (60.2 mmol) of N-hydroxysuccinimide, dissolved in 500 ml of dimethylformarnide. It is stirred for 3 hours at 0°C and then overnight at room temperature. Precipitated urea is filtered out, the filtrate is evaporated to the dry state ina vacuum, and it is chromatographed on silica gel. (Mobile solvent: dichloromethane/ethanol = 20:1).

Yield: 68.1 g (87% of theory) of a viscous oil.

Elementary analysis:

Cld.: C57.32 H4.89 N4.31 F24.86 S2.47

Fnd.: C 57.47 H550 N4.19 F24.72 S2.29 b) 2-N-[1-O-a-D-Carbonylmethyl-galactopyranose]-L-lysine-1-[(4- perfluorooctylsulfonyl)-piperazine]-amide 65.0 g (50.0 mmol) of the title compound of Example 111a) is dissolved in 1000 ml of ethanol, and 5.0 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated for 12 hours at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

® ® Yield: 45.85 g (quantitative) of a colorless solid.

Elementary analysis:

Cid.: C34.07 H3.63 N6.11 S3.50 F3524

Fnd.: C33.93 H3.74 N6.01 S3.39 F35.05 c) 6-N-[1,4,7-Tris(carbox ylatomethyl)]-1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-0xo-5-methyl-5-y1)]}-2-N-[1-O-a-D-carbonylmethyl- galactopyranose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex 50.0 g (54.55 mmol) of the title compound of Example 111b), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 3435¢g (54.55 mol) of 1,4,7-tris(carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5-methyl-pent-3- yl)-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 16.88 g (81.8 mol) of N,N- dicyclohexylcarbodiimide is added, and it then is stirred overnight at room temperature.

Yield: 37.95 g (91.0% of theory) of a colorless solid.

Water content: 8.6%.

Elementary analysis (relative to anhydrous substance):

Cld.: C3534 H4.09 N 824 S2.10 F21.12 Gd 10.28

Fnd.: C3522 H4.17 N&8.18 S2.19 F 20.91 Gd 10.12

®o Oo

Example 112 a) N-Trifluoroacetyl-L-glutamic acid-mono-benzyl ester 100 g (421.5 mmol) of L-glutamic acid-mono-benzyl ester is dissolved in a mixture that consists of 1000 ml of trifluoroacetic acid ethyl ester/500 ml of ethanol, and it is stirred for 24 hours at room temperature. It is evaporated to the dry state, and the residue is crystallized from diisopropyl ether.

Yield: 140.47 g (96% of theory) of a colorless, crystalline powder.

Elementary analysis:

Cld.: C50.46 H4.23 F17.10 N4.20

Fnd.: C 51.35 H4.18 F17.03 N4.28 b) 2-N-Trifluoroacetyl-L-glutamic acid-mono-benzylester-5-N-(methyl)-N- (2,3,4,5,6-pentahydroxyhexyl)-amide 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is added at 0°C to a solution that consists of 24.9 g (24.08 mmol) of the title compound of Example 112a, 2x g (24.08 mmol) of N-methylglucamine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide. It is stirred for 3 hours at 0°C, then overnight at room temperature. Precipitated urea is filtered out, the filtrate is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: = dichloromethane/ethanol = 20:1).

Yield: 9.xx g (89% of theory) of a viscous oil.

Elementary analysis:

@ [J Cld.: C5143 HS.51 F 13.56 N6.66

Fnd.: C5122 H541 F 13.40 N6.75 c) N-Trifluoroacetyl-L-glutamic acid-N-(methy1)-N-(2,3,4,5,6-pentahydroxyhexyl)- amide 21.9xx g (52.15 mmol) of the title compound of Example 112b is dissolved in 500 ml of ethanol, and 3 g of palladium catalyst (10% Pd/C) is added. It is hydrogenated at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 43.0 g (quantitative) of a colorless solid.

Elementary analysis:

Cld.: C40.01 H5.19 F17.26 N 8.48

Fnd.: C39.84 H5.13 F 17.09 N 8.68 d) Trifluoroacetyl-L-glutamic acid-5-N-(methyl)-N-(2,3,4,5,6-pentahydroxyhexyl)- amide-[ 1-(4-perfluorooctylsulfonyl)-piperazine]-amidepiperazine]-amide 16.42 g (66.4 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) is added at 0°C to 10.96 g (33.2 mmol) of the title compound of Example 112c and 18.87 g (33.2 mmol) of 1-perfluorooctylsulfonyl-piperazine (produced according to DE 19603033) in 80 ml of tetrahydrofuran, and it is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

Yield: 28.67 g (92% of theory) of a colorless solid.

® ® Elementary analysis:

Cld.: C39.61 H2.89 F35.66 N6.19 §3.54

Fnd.: C 39.68 H2.74 F35.81 N6.13 §3.40 e) L-Glutamic acid-5-N-(methyl)-N-(2,3,4,5,6-pentahydroxyhexyl)-amide-[ 1-(4- perfluorooctylsulfonyl)-piperazine]-amide

Ammonia gas is introduced at 0°C for one hour into a solution that consists of 28.36 g (30.22 mmol) of the title compound of Example 112d in 200 ml of ethanol. It then is stirred for 4 hours at 0°C. It is evaporated to the dry state, and the residue is absorptively precipitated from water. The solid is filtered off and dried in a vacuum (50°C).

Yield: 24.19 g (95% of theory) of an amorphous solid.

Elementary analysis:

Cld.: C41.12 H2.89 F35.66 N6.19 S3.54

Fnd.: C41.15 H2.83 F35.78 N6.28 S3.71 ) N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane- 10-(pentanoyl- 3-aza-4-o0xo-5-methyl-5-yl)]-L-glutamic acid-5-N-(methyl)-N-(2,3,4,5,6- pentahydroxyhexyl)-amide-5-[ 1-(4-perfluorooctylsulfonyl)-piperazine}-amide, Gd complex 20.43 g (24.25 mmol) of the title compound of Example 112¢, 2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of lithium chloride and 15.27 g (24.25 mmol) of 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-5-methyl-3-yl)}-

® @...... acid]-1,4,7,10-tetraazacyclododecane, Gd complex are dissolved in 200 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 8.25 g (40 mmol) of N,N- dicyclohexylcarbodiimide is added and then stirred overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (silica gel RP-18, mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 28.45 g (79% of theory) of a colorless solid.

Water content: 11.0%

Elementary analysis (relative to anhydrous substance):

Cld.: C34.41 H3.83 F23.13 N9.03 S230 Gd11.26

Fnd.: C34.34 H3.98 F23.29 N9.19 S2.15 Gd 11.07

Example 113 a) 6-N-Benzyloxycarbonyl-2-N-[1-O-a-D-carbonylmethyl-(2,3,4-tri-O-benzyl- glucuronic acid-benzylester]-L-lysine-[1 (d-perfluorooctylsulfonyl)-piperazine]- amide 41.27 g (200.0 mmol) of N,N-dicyclohexyicarbodiimide is added at 0°C to a solution that consists of 100.0 g (120.4 mol) of the title compound of Example 21c), 73.77 g (120.4 mol) of 1-O-a-D-carboxymethyl-2,3,4-tri-O-benzyl-glucuronic acid- benzylester and 13.86 g (120.4 mol) of N-hvdroxysuccinimide, dissolved in 500 mi of dimethylformamide. It is stirred for 3 hours at 0°C and then overnight at room temperature. Precipitated urea is filtered out, the filtrate is evaporated to the dry state in a vacuum and chromatographed on silica gel.

WEUVIF 1949 ® ® (Mobile solvent: dichloromethane/ethanol = 20:1).

Yield: 147.58 g (86% of theory) of a viscous oil.

Elementary analysis:

Cld.: C52.25 H4.31 N3.93 F22.66 S245

Fnd.: C5238 H4.17 N 4.12 F 22.78 S 2.39 b) 2-N-[1-O-a-D-Carbonylmethyl-glucuronic acid]-L-lysine-1-[(4- perfluorooctylsulfonyl)-piperazine]-amide 142.52 g (100.0 mmol) of the title compound of Example 113a) is dissolved in 2000 ml of ethanol, and 10.0 g of palladium catalyst (10% Pd/C) is added thereto. Itis hydrogenated for 12 hours at room temperature. Catalyst is filtered out, and the filtrate 1s evaporated to the dry state in a vacuum.

Yield: 93.06 g (quantitative) of a colorless solid.

Elementary analysis:

Cld.: C33.56 H3.36 N6.02 S3.45 F34.71

Fnd.: C 33.31 H3.42N 6.04 S340 F 35.51 c) 6-N-[1,4,7-Tris(carboxylatomethyl)]-1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-y1)]-2-N-[1-O-a-D-carbonylmethyl- glucuronic acid]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex, sodium salt 50.76 g (34.55 mmol) of the title compound of Example 113b), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chioride and 34.35 g

® 9... mol) of 1,4,7-tris(carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5-methyl-pent-5- y1)-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 16.88 g (81.8 mol) of N,N- dicyclohexylcarbodiimide is added, and it then is stirred overnight at room temperature.

The solution is poured into 3000 ml of acetone, and it is stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18 mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 75.149 g (88.0% of theory) of a colorless solid.

Water content: 8.6%

Elementary analysis (relative to anhydrous substance):

Cld.: C34.53 H3.80 N8.05 Nal.47 S2.05 F20.63 Gd 10.05

Fnd.: C 34.38 H3.95 N&.19 Nal.63 S2.15 F 20.83 Gd 10.14

Example 114 a) 6-N-Benzyloxycarbonyl)-2-[2-(N-ethyl-N-perfluorooctylsulfonyl]-amino]-acetyl-

L-lysine 49.46 g (200.0 mmol) of EEDQ (2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester) is added at 0°C to 31.820 g (113.5 mmol) of 6-N-benzyloxycarbonyl)-L- lysine and 66.42 g (113.5 mmol) of 2-(N-ethyl-N-perfluorooctylsulfonyl)-aminoacetic acid (produced according to DE 196 03 033) in 300 ml of tetrahydrofuran, and it is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: dichloromethane/methanol = 20:1).

Yield: 55.79 g (58% of theory) of a colorless solid.

® ® Elementary analysis:

Cld.: C36.85 H3.09 N4.96 F38.11 S3.78

Fnd.: C36.85 H3.19 N 4.87 F3828 S395 b) 6-N-Benzyloxycarbonyl-2-N-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]- acetyl-L-lysine-N-methyl-N-(2,3,4,5,6-pentahydroxy-hexyl)-amide 20.64 g (100.0 mmol) of N,N-dicyclohexylcarbodiimide is added at 0°C to a solution that consists of 51.02 g (60.2 mol) of the title compound of Example 114a), 11.75 g (60.2 mol) of N-methyl-glucamine and 6.93 g (60.2 mol) of N- hydroxysuccinimide, dissolved in 250 ml of dimethylformamide. It is stirred for 3 hours at 0°C and then overnight at room temperature. Precipitated urea is filtered out, the filtrate is evaporated to the dry state in a vacuum, and it is chromatographed on silica gel. (Mobile solvent: dichloromethane/ethanol = 20:1).

Yield: 53.05 g (86% of theory) of a viscous oil.

Elementary analysis:

Cld.: C38.68 H4.03 N 5.47 F31.52 S3.13

Fnd.: C3849 H4.17 N 5.32 F31.70 S3.29 c) 2-N-[2-(N-Ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-L-lysine-N-methyl-N- (2,3,4,5,6-pentahydroxy-hexyl)-amide 102.48 g (100.0 mmol) of the title compound of Example 114b) is dissolved in 2000 ml of ethanol, and 10.0 g of palladium catalyst (10% Pd/C) is added thereto. It is

NU for 12 hours at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 89.06 g (quantitative) of a colorless solid.

Flementary analysis:

Cld.: C33.72 H3.96 N6.29 S 3.60 F 36.26

Fnd.: C3391 H3.82 N6.14 S3.47 F 36.31 d) 6-N-[1,4,7-Tris(carboxylatomethyl)]-1,4,7,10-tetraazacyclododecane-1 0-N- (pentanoyl-3-aza-4-0xo-5-methyl-5-y1)]-2-N-[2-(N-ethyl-N-perfluorooctyl- sulfonyl)-amino]-acetyl-L-lysine-N-methyl-N~(2,3,4,5,6-pentahydroxy-hexyl)- amide, Gd complex 48.58 g (54.55 mmol) of the title compound of Example 114), 6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of lithium chloride and 34.35 g (54.55 mol) of 1,4,7-tris(carboxylatomethyl)-10-(carboxy-3-aza-4-oxo-5-methyl-pent-5- yl)-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while being heated slightly. At 10°C, 16.88 g (81.8 mol) of N,N- dicyclohexylcarbodiimide is added and then stirred overnight at room temperature. The solution is poured into 3000 ml of acetone and stirred for 10 minutes. The precipitated solid is filtered off and then purified by chromatography (RP-18 mobile solvent: gradient that consists of water/ethanol/acetonitrile).

Yield: 73.27 g (89.4% of theory) of a colorless solid.

Water content: 8.6%

Elementary analysis (relative to anhydrous substance):

® ® Cid: C35.18 H4.23 N4.23 S21.3 F21.50 Gd 10.47

Fnd.: C35.28 H4.15 N4.19 S2.18 F21.33 Gd 10.61

® ©

Example 115: MRT-Visualization of arteriosclerotic plaque after intravenous administration of metal complexes according to the invention

In rabbits with genetically induced arteriosclerosis (Watanabe rabbits), it was possible to observe a significant enhancement in the arteriosclerotic plaque 5-60 minutes as well as 24 hours and 48 hours after intravenous administration of 25 pmol of Gd/kg of body weight of the compounds according to the invention in T,-weighted gradient-echo images (TR 11.1 ms, TE 4.3 ms, 15° flip angle a). The healthy vessel wall showed only little or no contrast medium image and therefore also indicated only little or no signal rise in the T1-weighted images. Based on the contrast between the plaque with strong signals and the healthy vessel wall with little or no signals, a diagnosis of the arteriosclerotic vessel wall changes was possible.

The pictures in Fig.1 show MR images of the aorta before, as well as 24 hours and 48 hours after intravenous administration of 25 umol of Gd/kg of body weight of metal complex XV in Watanabe rabbits (genetically induced arteriosclerosis). The T,-weighted gradient-echo images (1.5 T; TR: 11.1 ms, TE: 4.3 ms; NA: 2; matrix: 2137256; layer thickness: 1.0 mm) illustrate a strong signal rise in the arteriosclerotic plaque. The localization of the plaque, especially in aortic arches and in vascular passages, was confirmed by means of Sudan-III-staining.

® ©

Example 116: MRT-Visualization of arteriosclerotic plaque after intravenous administration of metal complex XV in rats, and correlation of the post mortem image with Sudan-IlI-staining

The pictures in Fig. 2 show MR images of the aorta before as well as 35 minutes, 60 minutes and 24 hours after intravenous administration of 10 pmol of Gd/kg of body weight of gadolinium metal complex XV in Watanabe rabbits (genetically induced arteriosclerosis). The T,-weighted gradient-echo-images (MPRage: 1.5T; TR: 11.1 ms,

TE: 4.3 ms; NA: 2; matrix: 2137256; layer thickness: 1.0 mm) illustrate a strong signal rise in arteriosclerotic plaque. The localization of the plaque, especially in aortic arches as well as in vascular passages, was confirmed by means of Sudan-Ill-staining. Then, the

MR-imaging of the agar-embedded preparation was again examined with a Ti-weighted gradient-echo sequence (MPRage; 1.5 T; TR 11.1 ms, TE 4.3 ms, 15° flip angle a; NA: 2; matrix: 2137256) and a spin-echo sequence (1.5 T; TR: 400 ms, TE: 15 ms; NA: 16; matrix: 256 256) (post mortem image). In this case, there was shown an excellent correlation of the aortic sections with strong signal rise and stained plaque, which confirms an uptake of the compounds according to the invention in the arteriosclerotic plaque.

_ ® 117: Infarction visualization (MRT) after intravenous administration of metal complex XV in rats

The pictures in Fig. 3 show MR images of the heart (in vivo and post mortem) 24 hours after intravenous administration of 100 pmol of Gd/kg of body weight of metal complex XV in rats with acutely induced myocardial infarction. The T-weighted spin- echo images (1.5 T: TR: 400 ms, TE: 6 ms; NA: 4; matrix: 128°128:; layer thickness: 2.5 mm) illustrate the strong signal rise in the infarction area. The successful induction of an acute myocardial infarction was confirmed by means of NBT-staining.

Metal complex XV, 100 umol/kg i.v.; T1-SE, TR/TE 400/6 ms; arrow: myocardial infarction.

Example 118: Infarction visualization (MRT) after intravenous administration of metal complex I in rats

The pictures in Fig. 4 show MR images of the heart (in vivo and post mortem) 24 hours after intravenous administration of 100 umol of Gd/kg of body weight of metal complex I in rats with acutely induced myocardial infarction. The T,-weighted spin-echo images (1.5 T; TR: 400 ms, TE: 6 ms; NA: 4; matrix: 128°128; layer thickness: 2.5 mm) illustrate the strong signal rise in the infarction area. The successful induction of an acute myocardial infarction was confirmed by means of NBT-staining.

