NO323547B1 - Pharmaceutical agents containing perfluoroalkyl-containing metal complexes and their use in the manufacture of drugs in tumor therapy and interventional radiology. - Google Patents

Abstract

The invention relates to pharmaceutical agents containing perfluoroalkylated metal complexes of the general formula (I) RF-L-A and the use thereof in tumour therapy and interventional radiology, in which formula RF is a perfluorinated, straight-chain or branched carbon chain with the formula -CnF2nX, in which X is a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n represents the numbers 4-30, L is a binding group, and A is a metal complex or the salts thereof of organic and/or inorganic bases or amino acids or amino acid amides. L and A are defined in detail in the description.

Description

The present invention relates to the subject matter according to the patent claims, i.e. pharmaceutical agents containing monomeric, perfluoroalkyl-substituted metal complexes and complex salts and their use for the production of drugs for tumor therapy and interventional radiology.

The use of foreign materials - placed in the bloodstream by injection to induce an embolism - was already suggested at the beginning of this century [Dawbarn, Journal of the American Medical Association 43:792, (1904)].

However, this thought was only seriously revived after approx. 30 years (Young, British Medical Journal 283, 1144, 1981). The embolization was used for diagnostic and therapeutic purposes, especially for the treatment of tumors. The embolization of blood vessels that supply a tumor area with blood is a technique used to either produce a permanent blood vessel blockade and thereby cause the tumor to die, or a temporary embolization to increase the therapeutic effect of a simultaneously administered chemotherapeutic agent. The latter technique is called chemoembolization. The advantage of such treatment is its local limitation. A prerequisite is the presence of a sufficiently large (ie which enables catheterisation) blood vessel which supplies the tumor with blood.

In humans, liver tumors in particular are amenable to embolization therapy. Liver tumors are supplied to 80-100% with blood through the hepatic artery. In contrast, the normal liver parenchyma is supplied mainly (about 75%) through the portal vein (porta). By embolizing the hepatic artery, a selective treatment of primary and metastatic liver cancer can therefore be achieved.

Hepatocellular carcinoma (HCC) previously occurred rarely in Europe and the USA, but applies in Asia (Japan, South Korea) and Africa as the most frequent, malignant tumor disease of the head which in the majority of cases occurs together with liver cirrhosis produced by hepatitis B and C. [Therapie Konzepte Onkologie, S. Seber, J. Schtitte (Eds.) Springer, 536-545,

(1995)]. Despite extensive efforts, it is a long time

did not achieve any significant improvement in the very poor prognosis of this disease. Both untreated, and also after

systemic treatment with cytostatics (above all 5-fluorouracil, mitomycin C, cisplatin, doxorubicin) the average survival time is 1-9 months after diagnosis [K. Okuda et al.r Natural History of HCC and Prognosis in Relation to Treatment. Study of 850 patients. Cancer 56, 918-928,

(1985)]. Only by surgical removal of the tumor, which is in reality only possible for 20% of patients, can a significant extension of life be achieved, but only in the fewest cases a real cure. A relevant goal for new therapies is above all an improvement in the patients' quality of life because a complete cure can hardly be achieved for a majority of patients according to the current level of knowledge due to the basic primary disease hepatitis B. Operative removal of tumors, like systemic chemotherapy, represents a high burden . In recent years, chemoembolization has developed into the method of choice. By this is understood the simultaneous administration of a cytostatic drug mixed with an embolizing agent with the aim of forming a local embolus from which the drug is released slowly and above all over a long period of time (optimally 5-8 days). As a result of the reduced blood flow, the tumor tissue is exposed to an increased drug exposure [P. H. Madoule et al., Chemoembolization: principles and perspectives, J. Microencapsulation 1, 21-25, (1984)]. The locally developing ischemia supports the fight against tumours. In the most frequently used chemoembolization method in Japan and South Korea, an emulsion of "Lipiodol" (ethyl ester of iodized poppy seed oil) and aqueous cytostatic solutions are used as peripheral embolization and as a depot. Because there are no similar ready-made preparations on the market, the emulsions are prepared according to "homemade" prescriptions in the clinics on site. This means that the quality of the preparations varies greatly from clinic to clinic and that there is no new and reproducible data for the most important parameters such as particle size, residence time in the tumor and excretion capacity. The emulsions are selectively/superselectively introduced into the tumor-bearing branch of the hepatic artery by means of a percutaneous catheter. In addition, as a rule, the arterial supply is then stopped with the help of "Gelfoam" particles to prevent too rapid washing out of the lipiodol emulsion. "Lipiodol" is enriched to a certain extent in HCC (T. Konno et al., Selective Targeting of Anticancer Drug and Simultaneous Image Enhancement in Solid Tumor by Arterial Administered Lipid Contrast Medium, Cancer 54, 2367-2374, 1984) and is only found a smaller portion in healthy liver parenchyma. With this method, it is problematic that a non-quantifiable proportion passes through the capillary system and is then enriched in the lungs or spleen. The blood clot exists above. longer time {1-4 weeks) and entails, in addition to the longer residence time of the cytostatic agent in the tumor, an ischemic load on the tumor. Due to the lack of biodegradability, "Lipiodol" is practically not excreted and remains in the necrotic tumor tissue, which can therefore only be insufficiently resorbed. As a rule, this treatment is regularly repeated at intervals of several weeks. The survival rate with this method is slightly below the operative removal of the tumor, but significantly above pure chemotherapy (T. Kaneiriatsu, A '5-year Experience of Lipiodolization: Selective Regional Chemotherapy for 200 patients with HCC, Hepatology, 10, 98 -102, 1989, D. Vetter et al., Trans-catheter Oily Chemoembolization in the Management of Advanced HCC in Cirrhosis: Results of a Western Comparative Study in 60 Patients, Hepatology, 13, 427-433, 1991). Despite the described problems, the "lipiodol" method, compared to other embolization techniques with more or less biodegradable particle suspensions (see table 1), has been carried out as the most widespread therapy concept in the Asian area to date. The perfluoroalkyl-containing metal complexes according to the present invention exhibit unusual physiochemical properties in aqueous solution. They are to a surprisingly high degree thixotropic, so that these compounds are very suitable as embylosates. These solutions have a gel-like consistency in which position, but under the influence of shear forces they can become liquid (can be advanced with the help of pumps and through longer catheters). The high viscosity of the compounds suitable for use in the present invention will, at the lower shear forces, such as are prevalent in the tissue's capillary vascular system, lead to a reliable, temporary closure of these blood vessels. At the same time, these compounds have sufficiently good flow properties under pressure, which is necessary for administration through long catheters. The compounds according to the invention make it possible to formulate highly active cytostatics (e.g. 5-fluorouracil, mitomycin C, cisplatin, doxorubicin). In this way, the active substance is introduced into the body only locally in a higher concentration. The systemic burden with the known side effects is thereby small. The blood clot formed is not permanent, but can dissolve slowly. The components are transported away with the blood and excreted through the kidneys. This is beneficial because the incorporated cytostatic agent in the formulation is in this way released from a depot for a longer period of time in direct proximity to the tumor, and because a further administration is possible after dissolution of the blood clot. If the compounds according to the present invention contain paramagnetic or radiopaque ions, the embolization process and the following therapy can be followed diagnostically by means of NMR or X-ray (CT) diagnostics (interventional radiology). However, it is also possible to use combinations of compounds according to the present invention with other contrast agents that are useful in NMR and X-ray diagnostics (e.g. "Magnevist", "Isovist", "Iopamidol", "Ultravist" etc.). With the agents according to the present invention, the side effects described for the previously known agents are avoided, such as, above all, microembolism (e.g. in the lung). The perfluorinated compounds suitable for use in the present invention is described using the general formula I, according to the invention. The invention thus relates to a pharmaceutical agent, characterized in that they contain at least one perfluoroalkyl-containing compound of general formula I

in which

RF denotes a perfluorinated, straight-chain or branched hydrocarbon chain with the formula -C„F2nX, in which X denotes a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n denotes the numbers 4-30,

L denotes a direct bond, a methylene group, a

-NHCO group, a group

there

p denotes the numbers 0-10, q and u denote independent of

each other the number 0 or 1, and

R<1> denotes a hydrogen atom, a methyl group, a

-CH2-OH group, a -CH2-CO2H group or a C2-Cl5 chain which is optionally interrupted by 1-3 oxygen atoms, 1-2 >CO groups or an optionally substituted aryl group, and/or is substituted with 1-4 hydroxyl groups, 1-2 C1-C4 alkoxy groups, 1-

2 carboxy groups, a group -SO3H-, or- denotes a straight-chain, branched, saturated or unsaturated C2"C30 hydrocarbon chain which optionally contains and/or is interrupted by 1-10 oxygen atoms, 1-3 -KR<1->groups, 1-2 sulfur atoms, one piperazine group, one - CONE^ group, one -NR<x>CO group, one -SO2 group, one - NR<x->CO2 group, 1-2 -CO groups, a group

substituted aryl groups,

and/or is optionally substituted with 1-3 -OR<1->groupf 1-2

oxo groups, 1-2 -NH-COR<1> groups, 1-2 -CONHR<1->groups, 1-2 - (CH2)p-CO2H groups, 1-2 groups -

(CH2)p-(0)q-CH2CH2-RF,

where

R<1>, RF and p and q have the meanings indicated above, and

T denotes a C2-Cio chain which is optionally interrupted by

1-2 oxygen atoms or 1-2 -NHCO groups,

A denotes a metal complex, its salts of organic and/or inorganic bases or amino acids or amino acid amides, i.e. a complex of general formula II

in which

R<3>, Z<1> and Y are independent of each other, and

R3 has the meaning given for R<1> or denotes - (CH2)m-L-RF, where m is 0, 1 or 2, and L and RF have the meaning given above,

Z<1> denotes a metal ion equivalent with order number 12,

20-30, 39, 42, 44 or 57-83,

Y is -OZ<1> or

where Z<1>, L, R<p> and R<3> have the meanings given above,

or

denotes a complex of general formula III

wherein R<3> and Z<1> have the above meanings, and R<*> has

meaning given for R<1>,

or

denotes a complex of general formula IV

where Z<1> has the above meaning,

or

denotes a complex of general formula V

where Z<1> has the above meaning, and o and q denote the numbers 0 or 1 and the sum o + q = 1,

or

denotes a complex of general formula VI

wherein Z<l> has the above meaning,

or

denotes a complex of general formula VII

where Z<1> and Y have the meanings given above,

or

denotes a complex of general formula VIII

wherein R<3> and Z<l> have the meanings given above, and Ra has the meaning given for R<1>,

or

denotes a complex of general formula IX

where R<3> and Z<1> have the meanings given above,

or

denotes a complex of general formula X

where R<3> and Z<1> have the meanings given above,

or

denotes a complex of general formula XI

where Z<1> has the meaning given above, and R<2> has the meaning given for R1,

or

denotes a complex of general formula XII

where L, RF and Z<1> have the meanings given above,

or

denotes a complex of general formula XIII

where Z<1> has the meaning stated above, possibly with the usual additives in galenic pharmacy for tumor therapy.

The compounds of general formula I contain as preferred residues L the following:

-CH2-

- CHiCHi-

-<CH2)S- s- 3 - 15

^H2-P-CH2CH2^

-CH2-((K:H2-CH2-)t t=2-6

-CH2-NH-CO-

^H2-NH-CO-CH2-N(CH2COOH)-S02--CH2-NH^O.CH2-N(C2H5)-S02-

-CH2-NH-CO-CH2-N(C 10H21 >S02-^H2-NH-CO-CH2-N(C6H 13 )-S(>2- ^H2-NH-CO-<CH2) io-N(C2H5)-S02--CH2-NH-C0-CH2-N(-CH2-C6H5).SO2--CH2-NH-C0-CH2-N(- CH2-CH2-OH)SO2--CH2-NHCO-(CH2) 10-S-CH2CH2--CH2NHCOCH2-0-CH2CH2--CH2NHCO<CH2) 10-O-CH2CH2--CH2-C6H4.0-CH2CH2-- CH2-°-CHrC(CH2-OCH2CH2-C6F j 3)2.CH2-OCH2^:H2--CH2-NHCOCH2CH2C6n^:H2CH2NHCOCH2N(C2H5)S02C8F1 7 CH2-CH2NHCOCH7N(C2H5)-SO,--CH2-0- CH2-CH(OC i0H2 1KH2-0-CH2CH2--<CH2NHCO)4-CH2O.CH2CH2--(CH2NHCO)3.CH20-CH2CH2--CH2-OCH2C(CH2OH)2-CH2-0-CH2CH2-

-CH2NHCOCH2N(C6H5)-SO2-

-NHCO-CHvCH-)-

-nhco-ch2-o-ch2ch2-

-NH-CO-

-NH-CO-CH2-N(CH2COOH)-SO2-

-NH-CO-CH2-N(C2H5)-SO2-

-NH-CO-CH2-N(C in 0H21 )-SO2-

-NH-CO-CH2-N(C6H13)-SO2-

-NH-CO-(CH2)i0-N(C2H5)-SO2-

-NH-CO-CH2-N(-CH2.C6H5)-SO2-

-NH-CO-CH2-N(-CH2-CH2-OH)S02-

-NH-CO-CH2-

-CH2-0-C6H4-0-CH2-CH2-

-CH2-C6H4-0-CH2-CH2-

-N(C2H5)-SO2-

-N(C6H5)-SO2-

-N(CioH2l)-SO2-

-N(C6H13)-SO2--N(C2H40H)-SO2-

-NfCI^COOH^SO^

-N(CH2C6H5)-SO2-

-N-[CH(CH2OH)2]-SO2-

-N-[CH(CH2OH)CH(CH2OH)]-SO2-

Particularly preferred in the present invention are the residues L which are mentioned in the examples in the present description.

Further preferred compounds are those in which X in the formula -CRF3nX denotes fluorine and n denotes the numbers 4 to 15.

Compounds of general formula I where A is represented by the general formula IX, L containing at least one

-NHCO group, can be prepared from compounds of general formula 14

in which

R<3> has the meaning stated above, Z<1> denotes a metal ion equivalent with ordinal numbers 12, 20-30, 39, 42,

44 or 57-83, and

M<1> has the same meaning as L,

by reaction with compounds of general formula 15

in which

R' has the meaning given above, M<2> has the same meaning as L, and

Nu denotes a "nucleofuge".

As "nucleofuge" the residues are preferably used:

The reaction is carried out in a mixture of water and organic solvents such as: Isopropanol, ethanol, methanol, butanol, dioxane, tetrahydrofuran, dimethylformamide, dimethylacetamide, formamide or dichloromethane. Ternary mixtures of water, isopropanol and dichloromethane are preferred.

The turnover is carried out in a temperature interval between

-10 °C and 100 °C, preferably between 0 °C and 30 °C.

Inorganic and organic bases such as triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, dimethylaminopyridine, alkali and alkaline earth hydroxides, their carbonates or hydrogen carbonates, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, calcium hydrogen carbonate, serve as acid-binding agents. .

The compounds of general formula 15 are prepared from compounds of general formula 16

in which

R<p> and M<2> have the above meaning, according to well-known methods for acid activation, such as by reaction of the acid with dicyclohexylcarbodiimide, N-hydroxysuccinimide/dicyclohexylcarbodiimide, carbonyldiimidazole, 2-ethoxy-l-ethoxycarbonyl-1,2- dihydroquinoline, oxalic acid dichloride or chloroformic acid isobutyl ester, according to methods described in the literature: Activation of carboxylic acids. Overview in Houben-Weyl, Methoden der organischen Chemie, volume XV/2, Georg Thieme publishing house, Stuttgart, 19.

Activation with carbodiimides. R. Schwyzer and

H. Kappeler, Heiv., 45:1550 (1963).

E. Wtinsch et al., B. 100:173 (1967). Activation with carbodiimides/hydroxysuccinimide: J. Am. Chem. Soc, 85:1839 (1964), and J. Org. Chem., 53:3583 (1988). Synthesis, 453 (1972).

Anhydride method, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline: B. Belleau et al., J. Am. Chem. Soc, 90:1651 (1986), H. Kunz et al., Int. J. Pept. Prot. Res., 25:493 (1985), and J.R. Vaughan, Am. Soc, 73:3547 (1951).

Imidazolid method: B.F. Gisin, R.B. Menifield,

D.C. Tosteon, Am. Soc, 91:2691 (1969).

Acid chloride methods, thionyl chloride: Heiv., 42: 1653

(1959).

Oxalyl chloride: J. Org. Chem., 29:843 (1964).

The compounds with general formula 16 are commercial products (Fluorochem, ABCR) or are prepared from compounds with general formula 17

where

M<3> has the same meaning as L, and

Q denotes oxygen, sulphur, a >C0 group, >N-R<3>,

R<3->N-SO2- with a bond from the nitrogen atom to et

hydrogen atom,

by reacting compounds with general formula 18

where

Hal denotes Cl, Br, I, and

R<4> denotes H, Methyl, ethyl, t-butyl, benzyl, isopropyl,

e.g. according to CF. Ward, Soc, 121, 1161 (1922), by methods known to those skilled in the art, such as alkylation

of alcohols with alkyl halides [Houben-Weyl, Methoden der organischen Chemie, Sauerstoffverbindungen I, part 3, methods for the preparation and conversion of ethers, Georg Thieme forlag, Stuttgart, 1965, alkylation of alcohols with alkyl halides, p. 24, alkylation of alcohols with alkyl sulfates, p. 33] or N-alkylation of a sulfonamide with alkyl sulfonates [Houben-Weyl, Methoden der organischen Chemie^ XI 12, Stickstoffverbindungen, Georg Thieme forlag, Stuttgart, 1957, p. 680; J. E. Rickman and T. Atkins, Am. Chem. Soc, 1974, 95:2268; F. Chavez and A.D. Sherry, J. Org. Chem., 1989, 54:2990].

When Q denotes a >C0 group, the reaction with a Wittig reagent is carried out with the structure

where

r denotes the numbers 0-16.

It thereby formed. -CH=CH double bond can be maintained as a component of the structure, or it can be transferred to a CH2-CH2 group by catalytic hydrogenation (Pd 5%/C).

The compounds with general formula 18 are commercial products (Fluorochem, ABCR).

Alternatively, compounds of general formula I where A denotes general formula IX can be prepared from compounds of general formula 19

where

R<p>, R<3> and R<4> have the meanings indicated above, and

L' has the same meaning as L, possibly with protected

hydroxyl or carboxyl functions,

by. that,, if. necessary, present protective groups are cleaved off and the thus formed complex former is reacted according to methods known to those skilled in the art (EP 250358, EP 255471) with metal oxides or metal salts, at room temperature or elevated temperature, followed by - if desired - present acidic hydrogen atoms being substituted with cations of inorganic and/or organic bases, amino acids or amino acid amides.

The compounds with general formula 19 are prepared from compounds with general formula 20 (D03A or the ester)

there

R<*> has the above meaning,

by reaction with compounds of general formula 21

in which

R<3> has the same meaning as R<1>, possibly in a protected form, or denotes -(CHjJ^L1 -Rp, where m is 0, 1 or 2, and L' and R' have the meaning stated above.

The reaction is carried out in alcohols, such as methanol, ethanol, isopropanol, butanol; ethers, such as dioxane, tetrahydrofuran, dimethoxy ethers or in water or in a mixture of water and one of the aforementioned organic solvents, as well as also acetonitrile, acetone, dimethylformamide, dimethylacetamide or dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, at temperatures between -10 and 180 °C, preferably at 20-100 °C. Particularly advantageous is the addition of organic or inorganic bases such as triethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine, diisopropylamine, alkali or alkaline earth hydroxides or their carbonates or hydrogen carbonates, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate. In the case of low-boiling epoxides, the reaction is carried out in an autoclave.

The compounds of general formula 21 are commercial products (Fluorochem, ABCR) or can be prepared from compounds of general formula 22

by epoxidation, according to methods known to those skilled in the art, for example tungstate-catalyzed oxidation with H 2 O 2 according to Payne, cyclization of halogen hydrides' or alkaline H 2 O 2 oxidation in the presence of nitriles.

Particularly suitable for this reaction is 3-chloroper-benzoic acid in dichloromethane at room temperature, Houben-Weyl, Methoden der organischen Chemie, Sauerstoffverbindungen I, part 3, methods for the preparation and conversion of three-membered cyclic ethers (1,2-epoxides), Georg Thieme publisher, Stuttgart, 1965; GB Payne and P.H. Williams, J. Org. Chem., 159, 24:54; Y. Ogata and Y. Samaki, Tetrahedron, 1964, 20:2065; K. B. Sharpless et al., Pure Appl. Chem., 55, 589 (1983).

Compounds of general formula 22 are preferably prepared using the Wittig reaction or using the variants according to Homer, Schlosser or Bestmann, Houben-Weyl, Methoden der organischen Chemie, XII/1, Organische Phosphorverbindungen, part 1, Georg Thieme forlag, Stuttgart, 1963 , phosphonium salts, p. 79, phosphonium ylides, p. 112, Wittig reaction, p. 121; A.W. Johnson, Ylides and Imines of Phosphorus, John Wiley & Sons, Inc., New York, Chichester, Brisbane, Toronto, Singapore, 1993; Wittig reaction, p. 221; Schlosser modification of the Wittig reaction, p. 240; Wadsworth-Emmons reaction, p. 313; Horner reaction, p. 362, by reaction of a triarylphosphonium ylide

there

L<*> and R' have the meanings given above, and

Ar denotes aryl, especially phenyl,

with commercially available aldehydes (Merck, Fluka), or with aldehydes that can be prepared according to known methods, for example oxidation of primary alcohols with chromium trioxide/pyridine, Houben-Weyl, Methoden der organischen Chemie, Sauerstoffverbindungen II, part 1, Aldehyde, Georg Thieme publisher, Stuttgart, 1954, with general formula 24

where

R<3> can also be H.

Triarylphosphonium ylides 23 are prepared from the corresponding halides of general formula 25

there

Hal, L<*> and RF have the above meanings,

by known methods, for example by heating triarylphosphines with alkyl halide, Houben-Weyl, Methoden der organischen Chemie, XII/1, Organische Phosphorverbindungen, part 1, Georg Thieme .forlag, Stuttgart, 1963, or A.W. Johnson, Ylides and Imines of Phosphorus, John Wiley £ Sons, Inc., New York, Chichester, Brisbane, Toronto, Singapore, 1993. The compounds of general formula 25 are commercial (Fluorochem, ABCR, 3M).

The compounds of general formula 21 where R<3> - H are preferably prepared from compounds of general formula

I7a

where

Q' has the same meaning as Q, but cannot mean a >C0 group,

M<3> has the same meaning as L, with the exception of a direct one

binding, and

RF has the above meaning,

by reaction according to known methods for etherification or sulfonamide alkylation with epihalohydrins (Houben-Weyl, Methoden der organischen Chemie, Sauerstoffverbindungen I, part 3, methods for the preparation and conversion of ethers, Georg Thieme forlag, Stuttgart, 1965, alkylation of alcohols, p 24, 33; Houben-Weyl, Methoden der organischen Chemie, XI/2, Stickstoffverbindungen, Georg Thieme forlag, Stuttgart, 1957, p. 680; J. E. Rickman and T. J. J. Atkins, Am. Chem. Soc, 1974, 96:2268; F. Chavez and A.D. Sherry, 1989, 54:2990) with general formula 26

•in

where

Hal<*> denotes Hal, F, -OTs, OMs.

In the case of low-boiling epoxides, the reaction is carried out in an autoclave.

Compounds of general formula I where A denotes general formula VIII are prepared from compounds of general formula 27

where

R<2>1R<3>, R<4>, L' and RF have the meanings indicated above,

by cleavage of any protective groups present and complex formation in a known manner.

Compounds of general formula 27 are prepared by alkylating compounds of general formula 20 with compounds of general formula 28

where

Hal, R<2>, R<3>, R<4>, L<1> and RF have the meanings indicated above, in a known manner, in particular as described in EP 0 232 751 B1 (Squibb).

Compounds of general formula 28 are prepared from compounds of general formula 29

where

L', R<3> and R' have the meanings indicated above,

and an activated halocarboxylic acid of general formula 30

where

Now, R<3> and Hal have the meanings given above,

according to known methods for amide formation over activated carboxylic acids [see literature references p. 11].