® ©

Example 119: Lvmph node visualization (MRT) after intravenous administration of metal complex XV in VX2-tumor-carrving rabbits

The pictures in Fig. 5 show MR images of iliac lymph nodes precontrast and up to 24 hours after intravenous administration of 200 pmol of Gd/kg of body weight of metal complex XV in rabbits with VX2-tumors implanted i.m. The T,-weighted gradient-echo images (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, a 15°) illustrate the strong signal rise in healthy lymph node tissue. Zones without signal rise within the lymph node were diagnosed as metastases and confirmed histologically (H/E-staining of the lymph node section). Later (24 hours) after contrast medium administration, however, a signal reversal was observed, surprisingly enough. The signal rise in healthy lymph node tissue was reduced, while the metastasis now exhibited a considerable signal rise.

Surprisingly enough, even immediately after administration, a considerable enhancement of the primary tumor (especially the periphery) could be observed. Later (24 hours p.i.), this enhancement also propagates out from the center of the tumor.

© 0

Example 120: Tumor visualization (MRT) after intravenous administration of metal complex I in VX2-tumor-carrving rabbits

The pictures of Fig. 6 show MR images of an iliac lymph node and of a primary tumor (VX2-tumor implanted i.m.) precontrast, 60 minutes and 20 hours after intravenous administration of 100 pmol of Gd/kg of body weight of metal complex I in rabbits. The T;-weighted gradient-echo images (1.5 T; sequence: MPRange: TR 11.1 ms, TE 4.3 ms, a 15°) illustrate the strong signal rise in healthy lymph node tissue.

Shortly after administration (60 minutes p.i.), a considerable enhancement of the primary tumor (especially the periphery) can be observed. Subsequently (20 hours p.1.), the signal rise is also propagated in the more central region of the tumor.

The enhancement of a pathological structure (optionally secondary tumor or necrosis) on the contralateral side, which shows up only in late images ("late enhancement") is especially noteworthy.

® ® Complex X

Example 121: Infarction visualization (MRT) after intravenous administration of the contrast medium in rats

The pictures in Fig. 7 show MR images of the heart (in vivo and post mortem) 6 hours after intravenous administration of 100 pmol of Gd/kg of body weight of a polar

Gd-chelate with perfluorinated side chains (metal complex X) in rats with acutely induced myocardial infarction. The T,-weighted, EK G-triggered spin-echo images (1.5

T; TR (effective): 400 ms, TE: 12 ms; NA: 4; matrix: 1287128; layer thickness: 2.5 mm) illustrate the strong signal rise in the infarction area. The successful induction of an acute myocardial infarction was confirmed by means of NBT-staining.

©

Example 122: Organ distribution (including lymph node concentration) after intravenous administration of the contrast medium in rats

After intravenous administration of 100 umol of total gadolinium/kg of body weight of a polar Gd-chelate with perfluorinated side chains (metal complex X) in rats, the metal content in various organs as well as in the lymph nodes (pooled as mesenteric and peripheral lymph nodes) was determined 24 hours after administration (MW, n=2).

I EY SE ETS wee om nodes nodes

EE EE ET

® ® 123: Lymph node visualization (MRT) after intravenous administration of the contrast medium in rats

By way of example, the pictures in Fig. 8 show MR images of iliac lymph nodes precontrast and up to 60 minutes after intravenous administration of 100 pmol of Gd/kg of body weight of metal complex X in rats. The T,-weighted gradient-echo images (1.3

T: sequence: MPRange; TR 11.1 ms, TE 4.3 ms. a 15°) illustrate the strong signal rise in healthy lymph node tissue even very shortly after injection. The enhancement was thus 263% at the time of 13 minutes p.i. and 254% at the time of 60 minutes p.i.

Example 124: Lymph node visualization (MRT) after intravenous administration of the contrast medium in VX2-tumor-bearing rabbits

By way of example, the pictures in Fig. 9 show MR images of iliac lymph nodes precontrast and up to 60 minutes after intravenous administration of 200 pmol of Gd/kg of body weight of metal complex X in rabbits with VX2-tumors implanted i.m. The T- weighted gradient-echo images (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, a 15°) illustrate the strong signal rise in healthy lymph node tissue. The enhancement in the healthy lymph node tissue was 382% at the time of 15 minutes p.i. and 419% at the time of 60 minutes p.i. Zones without signal rise within the lymph node were diagnosed as metastases and confirmed histologically (H/E-staining of the lymph node section).

The ratio of signal intensities of healthy lymph node tissue to metastasis was 3.0 at the time of 15 minutes p.i. and 3.4 at the time of 60 minutes p.1.

Surprisingly enough, even immediately after administration, a considerable enhancement not only of the lvmph nodes but also of the primary tumor (especially the periphery) could be observed (15 minutes p.i.: 277%). Later (up to 24 hours p.i.), this enhancement also propagates out from the center of the tumor (24 hours p.i.: 217%).

® od Metal Complex V

Example 125: Infarction visualization (MRT) after intravenous administration of the contrast medium in rats

The pictures in Fig. 10 show MR images of the heart (in vivo and post mortem) 24 hours after intravenous administration of 100 pmol of Gd'kg of body weight of a polar

Gd-chelate with perfluorinated side chains (metal complex V) in rats with acutely induced myocardial infarction. The T;-weighted, EKG-triggered spin-echo images (1.5

Example 126: Organ distribution (including lymph node concentration) after intravenous administration of the contrast medium in rats

After intravenous administration of 200 pmol of total gadolinium/kg of body weight of a polar Gd-chelate with perfluorinated side chains (metal complex V) in rats, the metal content in various organs as well as in the lymph nodes (pooled as mesenteric and peripheral lymph nodes) was determined 24 hours after administration (MW, n=2).

oO

TS EE SE CA nodes nodes wT we

Example 127: Lymph node visualization (MRT) after intravenous administration of the contrast medium in rats

By way of example, the pictures in Fig. 11 show MR images of iliac lymph nodes precontrast and up to 60 minutes after intravenous administration of 200 ymol of Gd’kg of body weight of metal complex V in rats. The T)-weighted gradient-echo images (1.5

T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, a 15°) illustrate the strong signal rise in healthy lymph node tissue even very shortly after injection. The enhancement was thus 147% at the time of 135 minutes p.i. and 230% at the time of 60 minutes p.i.

oO

Example 128: Lymph node visualization (MRT) after intravenous administration of the contrast medium in VX2-tumor-bearing rabbits

By way of example, the pictures in Fig. 12 show MR images of iliac lymph nodes precontrast and up to 60 minutes after intravenous administration of 200 pmol of Gd/kg of body weight of metal complex V in rabbits with VX2-tumors implanted i.m. The T- weighted gradient-echo images (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, a 15°) illustrate the strong signal rise in healthy lymph node tissue. The enhancement in the healthy lymph node tissue was 246% at the time of 15 minutes p.i. and 282% at the time of 60 minutes p.i. Zones without signal rise within the lymph node were diagnosed as metastases and confirmed histologically (H/E-staining of the lymph node section).

The ratio of signal intensities of healthy lymph node tissue to metastasis was 2.5 at the time of 15 minutes p.i. and 1.7 at the time of 60 minutes p.1.

Surprisingly enough, even immediately after administration, a considerable enhancement not only of the lymph nodes but also of the primary tumor (especially the periphery) could be observed (15 minutes p.i.: 350%). Later (up to 24 hours p.1.), this enhancement also propagates out from the center of the tumor (24 hours p.i.: 106%).

® ® Complex XIV

Example 129: Infarction visualization (MRT) after intravenous administration of the contrast medium in rats

The pictures in Fig. 13 show MR images of the heart (in vivo and post mortem) 3 hours after intravenous administration of 100 pmol of Gd/kg of body weight of a polar

Gd-chelate with perfluorinated side chains (metal complex XIV) in rats with acutely induced myocardial infarction. The T-weighted, EK G-triggered spin-echo images (1.3

Example 130: Organ distribution (including tumor and lymph node concentration) after intravenous administration of the contrast medium in prostate-cancer-bearing rats

After intravenous administration of 200 pmol of total gadolinium/kg of body weight of a polar Gd-chelate with perfluorinated side chains (metal complex XIV) in rats (Cop-inbreeding with Dunning R3327 MAT-Lu prostate cancer i.m.-implanted 12 days earlier), the metal content in various organs, in tumors, as well as in the lymph nodes (pooled as mesenteric and peripheral lymph nodes) was determined 10 minutes, 1 hour and 24 hours after administration (MW = SD, n=3).

Metallkomplex XIV

Gd-Konzentration [umoill] % Dosis 10min p.i. 1h p.i. 24h p.i. 10min p.i. 1h p.i. 24h p.i.

Leber 192 + 12 | 147 + 7 | 64 + 4 262 + 011204 + 015|096 + 0.05

Miiz 200 + 13 {123 + 10 | 639 + 5 | 043 % 001] 008 + 0.01{006 + 0.00

Pankreas 191 + 14 {139 + 26 | 25 + 1 |035 + 002] 021 £ 005003 x 0.01

Niere 761 + 60 [1181 + 232 | 338 + 49 [176 + 0.14] 284 + 061] 081 x 0.09

Lunge 603 + 30 | 415 + 39 | 44 + 4 [104 z 002080 + 0.06] 0.09 + 0.01

Herz 320 + 8 | 190 + 15 | 19 £ 0 032 t 001]019 + 001]0.02 + 000

Gehirn 3B + 6 | 2 + 2 4 + 4 010 + 003006 + 000] 001 0.01

Muskel™* 93 + 5 | 56 + 3 8 + 1 |Jo006 + 002]004 = 000000 + 000

Tumor 246 + 25 | 266 £ 87 | 56 = 4 J025 x 0.05] 037 + 0140.04 = 001

Femur 115 + 3 [81 + 10 | 9 + 1 039 + 002028 + 003]003 £ 000 mes. LK 291 + 29 [179 + 16 | 50 + 6 {008 + 001]005 x 001]002 ££ 0.00 periph. LK 284 + 19 | 254 + 14 | 51 + 5 | 013 % 000] 014 = 0020.02 £ 000

Magen (entleert) | 244 + 17 165 + 21 19 + 2 056 + 007) 040 + 0.05] 0.05 t 0.00

Darm (entleert) | 242 + 15 | 201 + 32 | 36 + 5 | 155 t 009] 1.16 = 022] 026 + 0.04

Blut ** 957 + 38 | 575 t 56 | 22 + 1 {2673 t+ 0.84 16.13 + 1.77 | 0.61 t 003

Restkorper * 419 + 27 [392 + 25 | 42 + 0 {707% + 2746427 + 550] 6.81 + 0.16

Faeces 0-24 h 781 + 611 6.00 + 4.91 80.06 + 2.84 |72.94 + 583] 9.21 + 027 mane] |] Jesor x 241] * Blutproben sind im Restkdrper enthalten + 58m Blutkg KGW + Bilanz ohne Blutwerte, da diese im Restkérper enthalten -*** nur Gewebealiquot [Key to Table:]

Metallkomplex XIV = Metal complex XIV

Gd-Konzentration [pmol/l] = Gd concentration [umol/l] % Dosis = % Dose

Leber = Liver

Milz = Spleen

Pankreas = Pancreas

Niere = Kidney

Lunge = Lung

Herz = Heart

Gehim = Brain iy | 0371949 ® ® = Muscle”

Tumor = Tumor

Femur = Femur mes. LK = Mesenteric lymph nodes periph. LK = Peripheral lymph nodes

Magen (entleert) = Stomach (empty)

Darm (entleert) = Intestine (empty)

Blut” = Blood”

Restkorper = The remainder of the body’

Harn 0-24 h = Urine 0-24 hours

Faeces 0-24 h = Feces 0-24 hours

Summe der Organe™ = Sum of the organs

Bilanz' ~~ = Balance” "Blutproben sind im Restkorper enthalten = Blood samples are contained in the remainder of the body "583ml Blut/kg KGW = 58 ml of blood/kg of body weight ***Bilanz ohne Blutwerte, da diese im Restkorper enthalten = Balance without blood values, since the latter [are] contained in the remainder of the body “nur Gewebealiquot = Only tissue aliquot

® ©

Example 131: Lymph node visualization (MRT) after intravenous administration of the contrast medium in guinea pigs

By way of example, the pictures in Fig. 14 show MR images of iliac and inguinal lymph nodes precontrast and up to 24 hours after intravenous administration of 200 pmol of Gd/kg of body weight of metal complex XIV in guinea pigs with stimulated lymph nodes (Freund adjuvant). The T,-weighted gradient-echo images (2.0 T; TR 10 ms, TE 5 ms, a 40°) illustrate the strong signal rise in healthy lymph node tissue even very shortly after injection. The enhancement was 127% at the time of 60 minutes p.i.

® ©

Example 132: Lymph node visualization (MRT) after intravenous administration of the contrast medium in VX2-t-tumor- bearing rabbits

By way of example, the pictures in Fig. 15 show MR images of iliac lymph nodes precontrast and up to 23 hours after intravenous administration of 200 umol of Gd/kg of body weight of metal complex XIV in rabbits with VX2-tumors implanted i.m. The T;- weighted gradient-echo images (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, a 15°) illustrate the strong signal rise in healthy lymph node tissue. The enhancement in the healthy lymph node tissue was 297% at the time of 10 minutes p.i. and 269% at the time of 60 minutes p.i. Zones without signal rise within the lymph node were diagnosed as metastases and confirmed histologically (H/E-staining of the lymph node section).

The ratio of signal intensities of healthy lymph node tissue to metastasis was 5.1 at the time of 10 minutes p.1. and 1.9 at the time of 60 minutes p.i.

Surprisingly enough, even immediately after administration, a considerable enhancement not only of the lymph nodes but also of the primary tumor (especially the periphery) could be observed (15 minutes p.i.: 594%). Later (up to 24 hours p.i.), this enhancement also propagates out from the center of the tumor (120 hours p.i.: 162%).

Metal Complex III

Example 133: Infarction visualization (MRT) after intravenous administration of the contrast medium in rats

The pictures in Fig. 16 show MR images of the heart (in vivo and post mortem) 22 hours after intravenous administration of 100 umol of Gd/kg of body weight of a polar

Gd-chelate with perfluorinated side chains (metal complex III) in rats with acutely induced myocardial infarction. The T,-weighted, EKG-triggered spin-echo images (1.5

Example 134: Organ distribution (including lymph node concentration) after : intravenous administration of the contrast medium in rats

After intravenous administration of 200 umol of total gadolinium/kg of body weight of a polar Gd-chelate with perfluorinated side chains (metal complex III) in rats, the metal content in various organs as well as in the lymph nodes (pooled as mesenteric and peripheral lymph nodes) was determined 24 hours after administration (MW, n=2).

¢ O

ITE IE EE SR nodes nodes

I EE EE RC

Example 135: Lymph node visualization (MRT) after intravenous administration of the contrast medium in rats

By way of example, the pictures in Fig. 17 show MR images of iliac lymph nodes precontrast and up to 60 minutes after intravenous administration of 200 umol of Gd’kg of body weight of metal complex III in rats. The T,-weighted gradient-echo images (1.5

T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, a 15°) illustrate the strong signal rise in

® ® healthy lvmph node tissue even very shortly after injection. The enhancement was thus 320% at the time of 15 minutes p.i. and 401% at the time of 60 minutes p.i.

Example 136: Lymph node visualization (MRT) after intravenous administration of the contrast medium in VX2-tumor-bearing rabbits

By way of example, the pictures in Fig. 18 show MR images of iliac lymph nodes precontrast and up to 60 minutes after intravenous administration of 200 pmol of Gd/kg of body weight of metal complex III in rabbits with VX2-tumors implanted i.m. The T)- weighted gradient-echo images (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, a 15°) illustrate the strong signal rise in healthy lymph node tissue. The enhancement in the healthy lymph node tissue was 195% at the time of 15 minutes p.i. and 233% at the time of 60 minutes p.1. Zones without signal rise within the lymph node were diagnosed as metastases and confirmed histologically (FH/E-staining of the lymph node section).

The ratio of signal intensities of healthy lymph node tissue to metastasis was 1.9 at the time of 15 minutes p.i. and 1.8 at the time of 60 minutes p.i.

Surprisingly enough, even immediately after administration, a considerable enhancement not only of the lymph nodes but also of the primary tumor (especially the periphery) could be observed (15 minutes p.i.: 232%).

Claims

® ® Claims

1. Use of perfluoroalkyl-containing metal complexes that have a critical micelle formation concentration < 10” mol/l, a hydrodynamic micelle diameter (2Rh)> 1 nm and a proton relaxivity in plasma (RY > 10 I/mmol's as contrast media in MR imaging for visualization of plaque.

2. Use according to claim 1, characterized in that the metal complexes are also used as MRI contrast media for visualization of lymph nodes.

3. Use according to claim 1 or 2, wherein the metal complexes are also used as MRI contrast media for visualization of infarcted and necrotic tissue.

4. Use according to one of claims 1 to 3, wherein the metal complexes are also used as MRI contrast media for independent visualization of necroses and tumors.

5. Use according to claim 1, wherein metal complexes whose micelle formation concentration is < 10™ mol/l are used.

6. Use according to claim 1, wherein metal complexes whose hydrodynamic micelle diameter is > 3, preferably > 4 nm, are used.

7. Use according to claim 1, wherein metal complexes that have a proton relaxivity in plasma of > 13 I/mmol's, preferably > 15 /mmol's, are used.

8. Use according to one of claims 1 to 7, wherein as perfluoroalkyl-containing metal complexes, the compounds of general formula I RF-L-K I in which RF is a perfluorinated, straight-chain or branched carbon chain with formula -CyFoE, in which E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n stands for numbers 4-30, L means a direct bond, a methylene group, an -NHCO group, a group

PCT/EP01/08498

» . 2 ~feons,—(cy Ne SO,— q whereby p means the numbers 0 to 10, and q and u, independently of one another, mean numbers Oorl, and oo CR isa hydrogen atom, a methyl group, a ~-CHz-OH group, a -CH,-

CO.H group or a Ca-C)s chain, which optionally is interrupted by 1 ~~ to 3 oxygen atoms, 1 to 2 >CO groups or an optionally substituted g aryl group and/or is substituted with 1 to 4 hydroxyl groups, 1 to 2 C1-Cy alkoxy groups, 1 to 2 carboxy groups, a group -SO3H-, or is a straight-chain, branched, saturated or unsaturated C2-Cj30 carbon chain, which optionally contains 1 to 10 oxygen atoms, 1 to 3'NR? groups, 1 to 2 sulfur atoms, a piperazine, a -CONR? group, an -NR*CO group, an -SO; group, an -NR*-CO; group, 1 to 2 CO groups, a group —CO—N—T—NR®R*»—s50,—RF y : oo or 1 to 2 optionally substituted aryls and/or is interrupted by these groups and/or is optionally substituted with 1to 3 -OR* groups, 1 to 2 oxo groups, I to 2 -NH-COR" groups, 1 to 2 -CONHR" groups, 1 to 2 (CHy),-CO:H groups, 1 to 2 groups +(CH,),-(0)q-CH2CH,-R”, . whereby oo RY R’ and p and q have the above-indicated meanings, and AMENDED SHEET :

PCT/EP01/08498

T means a C>-Cyg chain, which optionally is interrupted by 1 to 2 oxygen atoms or 1 to 2 -NHCO groups, K stands for a complexing agent or metal complex or their salts of organic and/or inorganic bases or amino acids or amino acid amides, specifically for a complexing agent or complex of general formula II . . ,CH,CH, D — he - /~CO0—N N ‘ce : COR’ : N R o=(c Ng co R’ 1 / . OR N : cos (1) in which R%, R' and B are independent of one another, and R® has the meaning of R? or means «CHz)m-L-RF, whereby m is 0, 1 or 2, and L and Rf have the above-mentioned meaning, : R!, independently of one another, mean a hydrogen atom or a metal ion equivalent of atomic numbers 22-29, 42-46 or 5 8-70, B means -OR' or : : CH,CH—LR" TN —N 3 oder —N N-SO,-L-Rf NN; - vo R™ [or] — whereby R', L, RF and R have the above-mentioned meanings, or AMENDED SHEET :

PCT/EP01/08498

@ a K stands for 2 complexing agent or complex of general formula III 1 3 ya COZ 3 ; 1 Re ( N— CO,Z . _ N com CH, CH; N coz! o (TF N p- coz’ (In in which RE and R' have the above-mentioned meanings and R® has the meaning of R* . or | - K stands for a complexing agent or complex of general formula IV R'0,C a LR lo) A CO,R' » N —2 CO / COR’ "_ COR’ =v) in which R' has the above-mentioned meaning or AMENDED SHEET

PCT/EPO1/08498 ® 328 K stands for a2 complexing agent or complex of general formula V . : am CO, rl ( co, Rl Rlo,c — (CHa), — co,r! _~N (CH), \ co, .rl in which R' has the above-mentioned meaning, and 0 and q stand for number 0 or 1, and yields the sumo +q = 1, : : or’ K stands for a complexing agent or complex of general formula VI Rloc—\ ,/\ co,rl ¢ ~~ N N Ny C= co,Rl ~~ CO,rl oD in which R' has the above-mentioned meaning or : ’ AMENDED SHEET

PCT/EPO1/08498

K stands for a complexing agent or complex of general formula VII rlo,Cc / \7co.r! , J ( \ / CO-B cog! (VI) in which R' and B have the above-mentioned meanings or K stands for a complexing agent or complex of general formula VIII rl1O,C /—co,r! / \ 2 C Bb o} N N oo \ , N— CHCHy = ( Rb Cc COR! R : (VIII) in which R* and R! have the above-mentioned meanings, and R® has the above-mentioned meaning of R? or cee : AMENDED SHEET

PCT/EP01/08498

® - K stands for a complexing agent or complex of general formula [X ROC SN co, 5 C B | OH OF rN co, rl RG > | : in which R® and R! have the above-mentioned meanings, or | : : K stands for a complexing agent or complex of general formula X rl ON \ 7 co, i C BD OH . ¢ — RC Corl 0:9) . in which R® and R! have the above-mentioned meanings, or K stands for a complexing agent or complex of general formula XI RLO,C—\ /\ —COpRl N N C7) os N nN | 0 Ig NN pcr cin coe Coal NC SO, —— AW } in which R/, p and q have the above-mentioned meanings, and R® has the meaning of R?, AMENDED SHEET or K stands for a complexing agent or complex of general formula XII co __ pas N N—SO N NN ’ { coz Nn —co,Z' 0 — cn N—SO0_-L-R" N _/ : ‘coz (XII) in which L, RF and 7! have the above-mentioned meanings, or K stands for a complexing agent or complex of general formula XIII TT co, z' ( ~— cq, Z’ TN { C0, 2" N ~— co, z' (XIID in which R! has the above-mentioned meaning, are used.

9. Use according to claim 8, wherein the compounds of general formula I, in which L stands for : o-CH»y-f a-CHyCHy-B a-(CHp)s-B s= 3-15 a-CHp-O-CHCH»-B

® ® a-CHy-(O-CHy>-CHy-}4-p t= 2-6 a-CHy-NH-CO-8 a-CHp-NH-CO-CH,-N(CH2COOH)-SO5-B a-CHp-NH-CO-CHy-N(C7Hj5)-S05- a-CH-NH-CO-CH2-N(C1oH21)-SO5-B a-CH3-NH-CO-CH3-N(CgH{3)-SO9-B a-CHp-NH-CO-(CH2)1(-N(C7H5)-SO»-B a-CHp-NH-CO-CH3-N(-CH2-CgH5)-SO2-B a-CHp-NH-CO-CH,-N(-CHy-CH-OH)SO5-B : a-CH-NHCO-(CH»)1¢-S-CH2CH»-f a-CHoNHCOCH»-0-CH,CH»-f a-CHpNHCO(CH3)10-0-CHyCHy-B a-CHy-CgHy-O-CH,CH>-B a-CHp-0-CHp-C(CH2-OCHCHp-CgF 3)2-CH>-OCH»-CH)-B a-CHp-NHCOCHCHyCON-CHCHpNHCOCHN(C>oH5)S0O-CgF 17 CH,-CH,NHCOCH,N(C,H,)-S0,-p a-CH»-0-CHy-CH(OCgH31)-CH-O-CHCHy-8 a-(CHpNHCO)4-CH70O-CH2CHy-B a-(CHpNHCO)3-CHyO-CH,CH»-B a-CHp-OCH,C(CH,OH)-CH,-O-CHyCH-B — CH;— 0" '~CH,—0 — CH, —CH,— COOH (Please insert a and [3 here in this formula, we cannot access the formula! a-CHpNHCOCHN(CgH5)-SO7-B a-NHCO-CH,-CHy-B a-NHCO-CH7-O-CHCH»-B a-NH-CO-B a-NH-CO-CH3-N(CH,COOH)-SO>-B a-NH-CO-CHy-N(CyHs)-S09-p a-NH-CO-CH-N(C1gHp1)-SO»-8 a-NH-CO-CHp-N(CgHj3)-S02-8 a-NH-CO-(CH3)10-N(CoH5)-S02-B

® ® a-NH-CO-CHy-N(-CH3-CgHs5)-S05-B a-NH-CO-CH7-N(-CH>-CH;,-OH)SO»-B a-NH-CO-CH»-B : a-CHp-0-CgHy4-0-CH-CH)-B a-CHp-CgHy-0-CHy-CH)-B a-N(C2H;5)-SO2-B a-N(CgHs)-SO2-B a-N(C1oH21)-S02-B a-N(CgH13)-SO2-B a-N(CoH4OH)-S0O5-B8 a-N(CHpCOOH)-S0»-B a-N(CHCgHs)-SOo-B a-N-[CH(CH,0H);]-S05-B o-N-[CH(CH2OH)CH(CH,OH)]-SO5- and in which a represents the binding site to the complexing agent or metal complex K, and P represents the binding site to the fluorine radical, are used.

10. Use according to claim 8 or 9, wherein the compounds of formula I in which n in formula -C,F,,E stands for numbers 4-15 and/or E in this formula means a fluorine atom are used.

11. Use according to one of claims 8 to 10, wherein the following compounds are used: -- Gadolinium complex of 10-[1-methyl-2-0x0-3-aza-5-0x0-{4- perfluorooctylsulfonyl-piperazin-1-yl} -pentyl]-1,4,7-tris(carboxymethyl)- 1,4,7,10-tetraazacyclododecane, -- Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo0-7-oxa- 10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17- heptadecafluoroheptadecyl]-1 ,4,7-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecane,

® ® -- Gadolinium complex of 10-[2-hydroxy-4-aza-3,9-dioxo-9-{4- perfluorooctyl)-piperazin-1-yl}-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecane, - Gadolinium complex of 10-[2-hydroxy-4-aza-5-0x0-7-aza-7- (perfluorooctyl-sulfonyl)-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecane, -- Gadolinium complex of 10-[2-hydroxy-4-oxa- 1H,1H,2H,2H,3H,3H,5H,5H,6H,6H-perfluorotetradecyl]-1,4,7- tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, -- Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo0-7-0xa- 10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17,18,18,19,19- henicosafluoro-nonadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecane, -- Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-11-aza-11- (perfluorooctylsulfonyl)-tridecyl]-1,4,7-tris(carboxymethyl) 1,4,7,10- tetraazacyclododecane, -- Gadolinium complex of 10-[2-hydroxy-4-aza-5-0xo0-7-aza-7- (perfluorooctylsulfonyl)-8-phenyl-octyl]-1,4,7-tris(carboxymethyl)- 1,4,7,10-tetraaza-cyclododecane.

12. Use according to one of claims 1-7, wherein as perfluoroalkyl-containing metal complexes, the compounds of general formula Ia A-RF (Ia) in which

. A is a molecule portion that contains 2 to 6 metal complexes, which are bonded directly or via a linker to a nitrogen atom of an annular skeleton chain, : and

PCT/EP01/08498 ® 335 . RF is a perfluorinated, straight-chain or branched carbon chain with formula -C,Fa,E, in which : E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, . and n stands for numbers 4-30, whereby molecule portion A has the following structure: K oo | So : IR K—v—=N N-Dp =X — v ql Be whereby . q'isanumber0,1,2 or 3, . K stands for a complexing agent or metal complex or their salts of organic and/or inorganic bases or amino acids or amino acid amides, . X is a direct bond to the perfluoroalkyl group, a phenylene group or a C;- Cio-alkylene chain, which optionally contains 1-15 oxygen atoms, 1-5 : sulfur atoms, 1-10 carbonyl groups, 1-10 (NRY) groups, 1-2 NRYs0, groups, 1-10 CONRY groups, 1 piperidine group, 1-3 SO: groups and 1-2 phenylene groups or optionally is substituted by 1-3 radicals RF, in which R? stands for a hydrogen atom, a phenyl group, benzyl group ora C,-C;s- alkyl group, which optionally contains 1-2 NHCO groups, 1-2 CO groups, ; 1-5 oxygen atoms and optionally is substituted by 1-3 Hydroxy, 1-5 methoxy, 1-3 carboxy, or 1-3 RF radicals, : : AMENDED SHEET :

i PCT/EP01/08498 C 336 . V is a direct bond or a chain of general formula [Ia or IIIa: Oo B RCHa) —(W),—(CH,),—C—aqa Re (Ila) Poii-CHyC- ) o ~ H H 1 o (CHa cH RH (1a) in which Risa hydrogen atom, a pheny! group, a benzyl group or a C;-C-alkyl group, which optionally is substituted with a carboxy group, a methoxy group or a hydroxy group, un W is a direct bond, a polyglycol ether group with up to 5 glycol units, or a molecule portion of general formula IVa -CHR")- (IVa) in which R" is a C;-C;-carboxylic acid, a phenyl group, a benzyl group or a -(CH,),.s-NH-K group, = a represents the binding to the nitrogen atom of the skeleton chain, B : represents the binding to complexing agents or metal complex K, BM and in which variables k and m stand for natural numbers between 0 and oo .10, and | stands for O or 1, and whereby Co « DisaCO or SO; group, AMENDED SHEET :

are used.

13. Use according to claim 12, wherein the compounds of general formula Ia in which q is the number 1 are used.

14. Use according to claim 12, wherein the compounds of general formula Ia, in which molecule portion X is an alkylene chain, which contains 1-10 CH,CH,O groups or 1-5 COCH;NH groups, a direct bond or one of the following structures Q CoH y “CH,-O-(CH,),—~§ . “CH N-80;3 , 7~(CH,),;-N-C —CH,-N-S0, —5 : C,H, H y ~(CH)10-O-(CH,),— 5 , Gk y —CHN-8O;~5 . y— CH N-SO;s . 7 CHyN-SO,—5 Po NN C. H CoH, 10° "21 Sy CSO; CH,—. | Vi whereby y binds to D, and § binds to RF, are used.

15. Use according to claim 12, wherein the compounds of general formula Ia, in which V is a molecule portion with one of the following structures

PCT/EPO1/08498 ® ; ? a—C-CH,-NH-B , a— C-CH,-N- B , CH,COOH : 0 Ie i il a= £-GH —NH—8 , o—C ~CH-NH— B CH, - CH(CH,), 0 fooH 0 (HCOOH . @—C-CH,-CH-NH-B , @=C-CH,-CH-NH-p , ae a—C-CH-NH-p } | : (CH,)-NH-K ’ : are used.

16. Use according to claim 12, wherein the compounds of general formula Ia, in . which K represents a complex of general formula Va, Vla, VIIa or VIIa, : Ry coor! | ; 8 : N R :

rR. ( NR—U3-T--- D N N Rlooc LC N 0% fo) :

IN. (Va) AMENDED SHEET

PCT/EP01/08498 o Rp coor 1 N RB RR 4 U3 Io >—N N Trees ROOC oo C No OH

A 1. R COOR (Via) oo B COOR! N“ coor! oo Pi I OO GH oo ( [—COOoR? COOR | (VIIa)

O . Rlooe—) 1] YY COOR! : rRiooc__] L COOR! (Via) - whereby . R!, independently of one another, are a hydrogen atom or a metal jon equivalent of the elements of atomic numbers 25-29, 42-46 or 58-70, . Rlisa hydrogen atom or a straight-chain, branched, saturated or : unsaturated C;-Cyq-alkyl chain, which optionally is substituted by 1-3 hydroxy, 1-3 carboxy or 1 phenyl group(s) and/or optionally is interrupted by 1-10 oxygen atoms, 1 phenylene group or 1 phenylenoxy group, AMENDED SHEET oo hd ® . Réisa hydrogen atom, a straight-chain or branched C;-C;-alkyl radical, a phenyl radical or benzyl radical, . R’ is a hydrogen atom, a methyl group or ethyl group, which optionally is substituted by a hydroxy group or carboxy group, Se Visa straight-chain, branched, saturated or unsaturated C;-Cyp-alkylene group optionally containing 1-5 imino groups, 1-3 phenylene groups, 1-3 phenylenoxy groups, 1-3 phenylenimino groups, 1-5 amide groups, 1-2 hydrazide groups, 1-5 carbonyl! groups, 1-5 ethylenoxy groups, 1 urea group, 1 thiourea group, 1-2 carboxyalkylimino groups, 1-2 ester groups, 1-10 oxygen atoms, 1-5 sulfur atoms and/or 1-5 nitrogen atoms, and/or optionally substituted by 1-5 hydroxy groups, 1-2 mercapto groups, 1-5 0x0 groups, 1-5 thioxo groups, 1-3 carboxy groups, 1-5 carboxyalkyl ~ groups, 1-5 ester groups and/or 1-3 amino groups, whereby the optionally contained phenylene groups can be substituted by 1-2 carboxy groups, 1-2 sulfone groups or 1-2 hydroxy groups . T! stands for a -CO-B, -NHCO-8 or _NHCS-p group, whereby B represents the binding site to V, are used.

17. Use according to claim 16, wherein the C;-Cjj-alkylene chain that stands for U? contains the groups -CH,NHCO-, -NHCOCH,O0-, -NHCOCH,0C¢Ha-, -(CH,CO,H)-, -CH,OCHz-, -NHCOCH;C¢Hs-, -NHCSNHC¢Hy-, -CH,0C4Hy-, -CH,CH,0- and/or is substituted by the groups -COOH and -CH,COOH.

18. Use according to claim 16, wherein U° stands for a -CH;-, -CH,CH;-, -CH,CH,CH;-, -C¢Ha-, -C6H o-, -CH,CeHa-, -CHNHCOCH,CH(CH,CO;H)-C4Ha-, -CH;NHCOCH,OCHj-, or -CH,NHCOCH;C4Hy- group.

19. Use according to claim 12, wherein the compounds of general formula Ia, in which K has one of the following structures:

COOR* a ( ™ CH, ) R*00C 7 N-~-"C-... — C--- R‘00C Sg NY S ER N v N O ‘ COOR* \ R coc] coor COOR* B COOR* Sasa N TN COOR* N N } 4 NC ---- r‘ooc” | NT Lo NT Co--- | (N.S © [ees L 4 N COOR coor 000K’ 0) 0 NY i. 0. 'e oe woe” NN NYT R'O0C NS t on COOR* are used.