Compounds of general formula 30 can be prepared from the acids according to C. Hell, B. 14:891 (1881); J. Volhard, A 242, 141 (1887); N. Zelinsky, B. 20:2026 (1887), or from the halogen acids by the activation methods described for the general formula 15.

The compounds of general formula 29 can be easily prepared by known methods for amine synthesis [Houben-Weyl, Methoden der organischen Chemie, Stickstoffverbindungen II, Amino, 1. Herstellung, Georg Thieme forlag, Stuttgart, 1957] from the commercially available compounds (Fluorochem, ABCR) with general formula 31

or

for example by alkylation of a compound 31 with an amine, PhCH2NHR<3>, and subsequent deprotection of the amino group by catalytic hydrogenation or by the Mitsunobu reaction [H. Loibner and E. Zbiral, Heiv., 59, 2100 (1976), A.K. Bose and B. Lal, Tetrahedron Lett., 3973 (1973)] of a compound 32 with potassium phthalimide and deprotection with hydrazine hydrate.

Compounds of general formula I where A denotes general formula VII are prepared from compounds of general formula 33

where

L<*>, RF and R4" have the meanings given above, and Y has the same meaning as Y,

optionally with protective groups, by cleavage of any protective groups present and complex formation according to known methods (Protective Groups in Organic Synthesis,

2nd ed., T.W. Greene and P.G.M. Wuts, John Wiley & Sons, Inc., New York, 1991; EP 0 130 934, EP 0 250 358). Compounds of general formula 33 are prepared from compounds of general formula 20 and compounds of general formula 34

where.

Hal', L<1>, RF have the meanings given above, and Y' denotes the residues

in a known manner, for example as described in EP 0 232 751 B1, EP 0 292 689 A2 (both from Squibb) or EP 0 255 471 A1 (Schering). 4 •

Preparation of compounds of general formula 34 is carried out according to known methods, for example according to Hell-Volhard-Zeiinsky, from commercially available starting compounds

(ABCR)*

Compounds of general formula I where A denotes general formula VI are prepared from compounds of general formula 35

where

L', R<4> and R' have the meanings indicated above,

by eventual cleavage of protective groups and complex formation in a known manner [Protective Groups in Organic Synthesis, 2nd ed., T.W. Greene and P.G.M. Wuts, John Wiley & Sons, Inc., New York, 1991 (EP 0 130 934, EP 0 250 358)].

Compounds of general formula 35 are prepared by reacting α-halocarboxylic acid esters or acids of general formula 18 with compounds of general formula 36

where

L<*> and R' have the meanings given above,

according to known methods, such as, for example, described in EP

0 255 471 or US 4 885 363.

Compounds of general formula 36 can be prepared by cleavage of any protective groups present and subsequent reduction with diborane, according to known methods, from compounds of general formula 37

where

£•', r<p>, o, q have the meanings given above, and K denotes a protecting group.

Compounds of general formula 37 can be prepared by a condensation reaction from an activated N-protected iminoacetic acid 38 and the amine 39:

where

L', R<p>, o, q, Nu and K have the meanings indicated above.

N-hydroxysuccinimide is preferably used as a nucleofuge, and the benzyloxycarbonyl, trifluoroacetyl or t-butoxycarbonyl group is used as the protecting group.

Compounds of general formula 38 can be prepared according to known methods for protection of amino groups and activation of carboxylic acids [Protective Groups, activering von carboxylgrupper, p. 11] over the protected iminoacetic acid 40

where

K denotes a protecting group,

from iminodiacetic acid 41

Alternatively, compounds of general formula 36 can be prepared by eventual removal of protecting groups and reduction with diborane according to the procedure described for compound 37, from compounds of general formula 42 Compounds of general formula 42 are prepared by ring closure of Secco compound 43

where

L' and R' have the meanings given above, according to standard methods; for example by reaction with the Mukalyama reagent 2-fluoro-1-methylpyridine tosylate

[J. Org. Chem., 1994, 59, 415; Synthetic Communications, 1995, 25, 1401] or with the phosphoric acid diphenyl ester azide [J. Am. Chem. Soc, 1993, 115, 3420; WO 94/15925]. Compounds of general formula 43 can be prepared by condensation of the activated acid 44

where

Nu and K have the above meanings,

with a compound of general formula 45

where

L<1>, R<*> and R<r> have the meanings given above,

according to the methods described.

Compounds of general formula 44 can be prepared from the commercially available triglycine (Bachem, Fluka) 46 by protection of the amino group with subsequent activation of the acid function according to known methods for amine protection and carboxylic acid activation (literature as for formula 16).

Compounds of general formula 45 can be easily prepared from compounds of general formula 62 by introducing the protecting group R<*> according to known methods - for example transesterification of a sulfite tester.

Compounds of general formula I where A denotes general formula II are prepared from compounds of general formula 47

where

L', R<3>, R<4>, R<p> and Y<*> have the meanings indicated above,

by cleavage of any protective groups and complex formation in a known manner (Proteetive Groups, EP 0 250 358,

EP 0 130 934).

When Y' in general formula 47 denotes an OH group, the compounds are produced by reacting a compound 48

where

R4- .. has the meaning given above,

prepared according to DE-3 633 243, with an amine of general formula 29 under the conditions already described and subsequent removal of the protective groups.

If Y' in formula 47 is the group

the reaction is carried out with the DTPA-bisanhydride (commercial product, Merck) 49

under analogous conditions.

Compounds of general formula I where A denotes general formula III are prepared from compounds of general formula 50

where

L*, R<2>, R<3>, R* and R' have the meanings given above,

by cleavage of any protective groups and complex formation in a manner well known to professionals [Protective Groups,

EP 0 071 564, EP 0 130 934, DE-OS 3 401 052].

Compounds of general formula 50 are prepared according to the method described in J. Org. Chem., 1993, 58:1151, from compounds of general formula 51

and halocarboxylic acid derivatives of formula 52

where

R<4> and Hal have the meanings already described.

Compounds of general formula 51 can be prepared by acylation of an amine of general formula 29 with an activated N-protected amino acid of general formula 53

where

Now it has the meaning stated above, and

K denotes a protecting group, such as Z, -BOC,

FMOC, -COCF3,

and subsequent cleavage of the protecting group.

Compounds of general formula I where A denotes the general formula IV are prepared from compounds of general formula 54

where

L', R<r> and R<*> have the meanings given above,

by splitting off any protective groups and complex formation according to a known method that has already been described [Protective Groups, EP 0 071 564, EP 0 130 934, DE-OS

3,401,052]. Compounds of general formula 54 can be prepared in a known manner from the halogen compounds of general formula 55 which is a commercial product (Fluorochem, ABCR), by treatment with hydroxy acids 56

where

R<4> has the meaning given above.

The compounds with formula 56 can be prepared in a known manner according to J. Org. Chem., 58, 1151 (1993), from the commercially available serine esters 57 (Bachem, Fluka)

where

R<4> has the above meaning,

and halocarboxylic acid esters 58

Compounds of general formula I where A denotes general formula V are prepared from compounds of general formula 59

where

L', o, q, R* and RF have the above meanings,

by cleavage of any protective groups and complex formation according to a known method [Protective Groups,

EP 0 071 564, EP 0 130 934, DE-OS 3 401 052].

Compounds with general formula 59 can be prepared in a known manner, for example according to J. Org. Chem., 58, 1151

(1993), by reaction of halocarboxylic acid esters 18

where

Hal and R<4> have the meanings given above,

and a compound of general formula 39

where

L', o, q and R' have the meanings given above.

Compounds of general formula 39 are prepared, when Q = 0, from compounds of general formula 60

where

L', R<p> and K have the meanings given above,

in a known manner [Heiv. Chim. Acta, 77:23 (1994)] by reduction with diborane and removal of the protecting groups. Compounds of general formula 60 are produced by aminolysis of the activated compounds of general formula 61

where

L', Nu, R<r> and K have the meanings indicated above,

with ethylenediamine.

Compounds of general formula 61 are prepared according to known methods of protective group chemistry [Protective Groups] from the unprotected acids of general formula 62

that is, the antino group is protected in a first step, followed by activation of the acid group in a second step.

Compounds of general formula 62 can be prepared by methods of amino acid synthesis [Houben-Weyl, Methoden der organischen Chemie, XI/2, Stickstoffverbindungen II und III, II Aminosåuren, Georg Thieme forlag, Stuttgart, 1958, Strecker reaction, p. 305; Erlenmeyer reaction, p. 306; aminolysis of α-halocarboxylic acids, p. 309] from the commercially available aldehydes of general formula 63

for example after Strecker, via the azlactone or the cyanohydrin. Compounds of general formula 39 are prepared, when o ■ 0,-from compounds of general formula 64

where.

R<r>, L' and K have the above meanings,

in a known manner by removal of the protective groups and reduction with diborane.

Compounds of general formula 64 can be prepared by aminolysis of the N-protected, activated glycine 53 with compounds of general formula 65

where

RF and Lf have the above meanings.

Compounds of general formula 65 are prepared in a simple manner from compounds of general formula 61 by amide formation with ammonia and subsequent removal of the protecting group.

Compounds of general formula XIII can be prepared analogously to compounds of general formula III by reacting the halocarboxylic acid derivatives of general formula 52 with a compound of general formula 66

where

RF, L' and R<2> have the meanings indicated above.

Compounds of general formula 66 are prepared by reacting a compound of general formula 67

with the activated, N-protected amino acid of general formula 53, analogous to the reaction of amine 29 with compound 53. Compounds of general formula 67 can be prepared by reacting piperazine - free or optionally partially protected - with perfluoroalkyl sulfonic acid fluorides or -chlorides. (The sulfonamide formation from amine and sulfofluoride is described in DOS 2 118 190, DOS 2 153 270, both from Bayer AG.) Compounds of general formula XI where g denotes the number 0 or 1 are prepared analogously to compounds of general formula VIII in that compounds with general formula 20 is reacted with compounds of general formula 68

in which

R<r>, L', R<2> and Hal have the meanings given above, or with compounds of general formula 68a

where

RF, L", R<2>, p and Hal have the meanings given above.

Compounds of general formula 68 can be prepared from compounds of general formula 30 and piperazine derivatives of general formula 67 in a known manner.

Compounds of general formula 68a can be prepared from compounds of general formula 67 by amide coupling with compounds of general formula 68b

H00C-CHa (CH2)„—NH-C0-CHR2-Hal (68b)

Compounds of general formula XII are prepared analogously to compounds of general formula II, for example by reacting compounds of formula 49 with piperazine derivatives of general formula 67.

Compounds of general formula I where A denotes general formula X are prepared from compounds of general formula 69

where

L<*>, R<3>, R<*> and RF have the meanings indicated above, and

Sg denotes a protecting group,

by cleavage of any protective groups and complex formation in a known manner [Protective Groups in Organic Synthesis, 2nd ed., T.W. Greene and P.G.M. Wuts, John Wiley & Sons, Inc., New York, 1991 (EP 0 130 934, EP 0 250 358)].

Compounds of general formula 69 are prepared by reacting α-halocarboxylic acid esters or acids of general formula 18 with compounds of general formula 70

where

li', R<p>, R<3> pg Sg have the meanings given above,

in a manner known to those skilled in the art, as for example described in EP 0 255 471 or US 4 885 363.

Compounds of general formula 70 can be prepared by cleavage of any protective groups present and subsequent reduction with diborane, according to known methods, from compounds of general formula 71

where

L<*>, R<p>, R<3> and Sg have the meanings given above.

Compounds of general formula 71 can be prepared by a condensation reaction from an activated irainodiacetic acid derivative of general formula 72 and the diethylenetriamine of formula 73

where

L', R<r>, R<3>, Sg and Nu have the meanings given above.

N-hydroxysuccinimide is preferably used as nucleofuge Nu.

Compounds of general formula 72 can be prepared from compounds of general formula 74

where

L', R<r> and Sg have the meanings indicated above.

by activating the carboxylic acids, as described on p. 11.

Compounds of general formula 74 are prepared by reacting α-halocarboxylic acid esters or acids of general formula 18 with compounds of general formula 75

where

L', R<r>, R<3> and Sg have the meanings indicated above, with any ester groups present being saponified.

Compounds of general formula 75 are prepared from compounds of general formula 76

where

L<*>, R<p>, R<3>, Sg and K have the meanings given above, when the protecting group K is removed according to known methods.

Compounds of general formula 76 are prepared from compounds of general formula 77

where

L<»>, RF, R3 and K have the meanings given above,

by introducing a protection group Sg in a manner known to professionals..

Compounds of general formula 77 are prepared from compounds of general formula 78

where

L', RF and K have the meanings given above,

according to well-known methods for professionals (Houben-Weyl, Methoden der organischen Chemie, XIII 2a, organometallic compounds, Georg Thieme forlag, Stuttgart, 1973, p. 285 ff, reaction of organomagnesium compounds with aldehydes, p. 809 ff, reaction of organozinc compounds with aldehydes; Houben-Weyl, Methoden der organischen Chemie, XIII/1, organometallic compounds, Georg Thieme forlag, Stuttgart, 1970, p. 175 ff, reaction of organolithium compounds with aldehydes by reaction of the organometallic compounds that can be formed from compounds with general formula 79

where

Hal and R<3> have the meanings indicated above,

such as magnesium, lithium or zinc compounds.

Compounds with general formula 79 are commercial products (ABCR, Fluka).

Compounds of general formula 78 are prepared from compounds of general formula 80

where

L', R<r> and K have the meanings given above,

by reduction with diisobutylaluminum hydride (Tett. Lett., 1962, 619; Tett. Lett., 1969, 1779; Synthesis, 1975, 617).

Compounds of general formula 80 are prepared from compounds of general formula 45

where

L' and RF have the meanings given above,

in a manner known to those skilled in the art, by introducing the protecting group K.

Neutralization of possibly still present free carboxyl groups is carried out here with the help of inorganic bases (for example hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium, lithium, magnesium or calcium, and/or organic bases such as, among others, primary, secondary and tertiary amines, such as for example ethanolamine, morpholine, glucamine, N-methyl- and N,N-dimethyl-glucamine, as well as basic amino acids, such as for example lysine, arginine and ornithine, or of amides of originally neutral or acidic amino acids .

For the preparation of the neutral complex compounds, for example, the acid complex salts in aqueous solution or suspension can be added in such a quantity of the desired bases that the neutral point is reached. The resulting solution can then be evaporated in vacuo to dryness. It is often advantageous that the formed neutral salts are precipitated by the addition of water-miscible solvents, such as, for example, lower alcohols (methanol, ethanol, isopropanol and others), lower ketones {acetone and others), polar ethers {tetrahydrofuran, dioxane, 1,2 -dimethoxyethane and others), thereby obtaining crystallisates that can be easily isolated and purified. It has proven to be particularly advantageous that the desired base is added to the reaction mixture already during the complex formation and thus saves one process step.

The present invention also relates to pharmaceutical agents which contain at least one physiologically compatible compound with general formula I, possibly together with common additives in galenic pharmacy.

The invention also relates to the use of at least one physiologically compatible compound with formula I according to the invention for the production of a drug for tumor therapy and the use of at least one physiologically compatible compound according to the invention for the production of a drug for tumor therapy or interventional radiology.

Production of the pharmaceutical agents according to the invention is carried out in a known manner by suspending or dissolving the complex compounds according to the invention - optionally with the addition of common additives in galenic pharmacy - in an aqueous medium, followed by the suspension or solution being optionally sterilized. Suitable additives are, for example, physiologically harmless buffers (such as tromethamine), additions of complexing agents or weak complexes (such as diethylenetriaminepentaacetic acid or the Ca complexes corresponding to the metal complexes according to the invention) or - if necessary - electrolytes, such as sodium chloride , or - if necessary - anti-oxidants, such as ascorbic acid.

In principle, it is also possible to prepare the pharmaceutical agents according to the invention without isolating the complexes. In each case, special care must be taken to ensure that the chelation is carried out so that the complexes according to the invention are practically free of non-complexed, toxic metal ions.

This can, for example, be ensured by means of color indicators such as xylene orange through control titrations during the manufacturing process. The present invention thus also relates to methods for producing the complex compounds and their salts. As a last resort, a purification of the isolated complexes is carried out.

The pharmaceutical agents according to the invention preferably contain 0.1 umol-1 mol/l of the complexes and are usually dosed in quantities of 0.0001-5 mmol/kg. They are intended for enteral and parenteral administration. The complex compounds according to the invention are used. 1. with ions of elements with ordinal numbers 21-29, 39, 42, 44 and 57-83, for therapy control using NMR and X-ray diagnostics, 2. with ions of elements with ordinal numbers 12, 20-30, 39, 42, 44 and 57-83 in a mixture with contrast media, for NMR and X-ray diagnostics, 3. with ions of elements with order numbers 12, 20-30, 39, 42, 44 and 57-83, in a mixture with chemotherapeutics, ,' 4 .with ions of elements with ordinal numbers 12, 20-30, 39, 42, 44 and 57-83, in a mixture with contrast agents for NMR or X-ray diagnostics, and with chemotherapeutics.

The agents according to the present invention exhibit the high activity that is necessary to burden the body with the least possible amount of foreign substances, and the good compatibility that is necessary to maintain the non-invasive nature of the examinations.

The good water solubility and low osmolality of the agents according to the invention allow the preparation of highly concentrated solutions where osmotic effects do not lead to local unwanted reactions. Furthermore, the agents according to the present invention not only exhibit a high stability in vitro, but also a surprisingly high stability in vivo, so that a release or an exchange of the ions - which are in themselves toxic - bound in the complexes only occurs extremely slowly within that time period where the new contrast agents are secreted

complete.

The complex compounds of formula I can also advantageously be used as susceptibility reagents and as shift reagents for NMR spectroscopy in vivo.

The compounds of formula I are also distinguished by the fact that they are completely eliminated from the body and are thus well compatible.

When using the agents according to the invention in vivo, these can be administered together with a suitable carrier, such as e.g. serum or physiological saline solution, and together with another protein, such as e.g. human serum albumin. The dosage depends on the type of cellular disorder, the metal ions used and the type of imaging method.

The compounds of formula I are used in the form of their aqueous solutions with the applicable additives in the pharmacy (such as buffers, stabilizers etc.).

For compounds that are more sparingly soluble in water, the addition of solubilizers such as ethanol, dimethyl sulfoxide, propylene glycol or "Tween" 80, "Triton" X-100 has proven useful.

In 96% ethanol, the solubility of the substances according to the invention is very high, it can amount to more than 500 mmol/1. The highly concentrated alcohol also promotes the embolization process.

The different viscosities in the different solvents (above all 66% propylene glycol) can be used to administer a free-flowing solution through thin catheters with only little resistance. Through the dilution effect of the blood in the target organ, the viscosity of the erabolizing agent is greatly increased, so that a state similar to pure or plasma is established.

In combination preparations for the treatment of tumors, 5-fluorouracil, mitomycin C, cisplatin, doxorubicin and mitomycin are preferably used. Depending on the need, aqueous solutions, aqueous solutions with pharmaceutically usable diluents or microcrystal suspensions that can be mixed with compounds of formula I can be used.

Chemotherapeutics are administered in doses of 1-2,000 mg, preferably 5-1,000 mg per administration, and administration of multiple doses is possible.

The agents according to the present invention are preferably placed by means of a catheter in the active area of the tumor to be treated. The administered volume is adjusted according to the size of the smoker. As a rule, 20-80 ml are administered.

For the compounds of general formula I, possibly in combination with chemotherapeutics, it has overall succeeded in creating new possibilities for the therapy of tumors.

These compounds also enable a non-invasive therapy control using NMR or X-ray diagnostics (interventional radiology).

The following examples serve to further elucidate the object of the invention: Example 1

a) N-ethyl-N-(perfluorooctylsulfonyl)aminoacetic acid-t-butyl ester

20 g (37.94 mmol) of N-ethylperfluorooctylsulfonamide and

15.73 g (113.8 mmol) of potassium carborate are suspended in 200 ml

acetone and at 60 <*>C 14.80 g (75.87 mmol) of bromoacetic acid tert-butyl ester are added dropwise. The mixture is stirred for 3 hours at 60 °C. The salts are filtered off, and the filtrate is evaporated in vacuo to dryness. The precipitate is chromatographed on silica gel (eluent: hexane/dichloromethane/acetone = 10/10/1). After evaporation of the product-containing fractions, the precipitate is recrystallized from methanol/ether.

Yield: 21.66 g (89% of theory) of a waxy, colorless solid.

Elemental analysis:

b) N-ethyl-N-(perfluorooctylsulfonyl)aminoacetic acid

20 g (31.18 mmol) of the title compound from example

la) is dissolved in 200 ml of trifluoroacetic acid and stirred overnight at room temperature. The mixture is evaporated in vacuo to dryness. The precipitate is recrystallized from methanol/ether.

Yield: 17.34 g (95% of theory), of a colorless crystalline solid.

Elemental analysis.:

c) Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctylsulfonyl)nonyl]-!,4,7-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecane 10 g. (17.09 mmol) of the title compound from example 1b) and. 1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 ml of dimethylformamide and 50 ml of chloroform. At 0 °C, 3.88 g (18.79 mmol) of dicyclohexylcarbodiimide are added, and it is stirred for 1 hour at 0 °C, followed by 3 hours at room temperature. The mixture is cooled again to 0 °C and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol are added. 10.78 g (18.79 mmol) gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (WO 95/ 17451) dissolved in 50 ml of water, and it is stirred for 3 hours at room temperature. The mixture is evaporated to dryness, the precipitate is dissolved in a mixture of 200 ml of methanol and 100 ml of chloroform, and the dicyclohexylurea is filtered off. The filtrate is evaporated to dryness and purified by RP chromatography (RP-18/eluent: gradient of water/n-propanol/acetonitrile).

Yield: 16.37 g (78% of the theoretical value) of a colorless glassy solid.

Water content: 7.1%.

Tx relaxivity (1/mmol-sec) at 20 MHz, 37 °C:-

41 (water)

49. (human plasma).

Elemental analysis (with regard to anhydrous substance):

d) 10-[ 2- hydroxy- 4- aza- 5- oxo- 7- aza- 7-( perfluorooctyl-sulfonyl) nonyl]- 1, 4, 7- tris (carboxymethyl)- 1, 4, 7, 10 -tetraazacyclododecane 10 g (8.76 mmol) of the title compound from example lc) are dissolved in a mixture of 100 ml of water and 100 ml of ethanol and 1.73 g (13.71 mmol) of oxalic acid dihydrate are added. The mixture is heated for 8 hours at 80 °C. It is cooled to 0 °C, and the precipitated gadolinium oxalate is filtered off. The filtrate is evaporated to dryness, and the precipitate is purified on RP-18 (RP-18/eluent: gradient of water/i-propanol/acetonitrile).

Yield: 8.96 g (94% of theory) of a glassy solid.

Water content: 9.3%.

Elemental analysis (with regard to anhydrous substance):

e) Manganese complex of 10-[ 2- hydroxy- 4- aza- 5- oxo- 7- aza- 7-( perfluorooctylsulfonyl) nonyl]- 1, 4, 7- tris( carboxymethyl)-1, 4, 7, 10- tetraazacyclododecane (as sodium salt)

5 g (5.07 mmol) of the title compound from Example

ld) is dissolved in 100 ml of water and 0.58 g (5.07 mmol) • manganese(II) carbonate is added. The mixture is stirred for 3 hours at 80°C. The solution is filtered, and the filtrate is adjusted to pH 7.2 with 1 N caustic soda, followed by freeze-drying.

Yield: 5.87 g (quantitative) of a colorless, amorphous powder.

Water content: 8.4%.

Ti relaxivity (1/mmol-sec) at 20 MHz, 37 °C:

2.7 (water)

4.2 (human plasma).

Elemental analysis (with regard to anhydrous substance):

f) Ytterbium complex of 10-[ 2- hydroxy- 4- aza- 5- oxo- 7- aza- 7-( perfluorooctylsulfonyl) nonyl]- 1, 4, 7- tris( carboxymethyl)-1, 4, 7, 10- tetraazacyclododecane

To 5 g (5.07 mmol) of the title compound from example 1d) in 100 ml water/30 ml ethanol is added 1.33 g.

(2.53 mmol) of ytterbium carbonate, and **b the landing is stirred for 3 hours at 80 °C. The solution is filtered, and the filtrate is evaporated in vacuo to dryness.