20. Use according to one of claims 12 to 19, wherein the compounds of general formula Ia in which the perfluoroalkyl chain RF is -C¢F13, -CsF 17, -C oF; or -C oF are used.

-. ® 342 PCT/EPO1/08498

21. Use according to one of claims 12 to 20, wherein the gadolinium complex of 1,4,7-tris{1,4.7-tris(N~(carboxylatomethy!)- 1 0-[N- 1 -methyl-3,6-diaza-2,5, 8-triox ooctane- 1,8-diyl)]-1,4,7,10-tetraazacyclododecane, Gd complex }-10-[N-2H,2H,4H,4H,5H,5H-3- oxa-perfluoro-tridecanoyl]-1,4,7, 10-tetraazacyclododecane is used.

22. Use according to one of claims 1 to 7, wherein as perfluoroalkyl-containing metal complexes, the compounds of general formula Ib a K—N—LLR" (Ib) in which K means a complexing agent or a metal complex of general formula Ib COOR' ~ A: N reel ~ COOR' 7 {_ ND o Noor (IIb) whereby : R! stands for a hydrogen atom or a metal jon equivalent of atomic numbers 23-29, 42-46 or 58-70, R? and R? stand for a hydrogen atom, a C-Cy-alky! group, a benzyl group, a phenyl group, -CH,0H or -CH,-OCH;, U? stands for radical L!, whereby L! and U3 independently of : one another, can be the same or different, A' means a hydrogen atom, a straight-chain or branched C,-Cso-alkyl group, which optionally is interrupted by 1-15 oxygen atoms, and/or optionally is : substituted with 1-10 hydroxy groups, 1-2 COOH groups, a phenyl group, AMENDED SHEET

. . a benzyl group and/or 1-5 -OR’ groups, with R’ in the meaning of a hydrogen atom or a C,-Cs-alkyl radical, or -L'-RF, L! means a straight-chain or branched C,-C;p-alkylene group, which optionally is interrupted by 1-10 oxygen atoms, 1-5 -NH-CO groups, 1-5 - -CO-NH groups, by a phenylene group that is optionally substituted by a COOH- group, 1-3 sulfur atoms, 1-2 -N(B'")-SO, groups and/or 1-2 -SO- N(B')-groups with B' in the meaning of A', an NHCO group, a CONH group, an N(B")-S0, group or an -SO,-N(B') group and/or optionally is substituted with radical R”, and RF means a straight-chain or branched perfluorinated alkyl radical of formula CnF2nE, whereby n stands for numbers 4-30, and E stands for a terminal fluorine atom, chlorine atom, bromine atom, iodine atom or a hydrogen atom, and optionally present acid groups optionally can be present as salts of organic and/or inorganic bases or amino acids or amino acid amides, are used.

2. Use according to claim 22, wherein the compounds of general formula Ib, in which’ R%, R® and R’, independently of one another, mean hydrogen or a C;-C4 alkyl .- group, are used.

24. Use according to claim 22, wherein the compounds of general formula Ib, in which A! means hydrogen, a C,-Cs alkyl radical, the radicals C;H4-O-CHj3 , C3Hg-O-CH3, C2H-0-(C3Hi-0)-C2H,-OH, C2Hs-O~(C2Hy-0)-C3He-OCHS, C,H4OH, C3HeOH, C4HgOH, CsH,oOH, C¢H 20H, C;H,40H,

® @ CH(OH)CH,OH, CH(OH)CH(OH)CH, OH, CH,[CH(OH)].'CH,OH, CH[CH2(OH)]CH(OH)CH,0H, C,H4CH(OH)CH,0H, (CH»)s;COOH, C,H4-0-(CyH4-0)-CH,COOH or CyH4-0-(C,H4-0)-CHy-Co FE : whereby S stands for integers 1 to 15, t stands for integers 0 to 13, u' stands for integers 1 to 10, : n stands for integers 4 to 20, and E stands for a hydrogen, fluorine, chlorine, bromine or iodine atom, and if necessary, their branched isomers, are used.

25. Use according to claim 22, wherein the compounds of general formula Ib, in which A! means hydrogen, C;-Cjo-alkyl, C,H4-0-CH3, C3Hg-O-CHj, C,Hs-0-(C2Hy4-0)4-C,Hy-OH, CoHy-O-(C4Hy-0),-C,Hy-OCH3, C;H40H, C;HgOH, CH,[CH(OH)],CH,O0H, CH[CH,(OH)]CH(OH)CH,O0H, : (CH,)wCOOH, C,H4-0-(C,H4-0)4-CH,COOH, CoHy-0-(CoHa-0)x-CoHy-CoF nE whereby

X stands for integers 0 to 5, y stands for integers 1 to 6, w stands for integers 1 to 10, n stands for integers 4 to 15, and E stands for a fluorine atom, and, if necessary, their branched isomers, are used.

26. Use according to claim 22, wherein the compounds of general formula Ib, in which L' means o-(CHp)s-B a-CHp-CHp-(0-CH3-CHp-)yB a-CHp-(0-CHp-CHp-)yB a-CHy-NH-CO-f a-CHp-CH>-NH-SO»-B a-CHp-NH-CO-CH-N(CHpCOOH)-SO»-B a-CH-NH-CO-CHy-N(C7H5)-SOo-B o-CH3-NH-CO-CHy-N(C1gH21)-S02-B a-CHp-NH-CO-CH»-N(CgH1 3)-SO2-B a-CHp-NH-CO-(CHj)10-N(CoHj5)-SO9-B8 : a-CHy-NH-CO-CH)-N(-CH3-CgH3)-SOo-f a.-CHp-NH-CO-CHp-N(-CHp-CH-OH)S 09-8 a-CHp-NHCO-(CHj)1-S-CHoCH)-p a-CHpNHCOCH,-0-CHCH»-B a-CHp-CHpNHCOCH,-0-CH)CH»>-8 a-CH;-(CH,-CH;-O)-(CH,)sNHCO-CH,-O-CH,CH,-B a-CHpNHCO(CH3)1(-O-CHCHp-B a-CH,;CHypNHCO(CH»)1-O-CHoCH>-B a-CHp-CgHyg-O-CHpCH7-P whereby the phenylene group 1,4 or 1,3 is linked a-CH3-0-CHp-C(CH-OCHyCH»-CgF13)2-CHy-OCH>-CHy-f a-CHp-NHCOCHCH7CON-CH>CHpNHCOCH)N(CoH;5)SO-2CgF 178 a-CH,-CH:NHCOCH;N(C,H5)-S0,-B a-CHp-O-CHp-CH(OC gH» 1)-CH-0O-CHoCH-B a-(CHpNHCO)4-CHO-CHoCHy-B

® ® a-(CHoNHCO)3-CHyO-CHoCH)-B a-CH»-OCHC(CH,OH)7-CHp-O-CHpCH»-B a a —0—' —CH,—O0— = — a COOH B a-CHoNHCOCHN(CgH3)-SO7-B a-NHCO-CHp-CHp-p a-NHCO-CH3-0O-CHCH)-B a-NH-CO-p a-NH-CO-CH,-N(CHpCOOH)-SO7-p a-NH-CO-CH)-N(C7Hjs)-SO7-B a-NH-CO-CH3-N(C1oH21)-SO7-p : a-NH-CO-CHy-N(CgH13)-SO2-B a-NH-CO-(CH3)10-N(CoHs)-S07-B a-NH-CO-CHy-N(-CH»-CgHjs)-SO2-B a-NH-CO-CH,-N(-CHy-CH-OH)SO7-p a-NH-CO-CHy-B a-CHy-0-CgHy-O-CHy-CHp-B a-CHy-CgHyg-0O-CH)-CHp-B a-N(C2Hs)-S02-p o-N(CHs)-S02- a-N(C10H21)-S02-B a-N(CeH3)-S02-B a-N(CoH4OH)-S05-B a-N(CHpCOOH)-SO,-p a-N(CHpCgHj5)-SO7-8 a-N-[CH(CH,OH)3]-SO5-B a-N-[CH(CH,OH)CH(OH)(CH,OH)]-SO5-B whereby s stands for integers 1 to 15, and y stands for integers 1 to 6, are used.

27. Use according to claim 22, wherein the compounds of general formula Ib, in which L! means a-CH;-O-CH,CH,-B, . a-CH,-CH-(O-CH,-CHa)y-B, a-CH;-(O-CH,-CH,-)y-B, a-CH,-CH,-NH-SO,-B, Example 10 a-CHpNHCOCH>-0-CHpCHy-f a-CHp-CHpNHCOCH;-0-CHy CH -f a-CH;-(CH,-CH»-0),-(CH;);NHCO-CH,-O-CH,CH,-p a-CHpNHCO(CHj) ¢-O-CH7CH3-B a-CH,CHpNHCO(CH»)10-O-CHyCHy-B a-CHj-0-CH3-CH(OC1 gH71)-CH-O-CHoCHo-f a-CHp-O-CgHyg-O-CHp-CHy-B or a-CHp-CgHy-O-CHy-CHp-B whereby y stands for integers 1 to 6, are used.

28. Use according to claim 22, wherein the compounds of general formula Ib, in “which RF means a straight-chain or branched perfluorinated alkyl radical of formula CnF2nE, whereby n stands for number 4 to 15 and E stands for a terminal fluorine atom, are used.

® ©

29. Use according to one of claims 22 to 28, wherein the following compounds are used: -- 1,4,7-Tris(carboxylatomethyl)-10-(3-aza-4-oxo-hexan-5-ylic)-acid-N-(2,3- dihydroxypropyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-0xa)- perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex -- 1,4,7 ~Tris(carboxylatomethyl)- 10-{(3-aza-4-oxo-hexan-5-ylic)acid-N- (3,6,9,12,15-pentaoxa)-hexadecyl)-(1H,1 H,2H,2H.4H,4H,5H,5H-3-o0xa)- perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex -- 1,4,7-Tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-N-5- hydroxy-3-oxa-pentyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-o0xa)- perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex -- 1,4,7-Tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N- 3,6,9,15-tetraoxa-12-aza-15-0x0-C,7-Ca¢-hepta-decafluoro)hexacosyl]- amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex -- 1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-0xo-hexan-5-ylic]-acid-N-(2- methoxyethyl)-N-( 1H,1H,2H,2H,4H,4H,5H, 5H-3-oxa)-perfluorotridecyl]- amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex.

30. Use according to one of claims 1 to 7, wherein as perfluoroalkyl-containing metal complexes, the compounds with sugar radicals of general formula Ic (K)'=G = (Z-R')n' (Ic) (Y-R),' in which :

® ¢ R represents a mono- or oligosaccharide radical bonded by the 1-OH- or 1-

SH-position,

RF is a perfluorinated, straight-chain or branched carbon chain with the formula -C,F2,E, in which E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n stands for numbers 4-30,

K stands for a metal complex of general formula llc, :

COOR" g SN dd N ?OR 0 r00c” a NE N : COOR? (1c) in which

R! means a hydrogen atom or a metal ion equivalent of atomic numbers 23- 29, 42-46 or 58-70, provided that at least two R' stand for metal ion equivalents,

R? and R?, independently of one another, represent hydrogen, C,-Cs-alkyl, benzyl, phenyl, -CH,OH or -CH,OCH3, and

U represents -CgHy-O-CH;-, -(CHz)1.5-w, a phenylene group, -CH,-NHCO- CH,-CH(CH,COOH)-CsHs-w, -CsHs-(OCH,CH,)p.1-N(CH,COOH)-CH,- ®, or a C;-Cyz-alkylene group or C;-C2-C¢Hs-O group optionally interrupted by one or more oxygen atoms, 1 to 3 -NHCO groups or 1 to 3 : -CONH groups and/or substituted with 1 to 3 -(CHy)o.sCOOH groups, whereby ® stands for the binding site to -CO-,

or of general formula IIIc COOR" g S/N N COOR* Q R'OOC / p ~ COOR? (1llc) in which R' has the above-mentioned meaning, R* represents hydrogen or a metal ion equivalent mentioned under R! and U! represents -C¢Ha-O-CH;-w, whereby means the binding site to -CO-, or of general formula [Vc 0 OR" yh N N R2 R'O0C / p, hee COOR™ (IVe) in which R' and R? have the above-mentioned meaning or of general formula VcA or VcB —CO~ a N—Coor’ ~——N R'OOC / AN N —COOR" ~ ~~ 1 COOR (VcA)

® 0 nj COOR' 0 a ~~COCR’ nN NUN —COQR" ~— 1 COCR (VeB) in which R' has the above-mentioned meaning, or of general formula Vic RIO0C—” ey CO RO oC —~ ~—COOR" (VIc) in which R' has the above-mentioned meaning, or of general formula VIlc 0 R'O0C— N J, R*OOC—" J R'O0C ESN R'00C— (Vc) in which R! has the above-mentioned meaning, and U! represents -CgHis-O-CH,-0, whereby @ means the binding site to -CO- or of general formula VIIIc FF R’ 7 N _\ N N ~Ar R'0OC” Sh: NAN J oF COOR’ (VIIIc) in which R' has the above-mentioned meaning,

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

G for the case that K means metal complexes IIc to VIIc represents a radical that is functionalized in at least three places and is selected from the following radicals a) to j)

(a) H rN = (CH) = CG — CO —w ¥ NH 3 P (b) H Vom CO-C— (CH) N we B : i" a (c) a ya N ™N \ No | J a

®o © (d) oo ; awn — / > Y Mb B (e) CO B wan——N N——n H H (H) NH —CO Len, iN a ( NH N-wy : - CH, )~N ~~ H 2) * NH £ B o © @

NF co N=CO—CH—(CHyj NH

\

v NH—CO—CH—(CH, J NHB y

B

® H H a Ao N— (CH, fC —N—CO -C —(CH,) 7 N ——wB H LH | H I NH SE p QM cL H \ prem (CH) —~CON N—y

NH

) CN SE ct

» aw NH—=CH — CO —mr ¥ 4 B and G for the case that K means metal complex VIIIc represents a radical that is functionalized in at least three places and is selected from k) orl), (k) pva—N HCH GH—CO-wa iy Y M HCO CH CH=CH CO 1 p whereby a means the binding site of G to complex K, B is the binding site of G to radical Y, and y represents the binding site of G to radical Z, Y means -CHj, 8-(CH,)(;.5CO-B, 6-CH,-CHOH-CO-B or §-CH(CHOH- CH,OH)-CHOH-CHOH-CO-B, whereby 8 represents the binding site to sugar radical R, and B is the binding site to radical G, Z stands for re ~ : Y—N ~~ N —S05 tS

@ ® v-COCH,-N(C;H:+)-SOs-¢, y-COCH,;-0-(CH:)--S0,-¢. O Q yA or ANT On-sore or vy - NHCH,CH,-O-CH,CH,-¢ whereby vy represents the binding site of Z to radical G, and € means the binding site of Z to perfluorinated radical RF and I', m', independently of one another, mean integers 1 or 2, and p' means integers 1 to 4, are used.

31. Use according to claim 30, wherein the compounds of general formula Ic, in which R represents a monosaccharide radical with 5 to 6 C atoms or its deoxy compound, preferably glucose, mannose or galactose, are used.

32. Use according to claim 30, wherein the compounds of general formula Ic, in which R? and R?, independently of one another, mean hydrogen or C-Cy-alkyl and/or E in formula -C,F,, means a fluorine atom, are used.

33. Use according to claim 30, wherein the compounds of general formula Ic, in which G represents lysine radical @ or (b), are used.

34. Use according to claim 30, wherein the compounds of general formula Ic, in which Z means y—NT ON—SOsc

® ® whereby vy represents the binding site of Z to radical G, and & means the binding site of Z to perfluorinated radical Rf, and/or Y means §-C H,CO-B, whereby § represents the binding site to sugar radical R, and B represents the binding site to radical G, are used.

35. Use according to claim 30, wherein the compounds of general formula Ic, in which U in metal complex K represents -CH,- or -C¢H,-O-CH;-w, whereby © stands for the binding site to -CO-, are used.

36. Use according to claim 30, wherein the gadolinium complex of 6-N-{1,4,7- tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1 0-N-(pentanoyl-3-aza-4-o0xo-5- methyl-5-y1)]-2-N-[1 -0-a-D-carbonylmethyl-mannopyranose]-L-lysine. | 1-(4- perfluorooctylsulfonyl)-piperazine]-amide is used.