Yield: 6.36 g (quantitative) of a glassy solid.

Water content: 7.8%. *

Elemental analysis (with regard to anhydrous substance):

q) Dysprosium complex of 10-[ 2- hydroxy- 4- aza- 5- oxo- 7- aza- 7-( perfluorooctylsulfonyl) nonyl]- 1, 4, 7- tris( carboxymethyl)-1, 4, 7, 10- tetraazacyclododecane

To 5 g (5.07 mmol) of the title compound from example 1d) in 100 ml of water/30 ml of ethanol is added 0.95 g (2.53 mmol) of dysprosium oxide, and the mixture is stirred for 3 hours at 80 °C. The solution is filtered, and the filtrate is evaporated in vacuo to dryness.

Yield: 6.35 g (quantitative) of a colorless glassy solid.

Water content: 8.5%.

Elemental analysis (with regard to anhydrous substance):

Example 2

a) 13, 13, 13, 12, 12, 11, 11, 10, 10, 9, 9, 8, 8, 7, 7, 6, 6-heptade'cafluoro-3-oxatridecanoic acid-t-butyl ester

To a mixture of 10 g (21.55 mmol) 1H,1H,2H,2H-perfluorodecan-1-ol and 0.73 g (2.15 mmol) tetrabutylammonium hydrogen sulfate in 100 ml 60% potassium chloride/50 ml toluene is added dropwise under strong stirring at 0 °C 10.51 g (53.9 mmol) bromoacetic acid tert-butyl ester. The mixture is stirred for 1 hour at 0 °C. 200 ml of toluene is added, the aqueous phase is separated and extracted twice with 50 ml of toluene. The combined organic phases are dried over magnesium sulfate and evaporated in vacuo. The precipitate is chromatographed on silica gel (eluent: hexane/dichloromethane/acetone = 20/10/1).

Yield: 9.72 g (78% of the theoretical value) of a colorless, viscous oil.

Elemental analysis:

b) 13, 13, 13, 12, 12, 11, 11, 10, 10, 9, 9, 8, 8, 7, 7, 6, 6-heptadecafluoro-3-oxatridecanoic acid

9.0 g (15.56 mmol) of the title compound from example 2a) are dissolved in 180 ml of trifluoroacetic acid and stirred overnight at room temperature. The mixture is evaporated under vacuum to dryness. The precipitate is recrystallized from methanol/ether.

Yield: 7.80 g (96% of the theoretical value) of a colorless solid. Elemental analysis:

c) Gadolinium complex of 10-[ 2- hydroxy- 4- aza- 5- oxo- 7- oxaT 10, 10, 11, 11, 12, 12, 13, 13, 14, 14, 15, 15, 16, 16, 17, 17, 17- heptadeca-fluoroheptadecyl]- 1, 4, 7- tris(carboxymethyl)- 1, 4, 7, 10-tetraazacyclododecane

7.0 g (13.41 mmol) of the title compound from example 2b) and 1.70 g (14.75 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 30 ml of dimethylformamide and 20 ml of chloroform. At 0 °C, 3.04 g (14.75 mmol) of dicyclohexylcarbodiimide is added, and it is stirred for 1 hour at 0 °C, followed by 3 hours at room temperature. The mixture is cooled again to 0 °C and 4.48 g (44.25 mmol) of triethylamine/50 ml of 2-propanol are added. 8.4 6 g (14.75 mmol) gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane is then added in 40 ml water, and it is stirred for 3 hours

at room temperature. The mixture is evaporated to dryness, the precipitate is dissolved in a mixture of 100 ml of methanol and 30 ml of chloroform, and the dicyclohexylurea is filtered off. The filtrate is evaporated to dryness and purified by RP chromatography (RP-18/eluent: gradient of water/n-propanol/acetonitrile).

Yield: 11.8 g {75% of theory) of a colorless glassy solid.

Water content: 8.2%.

Ti relaxivity (1/mmol-sec) at 20 MHz, 37 °C:

19 {water)

33 {human plasma).

Elemental analysis:

Example 3

a) 1, 2- epoxy- 4- oxa- 1H, 1H, 2H, 3H, 3H, 5H, 5H, 6H, 6H- per-fluorotetradecane

To a mixture of 20 g (43.09 mmol) 1H,1H,2H,2H-perfluorodecan-1-ol and 0.79 g {2.32 mmol) tetrabutylammonium hydrogen sulfate in 200 ml 60% potassium hydroxide/100 ml toluene is added dropwise under strong stirring at 10 °C 7.97 g (86.18 mmol) of epichlorohydrin, and it is ensured that the temperature of the reaction solution does not become higher than 20 °C. The mixture is stirred for 2 hours at 15 °C and then, as described above, 3.99 g (43.09 mmol) of epichlorohydrin are added dropwise. The mixture is then stirred overnight at room temperature. 100 ml of methyl tert-butyl ether are added, and the aqueous phase is separated. This is extracted twice with 50 ml of toluene. The organic phases are combined, dried over magnesium sulphate and evaporated in vacuo. The precipitate is chromatographed on silica gel (eluent: dichloromethane/hexane/acetone = 20/10/1).

Yield: 19.05 g (85% of the theoretical value) of a colorless oil.

Elemental analysis:

b) 10-[2- hydroxy- 4-oxa- 1H, 1H, 2H, 3H, 3H, 5H, 5H, 6H, 6H- per-fluorotetradecyl]- 1, 4, 7- tris(carboxymethyl)- 1, 4 , 7, 10- tetraazacyclododecane

8.3 g (207.6 mmol) of sodium hydroxide are added to 12.0 g (34.60 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in 50 ml of water. To this, a mixture of 18.0 g (34.60 mmol) of the title compound from example 3a) dissolved in 60 ml n-butanol/60 ml 2-propanol is added dropwise, and the solution is heated overnight at 70 <*>C. The mixture is evaporated in vacuo to dryness, the precipitate is dissolved in 300 ml of water and adjusted to pH 3 with 3 N hydrochloric acid. The mixture is then extracted twice with 200 ml of n-butanol. The combined butanol phases are evaporated in vacuo to dryness, and the precipitate is purified by RP chromatography (RP-18/eluent: gradient of water/n-butanol/acetonitrile).

Yield: 26.61 g (79% of the theoretical value).

Water content: 11.0%.

Elemental analysis (with regard to anhydrous substance):

c) Gadolinium complex of 10-[ 2- hydroxy- 4-oxa-1H, 1H, 2H, 3H, 3H, 5H, 5H, 6H, 6H- perfluorotetradecyl]- 1, 4, 7- tris-(carboxymethyl)- 1, 4, 7, 10-tetraazacyclododecane 10 g (11.54 mmol) of the title compound from example 3b) are dissolved in a mixture of 100 ml of water and 50 ml of 2-propanol and 2.09 g (5.77 mmol) of gadolinium oxide are added. The mixture is stirred for 3 hours at 80 °C. The solution is filtered and evaporated in vacuo to dryness.

Yield: 12.48 g (quantitative) of a glassy solid.

Water content: 5.6%.

Tt relaxivity (l/mmol-sec) at 20 MHz, 37 °C:

15.2 (water)

27.5 (human plasma).

Elemental analysis (with regard to anhydrous substance):

Example 4

a) 1, 2- epoxy- 4- oxa- 1H, 1H, 2H, 3H, 3H, 5H, 5H, 6H, 6H- perfluorodecane

To a mixture of 20 g (54.93 mmol) 1H,1H,2H,2H-perfluorooctan-1-ol and 1.87 g (5.5 mmol) tetrabutylammonium hydrogen sulfate in 200 ml 60% aqueous potassium chloride/100 ml toluene is added dropwise under vigorous stirring at 10 °C 10.17 g (109.9 mmol) epichlorohydrin, and it is ensured that the temperature of the reaction solution does not become higher than 20 °C. The mixture is stirred for 2 hours at 15 °C and then, as described above, 5.08 g (54.93 mmol) epichlorohydrin is added dropwise. The mixture is then stirred overnight at room temperature. 100 ml of toluene and 100 ml of methyl tert-butyl ether are added, and the aqueous phase is separated. This is extracted twice with 50 ml of toluene. The organic phases are combined, dried over magnesium sulphate and evaporated in vacuo. The precipitate is chromatographed on silica gel (eluent: dichloromethane/hexane/acetone = 20/10/1).

Yield: 19.15 g (83% of the theoretical value) of a colorless oil.

Elemental analysis:

b) 10-[2- hydroxy- 4-oxa- 1H, 1H, 2H, 3H, 3H, 5H, 5H, 6H, 6H- perfluorodecyl]- 1, 4, 7- tris(carboxymethyl)- 1, 4, 7 , 10- tetraazacyclododecane

To 14.84 g (42.84 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (D03A) in 70 ml of water is added 10.3 g (257 mmol) of sodium hydroxide. A solution of 18 g (42.84 mmol) of the title compound from example 4a) dissolved in 80 ml n-butanol/60 ml 2-propanol is added dropwise to this mixture, and the solution is heated overnight at 70 °C. The mixture is evaporated in vacuo to dryness, the precipitate is dissolved in 300 ml of water and adjusted to pH 3 with 3 N hydrochloric acid. The mixture is then extracted twice with 200 ml of n-butanol. The combined butanol phases are evaporated in vacuo to dryness, and the precipitate is purified by RP chromatography (RP-18/eluent: gradient of water/n-butanol/acetonitrile).

Yield: 27.4 g (75% of the theoretical value) of et

glassy solid.

Water content: 10.1%.

Elemental analysis (with regard to anhydrous substance):

c) Gadolinium complex of 10-[ 2- hydroxy- 4-oxa-1H, 1H, 2H, 3H, 3H, 5H, 5H, 6H, 6H- perfluorododecyl]- 1, 4, 7- tris-(carboxymethyl)- 1, 4, 7, 10-tetraazacyclododecane 10 g (13.04 mmol) of the title compound from example 4b) are dissolved in a mixture of 100 ml of water and 50 ml of 2-propanol and 2.36 g (6.52 mmol) of gadolinium oxide are added. The mixture is stirred for 3 hours at 80 °C. The solution is filtered and evaporated in vacuo to dryness.

Yield: 12.77 g (quantitative) of a glassy solid.

Water content: 6.1%.

Elemental analysis (with regard to anhydrous substance):

Example 5

a) 9, 9, 9, 8, 8, 7, 7, 6, 6- nonafluoro- 3- oxanononoic acid- t-butyl ester

To a mixture of 20 g (75.73 mmol) 1H,1H,2H,2H-per-fluorohexan-1-ol and 2.57 g (7.57 mmol) tetrabutylammonium hydrogen sulfate in 300 ml 60% aqueous potassium chloride/200 ml toluene 29.54 g (151.5 mmol) of bromoacetic acid tert-butyl ester are added dropwise with vigorous stirring at 0 °C. The mixture is stirred for 1 hour at 0 °C. 100 ml of toluene is added, the aqueous phase is separated and extracted twice with 50 ml of toluene. The combined organic phases are dried over magnesium sulfate and evaporated in vacuo. The precipitate is chromatographed on silica gel (eluent: hexane/dichloromethane/acetone = 20/10/1).

Yield: 21.48 g (75% of the theoretical value) of a colorless oil.

Elemental analysis:

b) 9, 9, 9, 8, 8, 7, 7, 6, 6- nonanefluoro- 3- tfxa- nonanoic acid

20 g (52.88 mmol) of the title compound from example

5a) is dissolved in 300 ml of trifluoroacetic acid and stirred overnight at room temperature. The mixture is evaporated in vacuo to dryness. The precipitate is recrystallized from hexane/ether.

Yield: 14.82 g (87% of theory) of a colorless crystalline solid. ..'. ■ . ' ■ ■■

Elemental analysis:

c) Gadolinium complex of 10-[ 2- hydroxy- 4- aza- 5- oxo- 7- oxa-10, 10, 11, 11, 12, 12, 13, 13, 13- nonafluorotridecyl] 1, 4, 7- tris -( carboxymethyl)- 1, 4, 7, 10- tetraazacyclododecane

7.41 g (23.01 mmol) of the title compound from example 5b) and 2.91 g (25.31 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 40 ml of dimethylformamide and 20 ml of chloroform. At 0<*>C, 5.22 g (25.31 mmol) of dicyclohexylcarbodiimide are added,

and it is stirred for 1 hour at 0 °C, followed by 3 hours at room temperature. The mixture is cooled again to 0 °C and 6.98 g (69 mmol) of triethylamine/30 ml of 2-propanol are added. 13.2 g (23.01 mmol) gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane dissolved in 40 ml is then added water, and it is stirred for 3 hours at room temperature. The mixture is evaporated to dryness, the precipitate is dissolved in a mixture of 200 ml of methanol and 50 ml of chloroform, and the dicyclohexylurea is filtered off. The filtrate is evaporated to dryness and purified by RP chromatography (RP-18/eluent: gradient of water/n-propanol/acetonitrile).