37. Use according to one of claims 1 to 7, wherein as perfluoroalkyl-containing : metal complexes, the compounds with polar radicals of general formula Id K)'~ G ~ (Z-RO)! (1d) (R),” in which RF is a perfluorinated, straight-chain or branched carbon chain with formula -CuF2qE, in which E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n stands for numbers 4-30, K stands for a metal complex of general formula 11d,

® 9 COOR? : § ya ld N RO coo a HART NEN L COCR? (11d) in which R! means a hydrogen atom or a metal ion equivalent of atomic numbers 23- 29, 42-46 or 58-70, provided that at least two R' stand for metal ion equivalents, oo R? and R’, independently of one another, represent hydrogen, C,-C;-alkyl, benzyl, phenyl, -CH,0H or -CH,OCH3, and u represents -C¢Ha-O-CHj-w-, -(CHa),.s-0, a phenylene group, -CH;- ~ NHCO-CH,-CH(CH;COOH)-CgHy-0>-, -CeHa-(OCH;CHa)o.r- N(CH,COOH)-CH»-, or a C;-C-alkylene group or C7-C5-C¢Hs-0 group optionally interrupted by one or more oxygen atoms, 1 to 3 -NHCO groups, 1 to 3 -CONH groups and/or substituted with 1 to 3 -(CH2)o-sCOOH groups, whereby w stands for the binding site to -CO-, or of general formula IlId COCR? ( SN N COOR' 0 R'OOC —N N & jt : NA COOR" (111d)

in which R' has the above-mentioned meaning, R* represents hydrogen or a metal ion equivalent mentioned under R', and U' represents -C¢Hy-O-CH,-w-, whereby © means the binding site to -CO-, or of general formula IVd COOR’ ye f ~~ N R2 R'00C / ) o NA ~ \ 1 COOR (IVd) in which R' and R? have the above-mentioned meaning, or of general formula VdA or VdB a ~—COOR" ~—N R'OQC / Ng N —COOR" ~~ 1 : COOR (VdA) NTT COOR? 0 a ~~COOR" Il —N AN N —CQOOR"

~~. 1 COOR (VdB) in which R' has the above-mentioned meaning,

or of general formula VId R'OOC—__ ~~ \. _—CO—wm, MN NT R'OOC—" ~—COC0R" (VId) in which R' has the above-mentioned meaning, or of general formula VIId R10OOC—_ Q 1 __N J, R'OOC U R'O0C Sn R'OOC— (VIId) in which R' has the above-mentioned meaning, and - U' represents -C¢Hy-O-CHy--, whereby ® means the binding site to -CO-, and in radical K, optionally present free acid groups optionally can be present as salts of organic and/or inorganic bases or amino acids or amino acid amides, G represents a radical that is functionalized in at least three places and is selected from the following radicals a) to g) (a) H a N= (CH) C= CO—w Y NH 3 B (b) H Y + CO-C—(CHy Nw B oo Oo (c) a Jap CV pw~——N Nr.

Y Ca ~b a (d) p pup CNY Lwn—~N N ——a, ¥ NE Mp B (e) ¥ L yf | He

H H we N= (CH) C—N=CO C— (CH): ——wf3 I NH v B (2) 1 | \ a v p (h) Y COOH) PHOS SE) B ~w CO-(CHs H-CO~wy " 7 o a whereby a means the binding site of G to complex K, B is the binding site of G to radical R, and vy represents the binding site of G to radical Z Z stands for dN - Y—N: N—-S0s5-¢ y-C(O)CH,O(CHa)s-¢, whereby y represents the binding site of Z to radical G and € means the binding site of Z to perfluorinated radical Ry,

® e R represents a polar radical that is selected from complexes K of general formulas IId to VIId, whereby R' here means a hydrogen atom or a metal ion equivalent of atomic numbers 20, 23-29, 42-46 or 58-70, and radicals R%, R® ,R*, U and U' have the above-indicated meaning, or R means the folic acid radical or R means a carbon chain with 2-30 C atoms that is bonded to radical G via -CO- or SO;- and is straight or branched, saturated or unsaturated, optionally interrupted by 1-10 oxygen atoms, 1-5 -NHCO groups, 1-5 -CONH groups, 1-2 sulfur atoms, 1-5 -NH groups or 1-2 phenylene groups, which optionally can be substituted with 1-2 OH groups, 1-2 NH; groups, 1-2 -COOH groups, or 1-2 -SO;H groups, or optionally substituted with 1-8 OH groups, 1-5 -COOH groups, 1-2 SO;H groups, 1-5 NH; groups, 1-5 C,-Cy-alkoxy groups, and 1! m!, p’, independently of one another, mean integer 1 or 2, are used.

38. Use according to claim 37, wherein the compounds of general formula Id, in which K stands for a metal complex of general formula 1d, I1Id, VdB or VIId, are used.

39. Use according to claim 37, wherein the compounds of general formula Id, in which polar radical R has the meaning of complex K, preferably complex K of general formulas IId, 111d, VdA or VIId, are used.

40. Use according ta claim 37, wherein the compounds of general formula Id, in which polar radical R has the following meanings: -C(0)CH,CH,SOH

® LJ -C(0)CH,OCH,CH,0CH,CH,OH -C(O)CH,OCH,CH,0H -C(0)CH,OCH,CH(OH)CH,0OH -C(O)CH,NH-C(O)CH,COOH -C(O)CH,CH(OH)CH,OH -C(0)CH,OCH,COOH -SO,CH,CH,COOH -C(0)-C¢H3-(m-COOH)> -C(0O)CH,0(CH,)2-CeH3-(m-COOH), -C(0O)CH;0-C¢H4-m-SO3H -C(O)CH;NHC(O)CH,;NHC(O)CH,OCH,COOH -C(O)CH,0OCH;CH,0CH,;COOH -C(0O)CH,0OCH,CH(OH)CH,0-CH,CH,0H -C(O)CH,0OCH,CH(OH)CH,OCH,-CH(OH)-CH,OH -C(O)CH,SOsH -C(O)CH,CH,COOH -C(O)CH(OH)CH(OH)CH,0H -C(O)CH20[(CH,)20}1-9-CH3 -C(O)CH,O[(CH2)20]1.9-H -C(O)CH,OCH(CH;0H), -C(O)CH,OCH(CH,0CH,COOH), -C(0)-C¢H3-(m-OCH,;COOH), -CO-CH,0-(CH;)2,0(CH;),0-(CH,),0(CH,), OCH; preferably —C(O)CH,O{[(CH;),0]4-CH3, are used.

41. Use according to claim 37, wherein the compounds of general formula Id, in which polar radical R is the folic acid radical, are used.

42. Use according to claim 37, wherein the compounds of general formula Id, in which G represents lysine radical (a) or (b), are used.

43. Use according to claim 37, wherein the compounds of general formula Id, in which U represents group -CH;- or -C¢Hy-O-CH,-w in metal complex K, whereby ® stands for the binding site to -CO-, are used.

. 44. Use according to one of claims 37-43, wherein the gadolinium complex of 2,6-N,N'-bis[1,4,7-tris(carboxylatomethyl)-1,4,7,1 0-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-lysine-[ 1-(4-perfluorooctylsulfonyl-piperazine]- amide is used.

45. Use according to one of claims 1-7, wherein as perfluoroalkyl-containing metal complexes, galenical formulations that contain paramagnetic, perfluoroalkyl- containing metal complexes of general formulas I, Ia, Ib, Ic and/or Id and diamagnetic perfluoroalkyl-containing substances, preferably dissolved in an aqueous solvent, are used.

46. Use according to claim 45, wherein as diamagnetic perfluoroalkyl-containing substances, those of general formula XX

RF.12.B? (XX) in which RF represents a straight-chain or branched perfluoroalky! radical with 4 to 30 carbon atoms, L? stands for a linker and BZ stands for a hydrophilic group, are used.

47. Use according to claim 46, wherein linker L? is a direct bond, an -SO; group, or a straight-chain or branched carbon chain with up to 20 carbon atoms, which can be substituted with one or more -OH, -COO-, -SO; groups and/or optionally contains one or more -O-, -S-, -CO-, -CONH-, -NHCO-, -CONR’-, -NR’CO-, -SO,-, -PO4-, -NH- or NR’ groups, an aryl ring or a piperazine, whereby R’ stands for a C;- to Cyp-alkyl radical, which in turn can contain one or more O atoms, and/or can be substituted with -COO’ or SO; groups.

48. Use according to claim 46, wherein hydrophilic group B? is a mono- or disaccharide, one or more adjacent -COQO" or -SO5~ groups, a dicarboxylic acid, an isophthalic acid, a picolinic acid, a benzenesulfonic acid, a tetrahydropyrandicarboxylic acid, a 2,6-pyridinedicarboxylic acid, a quaternary ammonium ion, an aminopolycarboxylic acid, an aminodipolyethylene glycolsulfonic acid, an aminopolyethylene glycol group, an SO,-(CH,),-OH group, a polyhydroxyalkyl chain

® adi at least two hydroxyl groups or one or more polyethylene glycol chains with at least two glycol units, whereby the polyethylene glycol chains are terminated by an -OH or -OCH; group.

49. Use according to claim 45, wherein as diamagnetic perfluoroalkyl-containing substances, conjugates that consist of a-, B- or y-cyclodextrin and compounds of general formula XXII Al-LRF : (XXII) in which A? stands for an adamantane, biphenyl or anthracene molecule, L? stands for a linker, and RF stands for a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms, and whereby linker L* is a straight-chain hydrocarbon chain with 1 to 20 carbon atoms, which can be interrupted by one or more oxygen atoms, one or more CO-, SO,-, CONH-, NHCO-, CONR!-, NR!%CO-, NH- or NR'° groups or a piperazine, whereby R'? is a C,-Cs-alkyl radical, are used.

50. Use according to claim 45, wherein as diamagnetic perfluoroalkyl-containing substances, those of general formula XXI: RF-X! (XXI) in which RF represents a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms, and X' is a radical that is selected from the group of the following radicals (n in this case is a number between 1 and 10), are used: OH OH ONIN IN a

[] pd ~ WMR003/1949 n0 0 oN 0 NS ONT 0 OH words, HN A : TR 0 OH OH : wrtLs i ’ ee NT _ // "0 O ~ OH H PENEPON GNP HO 0

@ @ OH OH serfs 0 OH 0 OH Ne els AS NJ © oY 0) : | OH OH mle 0 0 LJ on H 0~__0 er lp, . OH ~~ od OH OO _~_.. ol Ha OH (a+P) Q 0 Ba SNPS

3 I id ~~ N 0 4 No ~~" 0H a oo. i OH cen Pe on . 0 Tr oOo _ __.- _OH Hl _— © oO” _o _— OH © ~—coo “ 0 — C00" COO” 2+ 0 Ca re ee O — SE N pl aL i.

N ~~ en - elelo} eee 0 .-S0 3 oe OL ease 7 Co / OH HO” oH OH Og HO™ HO OH coo’ - rm Om C00

PCT/EP01/08498 ® 370 o COO | : Pe SW H 00" oo PU, coo”

51. Use of perfluoroalkyl-containing metal complexes that have a critical micelle formation concentration < 10° mol/l, a hydrodynamic micelle diameter (2 Rh) > 1 om and a proton relaxivity in plasma (R!) > 10 1/mmol's in the manufacture of contrast media for MR imaging for visualization of plaque.

52. Use according to claim 51, characterized in that the metal complexes are also used as MRI contrast media for visualization of lymph nodes. a

53. Use according to claim 51 or 52, wherein the metal complexes are also used as MRI contrast media for visualization of infarcted and necrotic tissue.

54. Use according to one of claims 51 to 53, wherein the metal complexes are also used as MRI contrast media for independent visualization of necroses and tumors.

55. Use according to claim 51, wherein metal complexes whose micelle formation concentration is < 10 mol/l are used.

56. Use according to claim 51, wherein metal complexes whose hydrodynamic micelle diameter is = 3, preferably > 4 nm, are used.

57. Use according to claim 51, wherein metal complexes that have a proton relaxivity in plasma of > 13 I/mmol's, preferably > 15 I/mmol's, are used.

58. Use according to one of claims 51 to 57, wherein as perfluoroalkyl- containing metal complexes, the compounds of general formula I RF-L-K | a in which RF is a perfluorinated, straight-chain or branched carbon chain with formula -CuFE, in which E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n stands for numbers 4-30, L means a direct bond, a methylene group, an -NHCO group, a group AMENDED SHEET

PCT/EP01/08498 ® R* — on-wcoon,— ony, 1 N—SO,—

q . whereby p means the numbers 0 to 10, and q and u, independently of one another, mean numbers 0 or 1, and R? is a hydrogen atom, a methyl group, a -CH,-OH group, a -CH,- COH group or a C>-C,;s chain, which optionally is interrupted by 1 to 3 oxygen atoms, 1 to 2 >CO groups or an optionally substituted aryl group and/or is substituted with 1 to 4 hydroxyl groups, 1 to 2 C1-C4 alkoxy groups, 1 to 2 carboxy groups, a group -SO3H-, or is a straight-chain, branched, saturated or unsaturated C,-C; carbon chain, which optionally contains 1 to 10 oxygen atoms, 1 to 3 -NR? groups, 1 to 2 sulfur atoms, a piperazine, a -CONR? group, an -NR*CO group, an -SO; group, an -NR*-CO, group, 1 to 2 CO groups, a group : — CO —N—T—N®?—50,—RF or 1 to 2 optionally substituted aryls and/or is interrupted by these groups and/or is optionally substituted with 1 to 3 -OR?® groups, 1 to 2 oxo groups, 1 to 2 -NH-COR® groups, 1 to 2 -CONHR? groups, 1 to 2 -(CH,),-CO,H groups, 1 to 2 groups -(CHz),~(0)q-CHaCH,-RF , whereby R* RF and p and q have the above-indicated meanings, and AMENDED SHEET

PCT/EP01/08498

® T means a C,-C)g chain, which optionally is interrupted by 1 to 2 oxygen atoms or 1 to 2 -NHCO groups, K stands for a complexing agent or metal complex or their salts of organic and/or inorganic bases or amino acids or amino acid amides, specifically for a complexing agent or complex of general formula II 'CH,CH, ——w N /~co-— N Cen - COR oA (com OR! iy /—CO,R cos (1) in which RS, R' and B are independent of one another, and R® has the meaning of R® or means -(CHy)m-L-RF, whereby m is 0, 1 or 2, and L and RF have the above-mentioned meaning, : R, independently of one another, mean a hydrogen atom or a metal ion equivalent of atomic numbers 22-29, 42-46 or 58-70, B means -OR' or F —_— —n FR oder —N N-50,L-R" R [or] — whereby R!, L, RF and R® have the above-mentioned meanings, or AMENDED SHEET

PCT/EP01/08498

K stands for a complexing agent or complex of general formula III an COZ’ R® ’ N

; Re Ne COZ _ N oo CH, CH; N coz’ NENG N pu coz’ (II) in which R¢ and R' have the above-mentioned meanings and R® has the meaning of R* or K stands for a complexing agent or complex of general formula IV , ~ COR! R'0,C a _ © PN COR’ La N 2 Ng /— COR’ N — COR’ (Iv) in which R' has the above-mentioned meaning : or AMENDED SHEET

PCT/EP01/08498

K stands for a complexing agent or complex of general formula V amie ts N ( cq, Rl : CH N ~~ CH,) ( 2 q AN Co, rl V) in which R' has the above-mentioned meaning, and o and q stand for number 0 or 1, and yields the sumo + q=1, or K stands for a complexing agent or complex of general formula VI Rloc\ /\ Cos! ’ N N 4 A (= co, rl CO, rl I) in which R! has the above-mentioned meaning or AMENDED SHEET

PCT/EP01/08498

K stands for a complexing agent or complex of general formula VII rlo,g\ /\ cor! g N ) ( \ / CO-B COR! : (VID) in which R' and B have the above-mentioned meanings or K stands for a complexing agent or complex of general formula VIII ROL /\ ya CO, rl N N N aN CH CH. ——a N — 22 ( \__/ Rb R Cc CO,R1 (VIII) in which R® and R' have the above-mentioned meanings, and R® has the above-mentioned meaning of R? or

AMENDED SHEET

PCT/EP01/08498

K stands for a complexing agent or complex of general formula IX RIO,C™N / \ co, rl § N N ) OH ( — \. RI “0X Re (IX) in which R° and R' have the above-mentioned meanings, : or K stands for a complexing agent or complex of general formula X Rl OLN / \~ co, rl C PH : ( ~~ RC : CO,rl X) in which R° and R! have the above-mentioned meanings, or K stands for a complexing agent or complex of general formula XI RIO,C—\ /™\ CO! N N ( ) x1) N 0 [NH-CH,~(CH,) -CO]q-N N CO,r! J Ng 0,—— wwe in which R!, p and q have the above-mentioned meanings, and R® has the meaning of R?, . AMENDED SHEET

PCT/EP01/08498 C 377 or K stands for a complexing agent or complex of general formula XII _ N N—SO N —/ i ( coz N 1 0027" FN N—so, LR N —/ : —co,Z’ (XID) in which L, RF and Z' have the above-mentioned meanings, or K stands for a complexing agent or complex of general formula XIII _—cq, 2’

N_. S—co, 7 PE { _——C0Z" N S—co, 7! (XID) in which R' has the above-mentioned meaning, are used.