Yield: 15.20 g (71% of theory) of a colorless glassy solid.

Water content: 5.7%.

Elemental analysis (with regard to anhydrous substance):

Example 6 a) N-ethyl-N-(perfluorooctylsulfonyl)aminoacetic acid-N-(2-aminoethyl)amide 15 g (25.63 mmol) of the title compound from example 1b) and 3.24 g (28.19 mmol) of N- hydroxysuccinimide is dissolved in 80 ml of dimethylformamide and 5.82 g (28.19 mmol) of dicyclohexylcarbodiimide are added at 0 °C. The mixture is stirred for 1 hour at 0 °C and then for 2 hours at room temperature. Precipitated dicyclohexylurea is filtered off, and the filtrate is added dropwise within 30 minutes to a solution of 46.21 g (768.9 mmol) of ethylenediamine in 300 ml of dichloromethane. The mixture is stirred for 5 hours at room temperature. 1000 ml of H2O is added, and the organic phase is separated. This is washed twice with 500 ml of water, then dried over magnesium sulphate and evaporated in vacuo to dryness. The purification is carried out by chromatography on silica gel (eluent: dichloromethane/2-propanol = 15/1).

Yield: 11.79 g (75% of theory) of a colorless waxy solid.

Elemental analysis:

b) N-ethyl-N-(perfluorooctylsulfonyl)aminoacetic acid-N-[2-(bromoacetyl)aminoethyl]amide 10 g (16.3 mmol) of the title compound from example 6a) and 2.02 g (20 mmol) of triethylamine are dissolved in 40 ml of dichloromethane. At -10 °C, 3.29 g (16.3 mmol) of bromoacetyl bromide are added dropwise within 30 minutes, and the mixture is stirred for 2 hours at 0 °C. The solution is poured into 300 ml of 1 N hydrochloric acid and stirred well. The organic phase is separated, dried over magnesium sulphate and evaporated in vacuo. The precipitate is chromatographed on silica gel (eluent: dichloromethane/acetone - 20/1).

Yield: 11.1 g (91% of theory) of a light yellow waxy solid.

Elemental analysis:

S 4.10.

c) 10-[2-oxo-3-aza-6-aza-7-oxo-9-aza-9-(perfluorooctyl-sulfonyl) undecyl]-1,4,7-tris (carboxymethyl)-1,4 , 7, 10- tetraazacyclododecane

To 10 g (13.36 mmol) of the title compound from example 6b) in 180 ml of methanol is added 4.63 g (13.36 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (D03A) and 18.5 g (133.6 mmol) of potassium carbonate. The mixture is refluxed for 12 hours. The inorganic salts are filtered off, and the filtrate is evaporated to dryness. The precipitate is dissolved in 100 ml of water and adjusted to pH 3 with 5 N hydrochloric acid. The mixture is extracted twice with 150 ml of n-butanol. The combined phases are evaporated in vacuo to dryness, and the precipitate is purified by RP chromatography (RP-18/eluent: gradient of water/n-butanol/acetonitrile).

Yield: 10.43 g (67% of the theoretical value) of a colorless solid.

Water content: 13.0%.

Elemental analysis ' (with respect to anhydrous substance):

d) Gadolinium complex of 10-[ 2-oxo-3- aza- 6- aza- 7- oxo- 9- aza- 9-( perfluorooctylsulfonyl) undecyl]- 1, 4, 7- tris(carboxymethyl)-1, 4, 7, 10-tetraazacyclododecane 10 g (9.86 mmol) of the title compound from example 6c) are dissolved in a mixture of 50 ml of water and 20 ml of ethanol and 1.79 g (4.93 mmol) of gadolinium oxide are added. The mixture is stirred for 4 hours at 80 °C. The solution is filtered and evaporated in vacuo to dryness.

Yield: 12.4 g (quantitative).

Water content: 7.1%.

Elemental analysis (with regard to anhydrous substance):

Example 7

a) 1H, 1H, 2H, 2H-perfluorododecane-1-ol-p-toluenesulfonic acid ester

To 30 g (64.64 mmol) 1H,1H,2H,2H-perfluorodecan-1-ol

in 300 ml of dichloromethane and 10.12 g (100 mmol) of triethylamine are added at 0 °C 12.57 g (65.93 mmol) of p-toluenesulfonic acid chloride. The mixture is stirred for 2 hours at 0 °C and then for 2 hours at room temperature. The solution is poured into 500 ml of cold 2 N hydrochloric acid and stirred vigorously. The organic phase is separated, dried over magnesium sulphate and evaporated to dryness. The precipitate is recrystallized from a small volume of methanol.

Yield: 39.97 g (95% of the theoretical value) of a colorless crystalline powder.

Elemental analysis:

b) 10- t( 1- hydroxymethyl- 1- carboxy) methyl]- 1, 4, 7- tris-( carboxymethyl)- 1, 4, 7, 10- tetraazacyclododecane

To a solution of 20 g (57.78 mmol) 1,4,7-tris-(carboxymethyl)-1,4,7,10-tetraazacyclododecane (D03A), 3.21 g

(780 mmol) of sodium hydroxide and 2 g (12 mmol) of potassium iodide in 100 ml of dimethylformamide are added to 37.2 g (173.4 mmol) of 2-chloro-3-benzyloxypropanoic acid, and the mixture is stirred for 3 days at 60 °C. The mixture is evaporated to dryness, and the precipitate is dissolved in 300 ml of water. The pH is then adjusted to 3 with 1 N hydrochloric acid, and the mixture is extracted twice with 250 ml of dichloromethane. 4 g palladium catalyst (10% Pd/C) is added to the water phase, and the mixture is hydrated for 5 hours at 60 °C. The catalyst is filtered off, and the filtrate is evaporated to dryness. The precipitate is purified by RP chromatography (RP-18/eluent = gradient of water/2-propanol/acetonitrile).

Yield: 5.92 g (21% of the theoretical value with respect to D03A) of a colorless glassy solid.

Water content: 11.1%.

Elemental analysis (with regard to anhydrous substance):

c) 10-[ 1- hydroxymethyl- 1-( methoxycarbonyl) methyl]- 1, 4, 7- tris-( methoxycarbonylmethyl)- 1, 4, 7, 10- tetraazacyclododecane

9.53 g are added dropwise to 200 ml of methanol at 0 °C

(80 mmol) thionyl chloride. 5.8 g (13.35 mmol) are then added

of the title compound from Example 7b), and the mixture is stirred for 1 hour at 0 °C. The mixture is then heated for 6 hours at 60 °C. The mixture is evaporated to dryness, the precipitate is dissolved in 150 ml of methylene chloride and extracted three times with 200 ml of 8% aqueous soda solution. The organic phase is dried over magnesium sulfate and evaporated to dryness. 6.09 g (93% of the theoretical value) of the title compound is obtained as a light yellow oil.

Elemental analysis:

d) 10-[ 1-( methoxycarbonyl)- 3- oxal- 1H, 2H, 2H, 4H, 4H, 5H, SHper-fluorotridecyl]- 1, 4, 7- tris( methoxycarbonylmethyl)- 1, 4, 7, 10 -tetraazacyclododecane

To 6 g (12.23 mmol) of the title compound from example 7c) in 40 ml of dimethylformamide is added 0.44 g

(14.68 mmol) sodium hydride (80% suspension in mineral oil) and stirred for 30 minutes at -10 °C. Then 8.32 g (13.45 mmol) of the title compound from example 7a) are added, and the mixture is stirred for 8 hours at room temperature. 400 ml of ice water is carefully added, and the mixture is extracted twice with 300 ml of ethyl acetate. The combined acetic acid ethyl ester phases are washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The mixture is evaporated in vacuo to dryness, and the precipitate is chromatographed on silica gel (eluent: dichloromethane/methanol = 20/1).

Yield: 7.68 g (67% of the theoretical value) of a viscous yellow oil.

Elemental analysis:

e) 10-[ 1- carboxyl- 3-oxa- 1H, 2H, 2H, 4H, 4H, 5H, 5H- perfluoro tridecyl]- 1, 4, 7- tris(carboxymethyl)- 1, 4, 7, 10- tetraa2acyclo

Dodecanese

7.5 g (8.01 mmol) of the title compound from example 7d) are suspended in a mixture of 50 ml of water and 30 ml of ethanol and then 3.84 g (96 mmol) of sodium hydroxide are added. The mixture is refluxed overnight. It is cooled to room temperature and adjusted to pH 3 with 3 N hydrochloric acid. The mixture

is evaporated in vacuo to dryness, and the precipitate is purified by RP chromatography (RP-18/eluent ■ gradient of water/n-butanol/acetonitrile).

Yield: 6.84 g (87% of theory) of a glassy solid.

Water content: 10.3%.

Elemental analysis (with regard to anhydrous substance):

f) Gadolinium complex of 10-[l-carboxy-3-oxa-1H, 2H, 2H, 4H, 4H, 5H, 5H- perfluorotridecyl]- 1, 4, 7- tris-(carboxymethyl)- 1, 4, 7, 10-tetraazacyclododecane (as sodium salt) 6 g (6.81 mmol) of the title compound from example 7e) are suspended in 80 ml of water and 1.23 g (3.4 mmol) of gadolinium oxide are added. The mixture is heated for 3 hours at 90 °C. The mixture is cooled to room temperature and adjusted to pH 7.2 with 2 N caustic soda. The solution is then filtered and freeze-dried.

Yield: 7.83 g (quantitative) of a colorless flocculent powder.

Water content: 8.1

Elemental analysis (with regard to anhydrous substance):

Example 8

a) 2H, 2H-^ perfluorooctanal

Dissolve 30 g (82.4 mmol) of 1H,1H,2H,2H-perfluorooctan-1-ol in 500 ml of dichloromethane and add 17.76 g (82.4 mmol) of pyridine chlorochromate. The mixture is stirred overnight at room temperature. The solution is filtered through a short column filled with aluminum oxide (neutral), the filtrate is evaporated to dryness, and the precipitate is chromatographed on silica gel (eluent: dichloromethane/hexane/acetone = 10/10/1). ,

Yield: 26.55 g (89% of the theoretical value) of a waxy/solid substance.

Elemental analysis:

b) 2- amino- 2H, 3H, 3H- perfluorononanoic acid (as hydrochloride)

7.04 g (143.6 mmol) of sodium cyanide and 8.45 g

(158 mmol) of ammonium chloride is dissolved in 30 ml of water. 40 ml of ethanol and 26 g (71.8 mmol) of the title compound from example 8a) are added to this solution. The mixture is heated for 2 hours at 45 °C. 300 ml of water are added and extracted three times with 200 ml of benzene. The combined benzene phases are washed three times with 200 ml of water, and the organic phase is evaporated in vacuo to dryness. The precipitate is dissolved in 100 ml 6 N aqueous hydrochloric acid/5 ml methanol and refluxed for 2 hours. The mixture is evaporated in vacuo to dryness. The precipitate is recrystallized from a small volume of 2-propanol/methyl tert-butyl ether.

Yield: 11.15 g (35% of the theoretical value) of a crystalline solid.

Elemental analysis:

c) 2-[( N- benzyloxycarbonyl) triglycidyl] amino- 2H, 3H, 3H-perfluorononanoic acid

8.37 g (24.8 mmol) of N-benzyloxycarbonyl)triglycine and 3.14 g (27.28 mmol) of N-hydroxysuccinimide are dissolved in 80 ml of dimethylformamide and added at 0 °C 5.63 g (27.28 mmol) di-

cyclohexylcarbodiimide. The mixture is stirred for 1 hour at 0 °C and then for 2 hours at room temperature. The mixture is cooled to 0 °C, 7.53 g (74.4 mmol) of triethylamine and 11 g (24.8 mmol) of the title compound from example 8b) are added and then stirred overnight at room temperature. The mixture is evaporated in vacuo to dryness, the precipitate is dissolved in 300 ml of 5% aqueous citric acid and extracted three times with 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and evaporated in vacuo to dryness. The precipitate is chromatographed on silica gel (eluent: dichloromethane/2-propanol = 20/1).

Yield: 11.83 g (67% of theory) of a colorless scaly solid.

Elemental analysis:

d) 2-[ triglycidyl] amino- 2H, 3H, 3H- perfluorononanoic acid

11.5 g (16.14 mmol) of the title compound from

example 8c) is dissolved in 200 ml of 2-propanol and 3 g of palladium catalyst (10% Pd/C) are added. The mixture is hydrated overnight at room temperature. The catalyst is filtered off, and the filtrate is evaporated to dryness.

Yield: 9.33 g (quantitative) of a colorless solid.

Elemental analysis:

e) 2-(1H,1H-perfluoroheptyl)-1,4,7,10-tetraaza-3,6,9,12-tetraoxocyclododecane

9.2 g (15.91 mmol) of the title compound from example 8d) are dissolved in 1000 ml of dimethylformamide and 3.93 g (15.91 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline are added. The mixture is stirred for 3 days at room temperature. The mixture is evaporated to dryness, and the precipitate is chromatographed on silica gel (eluent: dichloromethane/2-propanol = 20/1).

Yield: 4.54 g (51% of theory) of a waxy solid.

Elemental analysis:

f) 2-(1H,1H-perfluoroheptyl)-1,4,7,10-tetraazacyclododecane (as tetrahydrochloride)

To 4.4 g (7.85 mmol) of the title compound from example 8e) is added 200 ml of 1 M borane-tetrahydrofuran complex solution and refluxed for 2 days. The mixture is evaporated in vacuo to dryness, and the precipitate is dissolved in 50 ml of concentrated hydrochloric acid. The mixture is added to 100 ml of ethanol and stirred for 8 hours under reflux. The mixture is evaporated in vacuo to dryness, and the precipitate is recrystallized from ethanol.

Yield: 4.75 g (93% of the theoretical value) of a colorless crystalline powder.

Elemental analysis:

q) 2-(1H,1H-perfluoroheptyl)-1,4,7,10-tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane

4.6 g (7.07 mmol) of the title compound from example 8f) and 4.0 g (42.4 mmol) of chloroacetic acid are dissolved in 40 ml of water, and by adding 30% aqueous potassium chloride, the pH is adjusted to 10. The mixture is heated in 8 hours at 70 °C, and the pH value is maintained between 8 and 10 (by adding 30% aqueous potassium hydroxide). The solution is cooled to room temperature, adjusted with concentrated hydrochloric acid to pH 2 and evaporated to dryness. The precipitate is dissolved in 150 ml of methanol, the salts are filtered off, and the filtrate is evaporated in vacuo to dryness. The precipitate is purified by RP-18 chromatography (RP-18/eluent: gradient of water/2-propanol/acetonitrile).

Yield: 5.03 g (87% of the theoretical value) of a glassy solid.

Water content: 10.1%.

Elemental analysis (with regard to anhydrous substance):

h) Gadolinium complex of 2-(1H,1H-perfluoroheptyl)-1,4,7,10-tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane (as

sodium salt)

4.5 g (6.11 mmol) of the title compound from example 8g) are suspended in 100 ml of water and 1.107 g (3.05 mmol) of gadolinium oxide are added. The mixture is heated for 3 hours at 90 °C. The mixture is cooled to room temperature and adjusted to pH 7.2 with 2 N caustic soda. The solution is then filtered and freeze-dried.

Yield: 6.03 g (quantitative) of a colorless powder.

Water content: 7.5%.

Elemental analysis (with regard to anhydrous substance):

Example 9

a) 10-[ 2- hydroxy- 1H, 1H, 2H, 3H, 3H- perfluorononyl]- 1, 4, 7- tris-(carboxymethyl)- 1, 4, 7, 10- tetraazacyclododecane

To 15 g (43.3 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in 50 ml of water is added 13.85 g (346.4 mmol) of sodium hydroxide. A solution of 27.68 g (64.95 mmol) 1,2-epoxy-1H,1H,2H,3H,3H-perfluorononane dissolved in 50 ml n-butanol/50 ml 2-propanol is added dropwise to this mixture, and the solution heated overnight at 80 °C. The mixture is evaporated in vacuo to dryness, the precipitate is dissolved in 200 ml of water and adjusted with 3 N hydrochloric acid to pH 3. The mixture is extracted twice with 200 ml of n-butanol. The combined butanol phases are evaporated in vacuo to dryness, and the precipitate is purified by RP chromatography (RP-18/eluent: gradient of water/n-butanol/acetonitrile).

Yield: 30.34 g (78% of theory) of a glassy solid.

Water content: 13.7%.

Elemental analysis (with regard to anhydrous substance):

b) Gadolinium complex of 10-[ 2-hydroxy- 1H, 1H, 2H, 3H, 3H- per-fluorononyl]- 1, 4, 7- tris(carboxymethyl)- 1, 4, 7, 10- tetraazacyclododecane 10 g (12 .94 mmol) of the title compound from example 9a) is dissolved in 100 ml of water/50 ml of ethanol and 2.34 g (6.47 mmol) of gadolinium oxide is added. The mixture is heated for 3 hours at 80 °C. The solution is filtered and evaporated in vacuo to dryness.

Yield: 13.16 g (quantitative) of a colorless glassy solid.

Water content: 9.1%.

Elemental analysis (with regard to anhydrous substance):

Example 10

a) 9H, 9H, 10H, 11H, 12H, 12H- perfluoroeicose- 10- one

24.77 g (52.26 mmol) of 1H,1H,2H,2H-perfluorodecyl-1-iodide and 13.71 g (52.26 mmol) of triphenylphosphine are heated in 500 ml of acetone with stirring at 70 °C. The clear solution quickly becomes milky cloudy and separates the colorless phosphonium salt. The phosphonium salt is filtered off and dried in a vacuum at 40 °C.

Yield: 38.9 g (89% of the theoretical value).

This phosphonium salt is used without purification directly in the following reaction: To the phosphonium salt prepared above, 38.9 g (46.5 mmol), in 250 ml of dichloromethane is added 5.22 g (46.5 mmol) of potassium tert.-butylate, 0.20 g (0.75 mmol) of 18-crown-6 and 19.54 g (42.28 mmol) of 2H,2H-perfluorodecanal, and it is stirred for 10 hours at room temperature. The mixture is evaporated to dryness, and the precipitate is chromatographed on silica gel (eluent: dichloromethane/n-hexane/diethyl ether = 10/20/1).

Yield: 30.3 g (65% of the theoretical value with respect to added iodide) of a colorless waxy solid.

Elemental analysis:

b) 10, ll- epoxy- 9H, 9H, 10H, 11H, 12H, 12H- perfluoroeicosane

To 25 g (28.02 mmol) of the title compound from

example 10a) dissolved in 250 ml of dichloromethane is added at 0 °C 10.47 g (36.42 mmol) of 3-chloroperoxybenzoic acid (approx. 60%), and it is stirred overnight at room temperature. The mixture is added to 300 ml of 5% aqueous sodium carbonate solution and stirred well. The organic phase is separated, dried over magnesium sulfate and evaporated in vacuo to dryness. The precipitate is chromatographed on silica gel (eluent: n-hexane/dichloromethane/diethyl ether = 10/10/1).

Yield: 24.17 g (95% of the theoretical value) of a colorless solid.

Elemental analysis:

c) 10-[ 1-( 1H, 1H- perfluorononyl)- 2- hydroxy- 1H, 2H, 3H, 3H- per-fluoroundecyl]- 1, 4, 7- tris(carboxymethyl)- 1, 4, 7, 10 - tetraazacyclododecane

To 7.63 g (22.02 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in 35 ml of water is added 7.04 g (0.176 mmol) of sodium hydroxide. A solution of 20 g (22.02 mmol) of the title compound from example 10b) dissolved in 50 ml n-butanol/40 ml 2-propanol is added dropwise to this mixture, and the solution is heated overnight at 120 °C in an autoclave. The mixture is evaporated in vacuo to dryness, the precipitate is dissolved in 200 ml of water and adjusted with 3 N hydrochloric acid to pH 3. The mixture is then extracted twice with 300 ml of n-butanol. The combined butanol phases are evaporated in vacuo to dryness, and the precipitate is purified by RP chromatography (RP-18/eluent:

gradient of water/n-butanol/acetonitrile).

Yield: 9.79 g (31% of: theoretical value) of a colorless glassy solid.

Water content: 12.5%.

Elemental analysis (with regard to anhydrous substance):

d) Gadolinium complex of 10-[ 1-( 1H, 1H- perfluorononyl)- 2-hydroxy- 1H, 2lf, 3H, 3H- perfluoroundecyl]- 1, 4, 7- tris(carboxymethyl)- 1, 4, 7, 10 - tetraazacyclododecane 8 g (6.38 mmol) of the title compound from example 10c) are dissolved in .50 ml of water/40 ml of ethanol/20 ml of chloroform and 1.16 g (3.19 mmol) of gadolinium oxide are added. The mixture is stirred for 4 hours at 90°C in an autoclave. The solution is filtered and evaporated in vacuo to dryness.

Yield: 9.47 g (quantitative) of a glassy solid.

Water content: 5.2%.

Elemental analysis (with regard to anhydrous substance):

Example 11

a) 7H, 7H, 8H, 9H, 10H, 10H- perfluorohexadecene-8-ene

18.7 g (50 mmol) 1H,1H,2H,2H-perfluorooctyl-1-iodide and

13.11 g (50 mmol) of triphenylphosphine is heated in 400 ml of acetone with stirring at 70 °C. The clear solution quickly becomes milky cloudy and separates the colorless phosphonium salt. The phosphonium salt is filtered off and dried in a vacuum at 40 °C.

Yield: 28.95 g (91% of the theoretical value).

This phosphonium salt is used without purification directly in the following reaction: To the phosphonium salt prepared above, 28.95 g (45.5 mmol), in 200 ml of dichloromethane is added 5.05 g -(45.5 mmol) t potassium tert.- butylate, 0.20 g (0.75 mmol) 18-crown-6 and 14.98 g (41.36 mmol) of the title compound from Example 8a), and it is stirred for 10 hours at room temperature. The mixture is evaporated to dryness, and the precipitate is chromatographed on silica gel (eluent: dichloromethane/n-hexane/diethyl ether = 10/20/1).

Yield: 19.65 g (61% of theory) of a colorless waxy solid.

Elemental analysis:

b) 8, 9- epoxy- 7H, 7H, 8H, 9H, 10H, 10H- perfluorohexadecane

To 19 g (29.5 mmol) of the title compound from

example lia) dissolved in 200 ml dichloromethane is added at 0 °C 11.03 g (38.35 mmol) 3-chloroperoxybenzoic acid (approx. 60%), and it is stirred overnight at room temperature. 300 ml of 5% aqueous sodium carbonate solution is added, and the mixture is stirred well. The organic phase is separated, dried over magnesium sulfate and evaporated in vacuo to dryness. The precipitate is chromatographed on silica gel (eluent: n-hexane/dichloromethane/diethyl ether = 10/10/1).

Yield: 19.43 g (93% of the theoretical value) of a colorless solid.

Elemental analysis:

c) 10- ti-( 1H, 1H- perfluoroheptyl)- 2- hydroxy- 1H, 2H, 3H, 3H- per-fluorononyl]- 1, 4, 7- tris(carboxymethyl)- 1, 4, 7, 10- tetraazacyclododecane

To 9.3 g (26.83 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in 50 ml of water is added 8.59 g (214.6 mmol) of sodium hydroxide. To this, a solution of 19 g (26.83 mmol) of the title compound from example 11b) dissolved in 70 ml n-butanol/60 ml 2-propanol is added dropwise, and the solution is heated overnight at 120 °C in an autoclave. The mixture is evaporated in vacuo to dryness, the precipitate is dissolved in 200 ml of water and adjusted with 3 N hydrochloric acid to pH 3. The mixture is then extracted twice with 300 ml of n-butanol. The combined butanol phases are evaporated in vacuo to dryness, and the precipitate is purified by RP chromatography (RP-18/eluent: gradient of water/n-butanol/acetonitrile).