59. Use according to claim 58, wherein the compounds of general formula I, in which L stands for a-CH,-8 a-CH,CH,-3 a-(CHy)-8 s=3-15 a-CH,-O-CH,CH,-8 AMENDED SHEET

PCT/EPUi/ 084538

® a-CH5-(O-CH;-CHz-)-B t=2-6 a-CH»-NH-CO-B a-CH»-NH-CO-CH>-N(CH,COOH)-SO5-B a-CH»-NH-CO-CH3-N(C2H3)-SO2-B a-CH>-NH-CO-CH-N(CjoH21)-SO2-B a-CH»-NH-CO-CHg-N(CgH13)-SO»-B a-CHo-NH-CO-(CH»)10-N(C2Hs)-SO2-B a-CH»-NH-CO-CH3-N(-CH>-CgHj5)-SO>-B a-CHy-NH-CO-CHj-N(-CH,-CH»-OH)S05-8 : a-CH-NHCO-(CH2)1¢-S-CHCH>-B : a-CHpNHCOCH-0-CH;CH2-B a-CHoNHCO(CH2)1¢-O-CH2CHo-B a-CHp-CgHy4-0O-CHoCH2-B a-CH»-0-CH3-C(CH2-OCHCH3-CgF 13)2-CH2-OCH7-CH3-B a-CH,-NHCOCH»CH>CON-CH2CH;NHCOCHN(C2H5)SO2CgF 17 CH,-CH,NHCOCH,N(C,H;)-SO,-p a-CHj-0-CH2-CH(OC gH] )-CH»-0-CHCH3-B a~(CHoNHCO)4-CH20-CH2CH2-B a-(CHoNHCO)3-CH0-CH,CH3-B a-CH3-OCH7C(CH20H)>-CH3-0O-CHoCH2-B : — CH ~ ——CH,=—CH,— COOH a-CHoNHCOCH2N(CgHj3)-SO2-B a-NHCO-CHp-CHa-B a-NHCO-CHp-0-CHoCHy-B a-NH-CO-B : a-NH-CO-CH;-N(CH>COOH)-SO5-B a-NH-CO-CHp-N(CoHs)-S09-8 a-NH-CO-CH>-N(CgH>1)-SO2-B a-NH-CO-CH3-N(CgH3)-S072-B a-NH-CO-(CH3)10-N(CoHs)-S02-8 AMENDED SHEET

PCT/EP01/08498 a-NH-CO-CH3-N(-CH2-CgHj5)-SO5-B a-NH-CO-CH2-N(-CH-CH2-OH)S0,-8 a-NH-CO-CH»>-B a-CHp-0-CgHy-O-CHy-CHy-B a-CHp-CgHg-O-CH-CH-B a-N(C2Hj5)-SO2-p a-N(CgHj5)-SO2-B a-N(C10H21)-SO2-B a-N(CgH{3)-SO2-B a-N(CoH40H)-SO»-B a-N(CHCOOH)-SO5-p a-N(CHzCgHs)-SO7-B a-N-[CH(CH;0H)2]-SO5-B a-N-[CH(CHyOH)CH(CH70H)]-S0O,-B and in which « represents the binding site to the complexing agent or metal complex K, and 8 represents the binding site to the fluorine radical, are used.

60. Use according to claim 58 or 59, wherein the compounds of formula I in which n in formula -C F, E stands for numbers 4-15 and/or E in this formula means a fluorine atom are used.

61. Use according to on of claims 58 to 60, wherein the following compounds are used: -- Gadolinium complex of 10-[1-methyl-2-0x0-3-aza-5-oxo-{4- perfluorooctylsulfonyl-piperazin-1-yl}-pentyl]-1,4,7- tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, -- Gadolinium complex of 10-[2-hydroxy-4-aza-5-0xo-7-oxa- 10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17- heptadecafluoroheptadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecane, AMENDED SHEET

PCT/EP01/08498 C 380 -- Gadolinium complex of 10-[2-hydroxy-4-aza-5,9-diox0-9-{4- perfluorooctyl)-piperazin-1-yl}-nonyl]-1 ,4 7-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecane, -- Gadolinium complex of 10-[2-hydroxy-4-aza-5-0xo-7-aza-7- (perfluorooctyl-sulfonyl)-nonyl}-1 4 7-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecane, - Gadolinium complex of 10-[2-hydroxy-4-oxa- 1H,1H,2H,2H,3 H,3H,5H,5H,6H,6H-perfluorotetradecyl]-1,4,7- tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, -- Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-0xa- 10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17,18,18,19,19- henicosafluoro-nonadecyl}-1,4,7-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecane, —- Gadolinium complex of 10-[2-hydroxy-4-aza-5-0xo0-1 l-aza-11- (perfluorooctylsulfonyl)-tridecyl]-1,4,7-tris(carboxymethyl) 1,4,7,10- tetraazacyclododecane, -- Gadolinium complex of 10-[2-hydroxy-4-aza-5-0x0-7-aza-7- (perfluorooctylsulfonyl)-8-phenyl-octyl]-1 ,4.7-tris(carboxymethyl)- : 1,4,7,10-tetraaza-cyclododecane.

62. Use according to one of claims 51 - 57, wherein as perfluoroalkyl- containing metal complexes, the compounds of general formula Ia : A-RF (Ia) in which . A is a molecule portion that contains 2 to 6 metal complexes, which are bonded directly or via a linker to a nitrogen atom of an annular skeleton chain, and AMENDED SHEET

PCT/EP01/08498

. RF is a perfluorinated, straight-chain or branched carbon chain with formula -C,F1,E., in which E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n stands for numbers 4-30, whereby molecule portion A has the following structure: K v TN K=—v—=N N-p -X— Ng N 0% v al whereby . q isa number 0, 1, 2 or 3, . K stands for a complexing agent or metal complex or their salts of organic and/or inorganic bases or amino acids or amino acid amides, . X is a direct bond to the perfluoroalkyl group, a phenylene group or a C;- Cio-alkylene chain, which optionally contains 1-15 oxygen atoms, 1-35 sulfur atoms, 1-10 carbonyl groups, 1-10 (NRY groups, 1-2 NRYSO, groups, 1-10 CONR® groups, 1 piperidine group, 1-3 SO, groups and 1-2 phenylene groups or optionally is substituted by 1-3 radicals RF, in which RY stands for a hydrogen atom, a phenyl group, benzyl group or a C;-C,s- alkyl group, which optionally contains 1-2 NHCO groups, 1-2 CO groups, 1-5 oxygen atoms and optionally is substituted by 1-5 Hydroxy, 1-5 methoxy, 1-3 carboxy, or 1-3 RF radicals, AMENDED SHEET

PCT/EP01/08498

. V is a direct bond or a chain of general formula IIa or Illa: 0 I B “NHECR) —(w),—(CH,)—C—ua Re (112) i -N- Co p | CH,-C \ o H H l KHN-CH,-C-N H H (Illa) in which =u R® is a hydrogen atom, a phenyl group, a benzyl group or a C;-C;-alkyl group, which optionally is substituted with a carboxy group, a methoxy group or a hydroxy group, u W is a direct bond, a polyglycol ether group with up to 5 glycol units, or a molecule portion of general formula [Va -CH(RM- (Iva) in which R"is a C,-Cy-carboxylic acid, a phenyl group, a benzyl group or a -(CHa)1-s-NH-K group, [| a represents the binding to the nitrogen atom of the skeleton chain, 8 represents the binding to complexing agents or metal complex K, and in which variables k and m stand for natural numbers between 0 and 10, and | stands for 0 or 1, and whereby . Dis a CO or SO, group, AMENDED SHEET

PCT/EP01/08498 ¢ 383 are used.

63. Use according to claim 62, wherein the compounds of general formula Ia in which q is the number 1 are used.

64. Use according to claim 62, wherein the compounds of general formula Ia, in which molecule portion X is an alkylene chain, which contains 1 - 10 CH,CH,0 groups or 1-5 COCH,NH groups, a direct bond or one of the following structures 0 CH y ~CH,-O-(CH,),— 5 + “CH NSO, 5 . y-(CHp),N-C—CH,-N-SO,— 1 C,H, H ty ~(CH2)1-0 (CH), — 5 , [ y —CH,-N-SO;—5 —{)cretvsors , y~CHyN-SO,—5 Lo C,H CgHy4 10° "21 Cy “CHAS : <0) whereby v binds to D, and & binds to RF, are used.

+65. Use according to claim 62, wherein the compounds of general formula Ia, in which V is a molecule portion with one of the following structures AMENDED SHEET

PCT/EP01/08498 C 384 7 7 @—C-CH,-NH-B , a —=C-C Hp-N- B , CH,COOH O I Q = C-CH—NH—P , o— C ~CH-NH—p CH, CH(CH,), . TOO 0 (H,COCH © @—C-CH,-CH-NH-B , ®=C-CH,-CH-NH-§ 7 a=C-CH-NH-p (CH,),-NH-K are used.

66. Use according to claim 62, wherein the compounds of general formula Ia, in which K represents a complex of general formula Va, VIa, VIIa or VIIIa, Ry oooR 8 N ™ R RY 4 NR'—Ud-T--- S— N N Roe (no) © A COOR* Va) AMENDED SHEET

PCT/EP01/08498

® Sr COOR 1 8 RY ¢ " 1 CE SU — N N 0% UT RO0OC Gg : Ne OH PN 1 R COOR (Vla) B COOR! N“~ coor! C RS : N Aco — (| [TCOOR 1 lL v 1 O R00 I [I COOR! RI0OC__| L COOR! i (Vila) whereby . R!, independently of one another, are a hydrogen atom or a metal ion equivalent of the elements of atomic numbers 23-29, 42-46 or 58-70, . . Risa hydrogen atom or a straight-chain, branched, saturated or unsaturated C;-Cjq-alkyl chain, which optionally is substituted by 1-5 hydroxy, 1-3 carboxy or 1 phenyl group(s) and/or optionally is interrupted by 1-10 oxygen atoms, 1 phenylene group or 1 phenylenoxy group, AMENDED SHEET.

PCT/EP01/08498

. R® is a hydrogen atom, a straight-chain or branched C,-Cs-alkyl radical, a phenyl! radical or benzyl radical,

. R’ is a hydrogen atom, a methyl group or ethyl group, which optionally is substituted by a hydroxy group or carboxy group, a UP is a strai ght-chain, branched, saturated or unsaturated C,-Cao-alkylene group optionally containing 1-5 imino groups, 1-3 phenylene groups, 1-3 phenylenoxy groups, 1-3 phenylenimino groups, 1-5 amide groups, 1-2 hydrazide groups, 1-5 carbonyl groups, 1-5 ethylenoxy groups, 1 urea group, 1 thiourea group, 1-2 carboxyalkylimino groups, 1-2 ester groups, 1-10 oxygen atoms, 1-5 sulfur atoms and/or 1-5 nitrogen atoms, and/or optionally substituted by 1-5 hydroxy groups, 1-2 mercapto groups, 1-5 . oxo groups, 1-5 thioxo groups, 1-3 carboxy groups, 1-5 carboxyalkyl groups, 1-5 ester groups and/or 1-3 amino groups, whereby the optionally ) contained phenylene groups can be substituted by 1-2 carboxy groups, 1-2 sulfone groups or 1-2 hydroxy groups . T' stands for a -CO-B, -NHCO-B or -NHCS-p group, whereby P represents the binding site to V, are used. :

67. Use according to claim 66, wherein the C,-C,,-alkylene chain that stands for U® contains the groups -CH,NHCO-, -NHCOCH,0-, -NHCOCH,0CH,-, -(CH,CO,H)-, -CH,0CH,-, -NHCOCH,C(H,-, -NHCSNHCH,-, -CH,0C¢H,-, -CH,CH,0- and/or is substituted by the groups -COOH and -CH,COOH.

68. Use according to claim 66, wherein US stands for a -CH,-, -CH,CH,-, -CH,CH,CH,-, -C¢H,-, -CH,y-, -CH,CH,-, -CH,NHCOCH,CH(CH,CO,H)-C:H,-, -CH,NHCOCH,OCH,-, or -CH,NHCOCH,C¢H,- group.

69. Use according to claim 62, wherein the compounds of general formula Ia, in which K has one of the following structures: AMENDED SHEET

PCT/EP01/08498 COOR* [ cH, | rR‘0OC 7 N 4 A ING ] TN Ya oN N N rR‘00C 5 0 [_coor* > ~ wfooc—] Loos COOR* [ooo OOK H N ~~ coor? N ™N dé NN rooc” | NY 5 eo (ne) © (coos L ) N COOR Lcoor® COOK’ 0) O

C__.0 ---- « _/—N NNN NIN R'O0C ne om |) coor are used.

70. Use according to one of claims 62 to 69, wherein the compounds of general formula Ia in which the perfluoroalkyl chain RF is ~-C¢F 3, -CgF;;, - C,oF,; or -C,,F,s are used. AMENDED SHEET

PCT/EP01/08498

71. Use according to one of claims 62 to 70, wherein the gadolinium complex of 1,4,7-tris{1,4,7-tris(N-(carboxylatomethyl)-10-[N-1-methyl-3,6-diaza- 2,5,8-trioxooctane-1,8-diyl)]-1,4,7,10-tetraazacyclododecane, Gd complex}-10-[N- 2H,2H,4H,4H,5H, 5H-3-0xa-perfluoro-tridecanoyl]-1,4,7, 10-tetraazacyclododecane is used.

72. Use according to one of claims 51 to 57, wherein as perfluoroalkyl- containing metal complexes, the compounds of general formula Ib al K—N— LR’ (Ib) in which K means a complexing agent or a metal complex of general formula IIb COOR! ~~ FoR 9 _—N ret COOR' {) © Noro (IIb) whereby R! stands for a hydrogen atom or a metal ion equivalent of atomic numbers 23-29, 42-46 or 58-70, R? and R? stand for a hydrogen atom, a C,-C,-alkyl group, a benzyl group, a phenyl group, -CH,OH or -CH,-OCH,, U? stands for radical L!, whereby L! and U?, independently of one another, can be the same or different, Al means a hydrogen atom, a straight-chain or branched C,-Cy;-alkyl group, which optionally is interrupted by 1-15 oxygen atoms, and/or optionally is substituted with 1-10 hydroxy groups, 1-2 COOH groups, a phenyl group, AMENDED SHEET

PCT/EP01/08498 C 389 a benzyl group and/or 1-5 -OR’ groups, with R® in the meaning of a hydrogen atom or a C,-C;-alkyl radical, or -L'-RF, L! means a straight-chain or branched C,-C,;-alkylene group, which optionally is interrupted by 1-10 oxygen atoms, 1-5 -NH-CO groups, 1-5 -CO-NH groups, by a phenylene group that is optionally substituted by a COOH- group, 1-3 sulfur atoms, 1-2 -N(B')-SO, groups and/or 1-2 -SO,-N(B')- groups with B! in the meaning of A!, and NHCO group, a CONH group, an N(B')-SO, group or an -SO,-N(B') group and/or optionally is substituted with radical RF, and RF means a straight-chain or branched perfluorinated alkyl radical of formula

C.F Es whereby n stands for numbers 4-30, and E stands for a terminal fluorine atom, chlorine atom, bromine atom, iodine atom or a hydrogen atom, and optionally present acid groups optionally can be present as salts of organic and/or inorganic bases or amino acids or amino acid amides, are used.

73. Use according to claim 72, wherein the compounds of general formula Ib, in which R?, R? and R’, independently of one another, mean hydrogen or a C,-C, alkyl group, are used.

74. Use according to claim 72, wherein the compounds of general formula Ib, in which A' means hydrogen, a C,-C; alkyl radical, the radicals C;Hs-O-CHj; , C3Hg-O-CHs, C2Ha-O~(C2Ha-0)-CaHu-OH, C;H4-0-(C,H4-0)-C3Ha-OCH:;, C,H4OH, C;HeOH, C4HsOH, CsH,,0OH, C¢H,-OH, C;H,40H, AMENDED SHEET

PCT/EP01/08498 o 390 CH(OH)CH,O0H, CH(OH)CH(OH)CH,OH, CHa[CH(OH)],'CH,0H, CH[CH>(OH)]CH(OH)CH,0OH, C-H4CH(OH)CH,0H, (CH,)sCOOQOH, C,H4-0-(C,H4-O)-CH, COOH or CoHy-0-(CoHy-0)-CoHy-CrFonE whereby s stands for integers 1 to 15, t stands for integers 0 to 13, u' stands for integers 1 to 10, n stands for integers 4 to 20, and E stands for a hydrogen, fluorine, chlorine, bromine or iodine atom, and if necessary, their branched isomers, are used.

75. Use according to claim 72, wherein the compounds of general formula Ib, in which A! means hydrogen, C,-C,, alkyl, C,H,4-O-CH3, C3Hg-O-CH;, C2Hy4-0-(CyHa-0)x-CoHa-OH, CoHy-0-(CoHy-0)y-CoHy-OCHs, C,H4OH, C;HsOH, CH,[CH(OH)],CH:0H, CH[CH,(OH)]CH(OH)CH,0H, (CH,)wCOOH, C,H,4-0-(C,Hs-0)-CH,COOH, C2H4-0-(C3Ha-O)x-CaHu-CoF on E whereby AMENDED SHEET

PCT/EP01/08498 ® 391 X stands for integers 0 to 5, y stands for integers 1 to 6, Ww stands for integers 1 to 10, n stands for integers 4 to 15, and E stands for a fluorine atom, and, if necessary. their branched isomers, are used.

76. Use according to claim 72, wherein the compounds of general formula Ib,m in which L' means o-(CHp)s-B a-CHp-CHp-(0-CHp-CHp-)yB a-CHp~(0-CHp-CHp-)yp a-CHy-NH-CO-f a-CHy-CH3-NH-S05-B o-CH-NH-CO-CH-N(CHCOOH)-S0»- a-CHy-NH-CO-CH»-N(CyH3)-SO5-8 a-CHp-NH-CO-CH3-N(CyoH21)-SO2-B a-CHp-NH-CO-CH2-N(CgH13)-SO5-B a-CH-NH-CO-(CH2)109-N(C2Hj5)-SO2-8 a-CH-NH-CO-CH2-N(-CHp-CgHj5)-S0»-B a-CH2-NH-CO-CH2-N(-CHp-CH7-OH)S 09-3 a-CH»-NHCO-(CH»)19-S-CH,CH»>-B a-CHpNHCOCH,-0-CH7CH-B a-CHp-CHoNHCOCH»>-0-CH»CH»-p a-CH;-(CH;-CH;-0)-(CH,);NHCO-CH,-O-CH,CH,-p a-CHpNHCO(CHj3)10-0-CH>CH»-B a-CH,CH2NHCO(CH3)19-0O-CH>CH>-B a-CHy-CgHg-O-CH2CHy-B whereby the phenylene group 1,4 or 1,3 is linked a-CH»-0-CH3-C(CH2-OCHpCHp-CgF13)2-CH-OCH,-CH>-B a-CH2-NHCOCHCH2CON-CH,CHoNHCOCH,N(CoH3)SOH»CgF 178 a-CH,-CH2NHCOCH;N(C,Hs)-S0,-B a-CHp-0-CH-CH(OCyH31)-CH»-0-CH>CH»- a-(CHoNHCO)4-CH0-CHoCH)- AMENDED SHEET

PCT/EFP.L/08453

® a-(CHANHCO)3-CH>O-CHCH2-B a-CH»-OCH»>C(CHyOH)-CH2-0-CH7CH2-B — 0 CH,— 0 Le * o COOH B a-CH>NHCOCH7N(CgH3)-502-B a-NHCO-CH,-CHp-B a-NHCO-CH»-O-CH7CH3-p a-NH-CO-B a-NH-CO-CH,-N(CH2COOH)-SO2-B a-NH-CO-CHp-N(CoHs)-SOp-B a-NH-CO-CHy-N(C}oH21)-SO2-B a-NH-CO-CH3-N(CgH13)-SO7-B a-NH-CO-(CH2)10-N(C2Hs)-802-B a-NH-CO-CHy-N(-CH3-CgHs)-SO2-f : a-NH-CO-CH3-N(-CH,-CH3-OH)SO5-B a-NH-CO-CHp-B a-CHy-0-CgH4-O-CHp-CHp-B a-CHy-CgHy4-O-CH»-CHj-B a-N(C2Hs)-S02-B o-N(CgHs)-SO02-B a-N(C0H21)-SO2-B a-N(CgH13)-SO2-B a-N(CoH40H)-S02-B a-N(CH,COOH)-SO2-B a-N(CH>CgHs)-SO2-B a-N-[CH(CH72OH),]-SO2-B a-N-[CH(CH,OH)CH(OH)(CH,OH)]-SO2-B whereby s stands for integers 1 to 15, and y stands for integers 1 to 6, are used.

AMENDED SHEET

PCT/EP01/08498 ® 393

77. Use according to claim 72, wherein the compounds of general formula Ib, in which L! means a-CH,-0O-CH,CH,-B, a-CH;-CHz-(O-CH,-CHa)y-B. a-CH,-(0-CH,-CHaz-),-B, a-CH,-CH,-NH-S0,-8, Example 10 a-CHoNHCOCH>-0-CH»CH»-B a-CH>-CHoNHCOCH;-0O-CH»CH>-B a-CH;-(CH;-CH»-0),~(CH2);NHCO-CH;-O-CH,CH,-p a-CHoNHCO(CH3)10-O-CH,CH»-B a-CH,CHoNHCO(CH3)10-O-CH,CH>- a-CH7-0-CH-CH(OC1gH71)-CH2-O-CH CHB a-CH>-0-CgHyg-O-CHp-CHp-B | or a-CHy-CgHyg-O-CH-CHp-p whereby y stands for integers 1 to 6, are used.

78. Use according to claim 72, wherein the compounds of general formula Ib, in which RF means a straight-chain or branched perfluorinated alkyl radical of formula C,F,,E, whereby n stands for number 4 to 15 and E stands for a terminal fluorine atom, are used. AMENDED SHEET

PCT/EP01/08498 C 394

79. Use according to one of claims 72 to 78, wherein the following compounds are used: -- 1,4,7-Tris(carboxylatomethyl)-1 0-(3-aza-4-oxo-hexan-5-ylic)-acid-N-(2,3- dihydroxypropyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-0xa)- perfluorotridecyl)-amide]-1,4,7,1 O-tetraazacyclododecane, gadolinium complex -- 1,4.7-Tnis(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)acid-N- (3,6,9,12,15-pentaoxa)-hexadecyl)-(1H,1H,2H,2H,4H 4H, 5H,5H-3 -oxa)- perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex -- 1,4,7-Tris(carboxylatomethyl)-10-{ (3-aza-4-oxo-hexan-5-ylic)-acid-N-5- hydroxy-3-oxa-pentyl)-N-(1H,1H,2H,2H,4H,4H,5H,5 H-3-oxa)- perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex -- 1,4,7-Tris(carboxylatomethyl)-10-{(3 -aza-4-0x0-hexan-5-ylic)-acid-[N- 3,6,9,15-tetraoxa-12-aza-15-0x0-C, 7-Ca¢-hepta-decafluoro)hexacosyl]- amide}-1,4,7,1 O-tetraazacyclododecane, gadolinium complex -- 1,4,7-Tris(carboxylatomethyl)-10-[(3 -aza-4-0xo0-hexan-5-ylic]-acid-N-(2- methoxyethyl)-N-(1H, 1 H,2H,2H,4H,4H,5H,5H-3 -oxa)-perfluorotridecyl}- armide}-1,4,7,10-tetraazacyclododecane, gadolinium complex.

80. Use according to one of claims 51 to 57, wherein as perfluoroalkyl- ~ containing metal complexes, the compounds with sugar radicals of general formula Ic (K)'~G ~ (Z-R)n' (Ic) (Y-R),' in which AMENDED SHEET

PCT/EP01/08498

® R represents a mono- or oligosaccharide radical bonded by the 1-OH- or 1- SH-position, RF is a perfluorinated, straight-chain or branched carbon chain with the formula -C,FanE, in which E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n stands for numbers 4-30, K stands for a metal complex of general formula llc, COOR? f a N Re RO rooc” hu Ne © COOR? (Ic) in which R! means a hydrogen atom or a metal ion equivalent of atomic numbers 23- 29, 42-46 or 38-70, provided that at least two R' stand for metal ion equivalents, R? and R® , independently of one another, represent hydrogen, C,-C;-alkyl, benzyl, phenyl, -CH,0H or -CH,OCHj, and U represents -C¢Hy-O-CHz-w, -(CH3)1.5-w, a phenylene group, -CH-NHCO- CH>-CH(CH,COOH)-C¢Hs-w, -C¢Ha-(OCH,CH,)o-1-N(CH,COOH)-CH,- o, or a C;-Cz-alkylene group or C7-C3-CsHa-O group optionally interrupted by one or more oxygen atoms, 1 to 3 -NHCO groups or 1 to 3 : -CONH groups and/or substituted with 1 to 3 -(CH2).sCOOH groups, whereby o stands for the binding site to -CO-, or AMENDED SHEET

PCT/EP01/08498 of general formula IIIc CCOOR™ Co / NTN Coort 0 \ > ~—N Alm R'OOC / COOR? (IIc) in which R' has the above-mentioned meaning, R* represents hydrogen or a metal ion equivalent mentioned under R', and U’ represents -CgHs-O-CH,-0, whereby © means the binding site to -CO-, : or of general formula IVc ~~ OR? CNN R2 R'0COC / i © . COOR? ave) in which R! and R? have the above-mentioned meaning or of general formula VcA or VcB NEES a ~~COOR’ ~—N R'O0C / NUNTE0 OR? ~— 1 COOR (VcA) ~ AMENDED SHEET

PCT/EP01/08498

® N ~—~COOR" 0 a ~COOCR" N NUN ~—COOR" ; ~COOR (VeB) in which R' has the above-mentioned meaning, or of general formula Vic RIOOC— CO, R'OOC—" ~—CQOR" (Vic) in which R' has the above-mentioned meaning, or of general formula VlIc R'O0C— 0 N J, R'OOC—" U R'O0C EEN R'O0C—~ (VII) in which R' has the above-mentioned meaning, and U! represents -CgHy-O-CH,-w, whereby © means the binding site to -CO- or of general formula VIiIc or R’ ya N —N N N ~~ rR'00C” / CTH NE Or COOR! (VIII) in which R' has the above-mentioned meaning, AMENDED SHEET

PCT/EP01/08498 and in radical K, optionally present free acid groups optionally can be present as salts of organic and/or inorganic bases or amino acids or amino acid amides,

G for the case that K means metal complexes llc to V1Ic represents a radical that is functionalized in at least three places and is selected from the following radicals a) to j)

PCT/EP01/08498 PS 399 (d) Co p MY p © i CO B wa—o0onN N—— H H ® NH —CO CCH, iN had ( NH N-rY CH) -Nw~~c H (CH) H 4 p AMENDED SHEET

PCT/EP01/08498

: ha Co N—CO—CH—(CH,) NH \ Y NH—CO—CH—(CH, J NH-8 \ B ® H H A Mme—N—(CH,);: C—N—CO-C— (CH); N ——wp H tH | H I NH ¥ B M CNN Ho \ p N= (CHC —CON N——.y NH Pp } NAN a AMENDED SHEET

PCT/EP01/08498 a gw~NH—CH — CO —w Ed B and G for the case that K means metal complex VIlIc represents a radical that is functionalized in at least three places and is selected from k) or 1), k) pom NH—(CHp J CH= Cove y So am CO— CH CH=CH CO p whereby a means the binding site of G to complex K, B is the binding site of G to radical Y, and vy represents the binding site of G to radical Z, Y means -CHj3, 6-(CHz)q.5CO-B, 8-CH,-CHOH-CO-8 or 6-CH(CHOH- CH,0OH)-CHOH-CHOH-CO-B, whereby represents the binding site to sugar radical R, and B is the binding site to radical G, Zz stands for STN ™ ¥—NC N—S05¢ AMENDED SHEET

PCT/EP01/08498 o 402 v-COCH,-N(C;H¢)-SO--¢, y-COCH,-0-(CH1 )»-SO,-¢, 0 0 TN or y - NHCH,CH,-O-CH,CH,-¢ whereby y represents the binding site of Z to radical G, and £ means the binding site of Z to perfluorinated radical RF and I, m!, independently of one another, mean integers 1 or 2, and p' means integers 1 to 4, are used.

81. Use according to claim 80, wherein the compounds of general formula Ic, in which R represents a monosaccharide radical with 5 to 6 C atoms or its deoxy compound, preferably glucose, mannose or galactose, are used.

82. Use according to claim 80, wherein the compounds of general formula Ic, in which R? and R?, independently of one another, mean hydrogen or C,-C alkyl and/or E in formula -C_F,, means a fluorine atom, are used.

83. Use according to claim 80, wherein the compounds of general formula Ic, in which G represents lysine radical (a) or (b), are used.

84. Use according to claim 80, wherein the compounds of general formula Ic, in which Z means

7’ . “~ —< —_ Y—N N—S05¢ AMENDED SHEET

PCT/EP01/08498 C 403 whereby 7 represents the binding site of Z to radical G, and € means the binding site of Z to perfluorinated radical RF, and/or Y means 8-CH,CO-B, whereby & represents the binding site to sugar radical R, and B represents the binding site to radical G, are used.

85. Use according to claim 80, wherein the compounds of general formula Ic, in which U in metal complex K represents -CH,- or -CiH,-O-CH,-w, whereby w stands for the binding site to -CO-, are used.

86. Use according to claim 80, wherein the gadolinium complex of 6-N-[1,4,7- tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-0x0-5- methyl-5-y1)]-2-N-[1-O-a-D-carbonylmethyl-mannopyranose]-L-lysine-[1-(4- perfluorooctylsulfonyl)-piperazine]-amide is used.

87. Use according to one of claims 51 to 57, wherein as perfluoroalkyl- containing metal complexes, the compounds with polar radicals of general formula Id (K)'- G — (Z-R)n' ag R)p’ in which RF is a perfluorinated, straight-chain or branced carbon chain with formula -C,F,,E, in which E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n stands for numbers 4-30, K stands for a metal complex of general formula IId, AMENDED SHEET

PCT/EP01/08498

® COOR? : ! ¢ NT N RRO rRooc” J al © COOR! _ in which R! means a hydrogen atom or a metal ion equivalent of atomic numbers 23- 29, 42-46 or 58-70, provided that at least two R! stand for metal ion equivalents, R? and R?, independently of one another, represent hydrogen, C,-Cs-alkyl, benzyl, phenyl, -CH,OH or -CH,OCH3, and U represents -C¢Hs-O-CH,-w-, -(CHa);.5-0, a phenylene group, -CH,- NHCO-CH,-CH(CH,COOH)-C¢H4-0-, _CHa-(OCH; CH). 1- ] N(CH>COOH)-CH;-w, or a C;-C,»-alkylene group or C4-C3-C¢H4-O group optionally interrupted by one or more oxygen atoms, 1 to 3 -NHCO groups, 1 to 3 -CONH groups and/or substituted with 1 to 3 -(CHa)o.sCOOH groups, whereby o stands for the binding site to -CO-, or of general formula II1d COOR? é SINT N COOR* © A SS A. rooc” NTU A COOR? (111d) AMENDED SHEET

PCT/EP01/08498 in which R' has the above-mentioned meaning, R* represents hydrogen or a metal ion equivalent mentioned under R', and U’ represents -CgHy-O-CHa-0-, whereby » means the binding site to -CO-, or of general formula IVd oa CNN R2 er R'O0C™ / p, 5 \ ~ COOR"? (IVd) in which R' and R? have the above-mentioned meaning, or of general formula VdA or VdB —CO—~ a N—coor: ~—N R'OQC / NUNTEC9 OR’ ~— 1 COOR (VAA) No CO OR" SNC Coor: [J N NUN —COOR" 1 ~COOR (VdB) in which R' has the above-mentioned meaning, : AMENDED SHEET

PCT/EP01/08498 or of general formula VId R'WOOC—_ 7 \. _—C0—wm, IR N NZ R R'OOC—" ~—CQOOR? (V1d) in which R' has the above-mentioned meaning, or of general formula VIId ROOC—_ > 1 — N AL, R'OQC U R'0QC SN R'0O0C— (VIld) in which R! has the above-mentioned meaning, and ~ U' represents -C¢H,-O-CHz-0-, whereby o means the binding site to -CO-, and in radical K, optionally present free acid groups optionally can be present as salts of organic and/or inorganic bases or amino acids or amino acid amides, G represents a radical that is functionalized in at least three places and is selected from the following radicals a) to g) (a) H o MN (CHy)—C—CO —wy NH i p (b) H y #~CO-C—(CH,)N wep od AMENDED SHEET

PCT/EP01/08498

® ) (c) (04 CNN \ pr—N No 3 (04 (d) Nd B (e) Ly B ww——N N—wa ca H H - AMENDED SHEET .

PCT/EP01/08498

® H H Gem —N— (CH) G—N-CO TCR — 3 I NH Y : P (2) HN N il 3 04 Y B (h} Y COACH) pr-0O™p (i) B ~w CO-(CHy)yyCH-COmy NH : NH a a whereby a means the binding site of G to complex K, B is the binding site of G to radical R, and vy represents the binding site of G to radical Z Zz stands for ZN ¥—N: -N—C0s-¢ y-C(O)CH,0(CH,),-¢, whereby vy represents the binding site of Z to radical G and € means the binding site of Z to perfluorinated radical Ry, AMENDED SHEET

PCT/EP01/08498 R represents a polar radical that is selected from complexes K of general formulas I1d to VIId, whereby R' here means a hydrogen atom or a metal ion equivalent of atomic numbers 20, 23-29, 42-46 or 58-70, and radicals rR? rR’, RY, U and U! have the above-indicated meaning, or R means the folic acid radical or R means a carbon chain with 2-30 C atoms that is bonded to radical G via -CO- or SO,- and is straight or branched, saturated or unsaturated, optionally interrupted by 1-10 oxygen atoms, 1-5 -NHCO groups, 1-5 -CONH groups, 1-2 sulfur atoms, 1-5 -NH groups or 1-2 phenylene groups, which optionally can be substituted with 1-2 OH groups, 1-2 NH; groups, 1-2 -COOH groups, or 1-2 -SOsH groups, or optionally substituted with 1-8 OH groups, 1-5 -COOH groups, 1-2 SO;H groups, 1-5 NH; groups, 1-5 C,-Cs-alkoxy groups, and I!, m', p%, independently of one another, mean integer 1 or 2, are used.

88. Use according to claim 87, wherein the compounds of general formula Id, in which K stands for a metal complex of general formula IId, IIId, VdB or VIId, are used.

89. Use according to claim 87, wherein the compounds of general formula Id, in which polar radical R has the meaning of complex K, preferably complex K of general formula IId, IIId, VdA or VIId, are used.

90. Use according to claim 87, wherein the compounds of general formula Id, in which polar radical R has the following meanings: -C(O)CH:CH,SO3H AMENDED SHEET

PCT/EP01/08498 ® 410 -C(0)CH>0OCH>CH,0CH,CH:OH -C(0)CH,OCH,CH,0OH -C(0)CH;OCH:CH(OH)CH,OH -C(O)CH;NH-C(O)CH,COOH -C(0)CH,CH(OH)CH:0OH -C(0)CH.OCH,COOH -SO,CH,CH.COOH -C(0)-CgH3-(m-COOH), -C(0)CH;0(CHa2),-C¢H3-(m-COOH)2 -C(0)CH,0-C¢H4-m-SOsH -C(O)CH,NHC(O)CH,NHC(0)CH,OCH,COOH -C(0)CH,0CH,CH,0CH,COOH -C(0)CH,0CH,CH(OH)CH,0-CH,CH,OH -C(0)CH,OCH,CH(OH)CH,OCH,-CH(OH)-CH,OH -C(O)CH,SOsH -C(0)CH,CH,COOH -C(O)CH(OH)CH(OH)CH,OH -C(0)CH,0[(CH2).0]:5-CHj -C(0O)CH;O[(CH2)20]19-H -C(O)CH,OCH(CH,0H), -C(0)CH,0OCH(CH>0CH,COOH)> -C(0)-C¢H3-(m-OCH,COOH), -CO-CH,0-(CH;).0(CH;),0-(CH;);0(CH,),OCH; preferably —C(O)CH0[(CH),0]4-CHs, are used.

91. Use according to claim 87, wherein the compounds of general formula Id, in which polar radical R is the folic acid radical, are used.

92. Use according to claim 87, wherein the compounds of general formula Id, in which G represents lysine radical (a) or (b), are used.

93. Use according to claim 87, wherein the compounds of general formula Id, in which U represents group -CH,- or -C¢H,-O-CH,-w in metal complex K, whereby w stands for the binding site to -CO-, are used. AMENDED SHEET

PCT/EP01/08498 ®

94. Use according to one of claims 87-93, wherein the gadolinium complex of 2,6-N,N'-bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-y1)]-lysine-[1-(4-perfluorooctylsulfonyl-piperazine]- amide is used.

95. Use according to one of claims 51-57, wherein as perfluoroalkyl-containing metal complexes, galenical formulations that contain paramagnetic, perfluoroalkyl- containing metal complexes of general formulas I, Ia, Ib, Ic and/or Id and diamagnetic perfluoroalkyl-containing substances, preferably dissolved in an aqueous solvent, are used.

96. Use according to claim 95, wherein as diamagnetic perfluoroalkyl- containing substances, those of general formula XX RF-12-B? (XX) in which RF represents a straight-chain or branched perfluoroalkyl radicai with 4 to 30 carbon atoms, L? stands for a linker and B? stands for a hydrophilic group, are used.

97. Use according to claim 96, wherein linker L? is a direct bond, an -SO, group, or a straight-chain or branched carbon chain with up to 20 carbon atoms, which can be substituted with one or more -OH, -COO-, -SO; groups and/or optionally contains one or more -O-, -S-, -CO-, -CONH-, -NHCO-, -CONR’-, -NR°CO-, -SO,-, -PO,-, -NH- or -NR® groups, an aryl ring or a piperazine, whereby R® stands for a C,- to Cy-alkyl radical, which in turn can contain one or more O atoms, and/or can be substituted with -COO’ or SO; groups.

98. Use according to claim 96, wherein hydrophilic group B? is a mono-or disaccharide, one or more adjacent -COO" or -SO; groups, a dicarboxylic acid, an isophthalic acid, a picolinic acid, a benzenesulfonic acid, a tetrahydropyrandicarboxylic acid, a 2,6-pyridinedicarboxylic acid, a quaternary ammonium ion, an aminopolycarboxylic acid, an aminodipolyethylene glycolsulfonic acid, an aminopolyethylene glycol group, an SO,-(CH,),-OH group, a polyhydroxyalkyl chain AMENDED SHEET

PCT/EP01/08498 ® with at least two hydroxyl groups or one or more polyethylene glycol chains with at least two glycol units, whereby the polyethylene glycol chains are terminated by an -OH or -OCH; group.

99. Use according to claim 95, wherein as diamagnetic perfluoroalkyl- containing substances, conjugates that consist of a-, 8- or y-cyclodextrin and compounds of general formula XXII Al-L*-RF (XXII) in which A? stands for an adamantane, biphenyl or anthracene molecule, L? stands for a linker, and RF stands for a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms, and whereby linker L3 is a straight-chain hydrocarbon chain with 1 to 20 carbon atoms, which can be interrupted by one or more oxygen atoms, one or more CO-, SO,-, CONH-, NHCO-, CONR"-, NR¥CO-, NH- or NR" groups or a piperazine, whereby RY is a C,-Cs-alkyl radical, are used.

100. Use according to claim 95, wherein as diamagnetic perfluoroalkyl- containing substances, those of general formula XXI: RF-X! XXI) in which RF represents a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms, and X' is a radical that is selected from the group of the following radicals (n is this case is a number between 1 and 10), are used: OH OH were a. Ise o 0 AMENDED SHEET

PCT/EP01/08498

OH 0 OH [a HE2 ° No NS dd ¢ Oo OH O swore, HN rr (PANO TR Oo OH OH O HE2 do Oo OL Ng sl. _ // "0 : Oo OH gO O Ne ~ AT HO Oo AMENDED SHEET

PCT/EP01/08498 OH OH o Hg? 0] O a ~o OH 0 OH NE HAC O AN 0) Ne oN 0) OH OH 0 HES 0 IM ~~

H

0.0 wore, on DC aN OH OL JG HO OH (a+B) i 2 a a ON 0 AMENDED SHEET

PCT/EP01/08498

0] Oo OH u Noo Oe oy @) OH NON Q 0 OH rem Gm NTN NNN I Ne 0 TNO __ OH o LL - 0 / COO . @) coo : 0 ad ca®* N COO" NN 0; 0 en IN Git HO OH OH NS OH HO HO OH ) COO ne SNOT AMENDED SHEET

416 PCT/EP01/08498 @ eo) COO oN coo H COO” “coo

101. A contrast medium for use in a method of MR imaging for visualization of plaque, said contrast medium comprising perfluoroalkyl-containing metal complexes that have a critical micelle formation concentration < 10? mol/l, a hydrodynamic micelle diameter (2 Rh) > 1 nm and a proton relaxivity in plasma (R') > 10 I/mmol's, and said method comprising administering said contrast medium.

102. A contrast medium for use in a method of MR imaging according to claim 101, characterized in that the metal complexes are also used as MRI contrast media for visualization of lymph nodes.

103. A contrast medium for use in a method of MR imaging according to claim 101 or 102, wherein the metal complexes are also used as MRI contrast media for visualization of infarcted and necrotic tissue.

104. A contrast medium for use in a method of MR imaging according to one of claims 101 to 103, wherein the metal complexes are also used as MRI contrast media for independent visualization of necroses and tumors.

105. A contrast medium for use in a method of MR imaging according to claim 101, herein metal complexes whose micelle formation concentration is < 10* mol/l are used.

106. A contrast medium for use in a method of MR imaging according to claim 101, wherein metal complexes whose hydrodynamic micelle diameter is = 3, preferably > 4 nm, are used.

107. A contrast medium for use in a method of MR imaging according to claim AMENDED SHEET

417 PCT/EP01/08498 @ 101, wherein metal complexes that have a proton relaxivity in plasma of > 13 I/mmol's, preferably > 15 1/mmol's, are used.

108. A contrast medium for use in a method of MR imaging according to one of claims 101 to 107, wherein as perfluoroalkyl-containing metal complexes, the compounds of general formula I as defined in claim 8, are used.

109. A contrast medium for use in a method of MR imaging according to claim 108, wherein the compounds of general formula I as defined in claim 9, are used.

110. A contrast medium for use in a method of MR imaging according to claim 108 or 109, wherein the compounds of formula I in which n in formula -C,F,E stands for numbers 4-15 and/or E in this formula means a fluorine atom are used.

111. A contrast medium for use in a method of MR imaging according to one of claims 108 to 110, wherein the compounds listed in claim 11, are used.

112. A contrast medium for use in a method of MR imaging according to one of claims 101 - 107 wherein as perfluoroalkyl-containing metal complexes, the compounds of general formula Ia as defined in claim 12, are used.

113. A contrast medium for use in a method of MR imaging according to claim 112, wherein the compounds of general formula Ia in which q is the number 1 are used.

114. A contrast medium for use in a method of MR imaging according to claim 112, wherein the compounds of general formula Ia as defined in claim 14, are used.

115. A contrast medium for use in a method of MR imaging according to claim 112, wherein the compounds of general formula Ia, in which Vis a molecule portion with one of the structures listed in claim 15, are used.

116. A contrast medium for use in a method of MR imaging according to claim 112, wherein the compounds of general formula Ia, in which K represents a complex of general formula Va, Va, VIIa or VIIIa as defined in claim 16, are used.

117. A contrast medium for use in a method of MR imaging according to claim 116, wherein the C,-C,;-alkylene chain that stands for U* contains the groups -CH,NHCO-, -NHCOCH,O-, -NHCOCH,0CH,-, -(CH,CO,H)-, -CH,0CH,-, -NHCOCH,C.H,-, -NHCSNHCH,-, -CH,0CH,-, -CH,CH,O- and/or is substituted by the groups -COOH and -CH,COOH.

118. A contrast medium for use in a method of MR imaging according to claim 116, wherein U? stands for a -CH,-, -CH,CH,-, -CH,CH,CH,-, -CH,-, -CH,,-, AMENDED SHEET

418 PCT/EP01/08498 @ CCH -CH,NHCOCH,CH(CH,CO,H)-C H,-, -CH,NHCOCH,0CH,-, or -CH,NHCOCH,C¢H,- group.

119. A contrast medium for use in a method of MR imaging according to claim 112, wherein the compounds of general formula Ia, in which K has one of the structures listed in claim 19, are used.

120. A contrast medium for use in a method of MR imaging according to one of claims 112 to 119, wherein the compounds of general formula Ia in which the perfluoroalky! chain RF is -CyF;, -CgF 4, - CF, or -C,,F,5 are used.

121. A contrast medium for use in a method of MR imaging according to one of claims 112 to 120, wherein the gadolinium complex of 1,4,7-tris{1,4,7-tris(N- (carboxylatomethyl)-10-[N-1-methyl-3,06-diaza-2,5,8-trioxooctane-1,8-diyl)]-1,4,7,10- tetraazacyclododecane, Gd complex}-10-[N-2H,2H,4H,4H,5H,5H-3-o0xa-perfluoro- tridecanoyl]}-1,4,7,10-tetraazacyclododecane is used.

122. A contrast medium for use in a method of MR imaging according to one of claims 101 to 107, wherein as perfluoroalkyl-containing metal complexes, the compounds of general formula Ib as defined in claim 22, are used.

123. A contrast medium for use in a method of MR imaging according to claim 122, wherein the compounds of general formula Ib, in which R?, R? and R®, independently of one another, mean hydrogen or a C,-C, alkyl group, are used.

124. A contrast medium for use in a method of MR imaging according to claim 122, wherein the compounds of general formula Ib as defined in claim 24, are used.

125. A contrast medium for use in a method of MR imaging according to claim 122, wherein the compounds of general formula 1b as defined in claim 25, are used.

126. A contrast medium for use in a method of MR imaging according to claim 122, wherein the compounds of general formula Ib as defined in claim 26, are used.

127. A contrast medium for use in a method of MR imaging according to claim 122, wherein the compounds of general formula Ib as defined in claim 27, are used.

128. A contrast medium for use in a method of MR imaging according to claim 122, wherein the compounds of general formula Ib, in which RF means a straight-chain or branched perfluorinated alkyl radical of formula CF, E, whereby n stands for number 4 to 15 and E stands for a terminal fluorine atom, are used.

129. A contrast medium for use in a method of MR imaging according to one of claims 122 to 128, wherein the compounds listed in claim 29, are used.

130. A contrast medium for use in a method of MR imaging according to one of claims 101 to 107, wherein as perfluoroalkyl-containing metal complexes, the AMENDED SHEET :

419 PCT/EP01/08498 @ compounds with sugar radicals of general formula Ic as defined in claim 30, are used.

131. A contrast medium for use in a method of MR imaging according to claim 130, wherein the compounds of general formula Ic, in which R represents a monosaccharide radical with 5 to 6 C atoms or its deoxy compound, preferably glucose, mannose or galactose, are used.

132. A contrast medium for use in a method of MR imaging according to claim 130, wherein the compounds of general formula Ic, in which R? and R?, independently of one another, mean hydrogen or C,-C,-alkyl and/or E in formula -C_F,, means a fluorine atom, are used.

133. A contrast medium for use in a method of MR imaging according to claim 130, wherein the compounds of general formula Ic, in which G represents lysine radical (a) or (b), are used.

134. A contrast medium for use in a method of MR imaging according to claim 130, wherein the compounds of general formula Ic as defined in claim 34, are used.

135. A contrast medium for use in a method of MR imaging according to claim 130, wherein the compounds of general formula Ic, in which U in metal complex K represents -CH,- or -C¢H,-O-CH,-w, whereby w stands for the binding site to -CO-, are used.

136. A contrast medium for use in a method of MR imaging according to claim 130, wherein the gadolinium complex of 6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10- tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5-y1)]-2-N-[1-O-a-D- carbonylmethyl-mannopyranose]-L-lysine-[ 1-(4-perfluorooctylsulfonyl)-piperazine]-amide is used.

137. A contrast medium for use in a method of MR imaging according to one of claims 101 to 107, wherein as perfluoroalkyl-containing metal complexes, the compounds with polar radicals of general formula Id as defined in claim 37, are used.

138. A contrast medium for use in a method of MR imaging according to claim 137, wherein the compounds of general formula Id, in which K stands for a metal complex of general formula IId, ITId, VdB or VIId, are used.

139. A contrast medium for use in a method of MR imaging according to claim 137, wherein the compounds of general formula Id, in which polar radical R has the meaning of complex K, preferably complex K of general formula IId, IIId, VdA or VIId, are used.

140. A contrast medium for use in a method of MR imaging according to claim 137, wherein the compounds of general formula Id, in which polar radical R has the AMENDED SHEET

420 PCT/EP01/08498 @ meanings listed in claim 40, are used.

141. A contrast medium for use in a method of MR imaging according to claim 137, wherein the compounds of general formula Id, in which polar radical R is the folic J acid radical, are used.

142. A contrast medium for use in a method of MR imaging according to claim 137, wherein the compounds of general formula 1d, in which G represents lysine radical (a) or (b), are used.

143. A contrast medium for use in a method of MR imaging according to claim 137, wherein the compounds of general formula Id, in which U represents group -CH,- or -C¢H,-O-CH,-w in metal complex K, whereby w stands for the binding site to -CO-, are used.

144. A contrast medium for use in a method of MR imaging according to one of claims 137-143, wherein the gadolinium complex of 2,6-N,N'-bis[1,4,7- tris(carboxylatomethyl)-1,4,7, 10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5- methyl-5-yl)]-lysine-[ 1-(4-perfluorooctylsulfonyl-piperazine]-amide is used.

145. A contrast medium for use in a method of MR imaging according to one of claims 101-107, wherein as perflyoroalkyl-containing metal complexes, galenical formulations that contain paramagnetic, perfluoroalkyl-containing metal complexes of general formulas I, Ia, 1b, Ic and/or Id and diamagnetic perfluoroalkyl-containing substances, preferably dissolved in an aqueous solvent, are used.

146. A contrast medium for use in a method of MR imaging according to claim 145, wherein as diamagnetic perfluoroalkyl-containing substances, those of general formula XX RF-L2-B? (XX) in which RF represents a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms, L? stands for a linker and B? stands for a hydrophilic group, are used.

147. A contrast medium for use in a method of MR imaging according to claim 146, wherein linker L? is a direct bond, an -SO, group, or a straight-chain or branched carbon chain with up to 20 carbon atoms, which can be substituted with one or more -OH, -COO-, -SO, groups and/or optionally contains one or more -O-, -S-, -CO-, -CONH-, -NHCO-, -CONR®-, -NR’CO-, -SO,-, -PO,-, -NH- or -NR’ groups, an aryl ring or a piperazine, whereby R® stands for a C,- to Cyy-alkyl radical, which in turn can contain one or more O atoms, and/or can be substituted with -COO™ or SO; groups.

148. A contrast medium for use in a method of MR imaging according to claim 146, wherein hydrophilic group B? is a mono-or disaccharide, one or more adjacent -COO" AMENDED SHEET

A 421 PCT/EP01/08498 o> -SO;" groups, a dicarboxylic acid, an isophthalic acid, a picolinic acid, a ‘ benzenesulfonic acid, a tetrahydropyrandicarboxylic acid, a 2,6-pyridinedicarboxylic acid, a quaternary ammonium ion, an aminopolycarboxylic acid, an aminodipolyethylene glycolsulfonic acid, an aminopolyethylene glycol group, an SO,-(CH,),-OH group, a polyhydroxyalkyl chain with at least two hydroxyl groups or one or more polyethylene glycol chains with at least two glycol units, whereby the polyethylene glycol chains are terminated by an -OH or -OCH, group.

149. A contrast medium for use in a method of MR imaging according to claim 145, wherein as diamagnetic perfluoroalkyl-containing substances, conjugates that consist of a-, B- or y-cyclodextrin and compounds of general formula XXII ALL-RF (XXII) in which A? stands for an adamantane, biphenyl or anthracene molecule, L3? stands for a linker, and RF stands for a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms, and whereby linker L? is a straight-chain hydrocarbon chain with 1 to 20 carbon atoms, which can be interrupted by one or more oxygen atoms, one or more CO-, SO,-, CONH-, NHCO-, CONR'"-, NR'CO-, NH- or NR" groups or a piperazine, whereby R' is a C,-Cs-alkyl radical, are used.

150. A contrast medium for use in a method of MR imaging according to claim 145, wherein as diamagnetic perfluoroalkyl-containing substances, those of general formula XXI as defined in claim 50, are used.

151. Use according to any one of claims 1 to 100, substantially as herein described and illustrated. :

152. A contrast medium for use in a method of MR imaging according to any one of claims 101 to 150, substantially as herein described and illustrated.

153. A new use of a contrast medium as defined in claim 1, or a contrast medium for a new use in a method of MR imaging, substantially as herein described. AMENDED SHEET