Yield: 9.4 g (29% of the theoretical value) of a glassy solid.

Water content: 12.7%.

Elemental analysis (with regard to anhydrous substance):

d) Gadolinium complex of 10-[ 1-( 1H, 1H- perfluoroheptyl)- 2-hydroxy- 1H, 2H, 3H, 3H- perfluorononyl]- 1, 4, 7- tris(carboxymethyl)-1, 4, 7, 10 - tetraazacyclododecane 9 g (8.53 mmol) of the title compound from example lic) are dissolved in 60 ml of water/40 ml of ethanol/30 ml of chloroform and 1.54 g (4.27 mmol) of gadolinium oxide are added. The mixture is stirred for 4 hours at 90°C in an autoclave. The solution is filtered and evaporated in vacuo to dryness.

Yield: 11.45 g (quantitative) of a colorless glassy solid.

Water content: 10.2%.

Elemental analysis (with regard to anhydrous substance):

Example 12

a) 7, 12- dioxa- 5H, 5H, 6H, 6H, 8H, 8H, 9H, 10H, 11H, 11H, 13H,-13H, 14H, 14H- perfluorooctadecan-9-ene 30 g (91.74 mmol) 1H,1H,2H,2H-perfluorohexyl-1-bromide is dissolved in 100 ml of toluene and then 3.23 g (36.7 mmol) of cis-1,4-butenediol and 1 g (2.95 mmol) of tetrabutylammonium hydrogen sulfate are added. The mixture is cooled to 0 °C, and 16 g (400 mmol) of finely powdered sodium hydroxide are added. The mixture is then stirred for 1 hour at 0 °C and overnight at room temperature. Solid material is filtered off, the filtrate is washed twice with 200 ml of water, the organic phase is dried over magnesium sulphate and evaporated in vacuo to dryness. The precipitate is chromatographed on silica gel (eluent: dichloromethane/n-hexane/acetone = 15/15/1).

Yield: 11.71 g (55% of the theoretical value with respect to diol) of a waxy solid.

Elemental analysis:

b) 9, lO- epoxy- 7, 12- dioxa- 5H, 5H, 6H, 6H, 8H, 8H, 9H, 10H,-11H, 11H, 13H, 13H, 14H, 14H- perfluorooctadecane

To 11 g (18.96 mmol) of the title compound from example 12a) dissolved in 100 ml of dichloromethane, 7.08 g (24.64 mmol) of 3-chloroperoxybenzoic acid (approx. 60%) are added at 0 °C, and it is stirred overnight at room temperature. 150 ml of 5% aqueous sodium carbonate solution are added, and the mixture is stirred well. The organic phase is separated, dried over magnesium sulfate and evaporated in vacuo to dryness. The precipitate is chromatographed on silica gel (eluent: n-hexane/dichloromethane/diethyl ether = 10/10/1).

Yield: 10.74 g (95% of theory) of a colorless solid.

Elemental analysis:

c) 10-[ 1-( 2-oxa- 1H, 1H, 3H, 3H, 4H, 4H- perfluorooctyl)- 2- hydroxy- 4-oxa- 1H, 2H, 3H, 3H, 5H, 5H, 6H, 6H - perfluorodecyl)- 1, 4, 7- tris-(carboxymethyl)- 1, 4, 7, 10- tetraazacyclododecane

To 6.1 g (17.61 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in 40 ml of water is added 5.63 g (141 mmol) of sodium hydroxide. A solution of 10.5 g (17.61 mmol) of the title compound from example 12b) dissolved in 50 ml n-butanol/40 ml 2-propanol is added dropwise to this mixture, and the solution is heated overnight at 120 °C in an autoclave. The mixture is evaporated in vacuo to dryness, the precipitate is dissolved in 200 ml of water and adjusted with 3 N hydrochloric acid to pH 3. The mixture is then extracted twice with 300 ml of n-butanol. The combined butanol phases are evaporated in vacuo to dryness, and the precipitate is purified by RP chromatography (RP-18/eluent: gradient of water/n-butanol/acetonitrile).

Yield: 4.96 g (27% of theory) of a colorless glassy solid.

Water content: 9.7%.

Elemental analysis (with regard to anhydrous substance):

d) Gadolinium complex of 10-[ 1-( 2-oxa- 1H, 1H, 3H, 3H, 4H, 4H-perfluorooctyl)- 2- hydroxy- 4-oxa- 1H, 2H, 3H, 3H, 5H, 5H, 6H ,6H-perfluorodecyl]- 1, 4, 7- tris(carboxymethyl)- 1, 4, 7, 10- tetraazacyclododecane

4.7 g (5 mmol) of the title compound from example 12c) are dissolved in 30 ml of water/30 ml of ethanol/20 ml of chloroform and 0.90 g (2.5 mmol) of gadolinium oxide are added. The mixture is stirred for 3.5 hours at 90°C in an autoclave. The solution is filtered and evaporated in vacuo to dryness.

Yield: 5.89 g (quantitative) of a colorless glassy solid.

Water content: 7.1%.

Elemental analysis (with regard to anhydrous substance):

Example 13

a) 1- phenvl- 2, 6- dioxa- 1H, 1H, 3H, 3H, 4H, 5H, 5H, 7H, 7H, 8H, 8H-perfluorohexadecan-4-ol

To 7.14 g (39.2 mmol) of glycerol-1-monobenzyl ether and 25 g (43.55 mmol) of 1H,1H,2H,2H-perfluorodecyl-1-iodide in 100 ml of toluene is added 1 g (2.94 mmol ) tetrabutylammonium hydrogen sulfate and 15.6 g (390 mmol) finely powdered sodium hydroxide. The mixture is stirred for 24 hours at room temperature. Solid material is removed from the organic phase and washed twice with 5% aqueous hydrochloric acid. The organic phase is dried over magnesium sulfate and evaporated in vacuo to dryness. The precipitate is chromatographed on silica gel (eluent: n-hexane/acetone = 15/1).

Yield: 19.95 g (81% of the theoretical value) of a colorless oil.

Elemental analysis:

b) 1- phenyl- 2, 6- decyloxy- 1H, 1H, 3H, 3H, 4H, 5H, 5H, 7H, 7H, 8H, 8H-perfluorohexadecane

To 19.5 g (31.03 mmol) of the title compound from example 13a) dissolved in 100 ml of dimethylformamide, 1.12 g (37.24 mmol) of sodium hydride (80% suspension in mineral oil) is added in portions, and it is stirred for 2 hours at room temperature. 8.24 g (37.24 mmol) of n-decyl bromide are then added, and the mixture is stirred overnight at 50 °C. The mixture is added to 150 ml of ice water and extracted twice with 150 ml of acetic acid ethyl ester. The combined organic phases are washed twice with 150 ml of water, dried over magnesium sulphate and evaporated to dryness. The precipitate is chromatographed on silica gel (eluent: n-hexane/acetone = 20:1).

Yield: 22.66 g (95% of theory) of a waxy solid.

Elemental analysis:

c) 2-(decyloxy)-4-oxa- 1H, 1H, 2H, 3H, 3H, 5H, 5H, 6H, 6H- perfluorohexadecane 20 g (26.02 mmol) of the title compound from example 13b) are dissolved in 200 ml of isopropanol and 3 g of palladium catalyst are added (10% Pd/C). The mixture is hydrated overnight at room temperature. The catalyst is filtered off, and the filtrate is evaporated in vacuo to dryness.

Yield: 17.65 g (quantitative) of a colorless solid.

Elemental analysis:

d) 1, 2- epoxy- 4-oxa-(6-decyloxy)-8-oxa-1H, 1H, 2H, 3H, 3H, 5H, 5H, 6H, 7H, 7H, 9H, tOH, 1OH- perfluorooctadecane

To a mixture of 17 g (25.06 mmol) of the title compound from example 13c) and 2 g (5.89 mmol) of tetrabutylammonium hydrogen sulfate in 300 ml of 60% aqueous potassium chloride/100 ml of toluene is added dropwise with vigorous stirring at 10° C 9.25 g (100 mmol) epichlorohydrin', and. it is ensured that the temperature of the reaction solution does not become higher than 20 °C. The mixture is stirred for 2 hours at 15°C and then, as described above, 4.63 g (50 mmol) of epichlorohydrin is added dropwise. The mixture is then stirred overnight at room temperature. 100 ml of toluene and methyl tert-butyl ether are added, . and the aqueous phase is separated. This is extracted again twice with 100 ml of toluene. The organic phases are combined, dried over magnesium sulfate and evaporated in vacuo. The precipitate is chromatographed on silica gel (eluent: dichloromethane/hexane/acetone = 20/10/1 ).

Yield: 14.91 g (81% of the theoretical value) of a colorless solid.

Elemental analysis:

e) 10-[ 2- hydroxy- 4, 8- dioxa-( 6-decyloxy)-1H, 1H, 2H, 3H, 3H, 5H, 5H, 6H, 7H, 7H, 9H, 9H, 10H, 10H- per -fluorooctadecyl]- 1, 4, 7- tris(carboxymethyl)- 1, 4, 7, 10- tetraazacyclododecane

To 6.6 g (19.06 mmol) of 1,4,7-tris (carboxymethyl)-1,4,7,10-tetraazacyclododecane in 60 ml of water is added 6.11 g (152.8 mmol) of sodium hydroxide. A solution of 14 g (19.06 mmol) of the title compound from example 13d) dissolved in 80 ml of n-butanol/40 ml of 2-propanol is added dropwise to this mixture, and the solution is heated overnight at 80 <*>C in an autoclave. The mixture is evaporated in vacuo to dryness, the precipitate is dissolved in 200 ml of water and adjusted to pH 3 with 3 N hydrochloric acid. The mixture is then extracted twice with 300 ml of n-butanol. The combined butanol phases are evaporated in vacuo to dryness, and the precipitate is purified by RP chromatography (RP-18/eluent: gradient of water/n-butanol/acetonitrile).

Yield: 17.88 g (76% of the theoretical value) of a glassy solid.

Water content: 12.5%.

Elemental analysis (with regard to anhydrous substance):

f) Gadolinium complex of 10-[ 2- hydroxy- 4, 8- dioxa- 6-( decyloxy) 1H, 1H, 2H, 3H, 3H, 5H, 5H, 6H, 7H, 7H, 9H, 9H, 10H, 10H - per-fluorooctadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane 10 g (9.26 mmol) of the title compound from example 13e) are dissolved in 30 ml of water/100 ml of ethanol/ 30 ml of chloroform and 1.68 g (4.63 mmol) of gadolinium oxide are added. The mixture is stirred for 3.5 hours at 90<6>C in an autoclave. The solution is filtered and evaporated in vacuo to dryness.

Yield: 12.39 g (quantitative). of a colorless glassy solid.

Water content: 7.8%. Elemental analysis (with regard to anhydrous substance):

Example 14

a) 1-phenyl-2-oxa-4,4,4-tris-(2-oxa-1H,1H,3H,3H,4H,4Hper-fluorodecyl)butane

To 4.24 g (18.74 mmol) of pentaerythritol-1-monobenzyl ether and 40 g (93.7 mmol) of 1H,1H,2H,2H-perfluorooctyl-1-bromide in 150 ml of toluene are added 2 g (5.89 mmol ) tetrabutylammonium hydrogen sulfate and 22.48 g (562 mmol) finely powdered sodium hydroxide. The mixture is stirred for 24 hours at room temperature. Solid material is removed from the organic phase and washed twice with 5% aqueous hydrochloric acid. The organic phase is dried over magnesium sulfate and evaporated in vacuo to dryness. The precipitate is chromatographed on silica gel (eluent: n-hexane/acetone 25/1).

Yield: 14.45 g (61% of the theoretical value with respect to the benzyl ether) of a colorless waxy solid.

Elemental analysis:

b) 2, 2, 2-tris-(2-oxa-1H, 1H, 3H, 3H, 4H, 4H- perfluorodecyl) ethan-1-ol

14 g (11.07 mmol) of the title compound from example

14a) is dissolved in 100 ml of isopropanol/100 ml of tetrahydrofuran and 3 g of palladium catalyst (10% Pd/C) are added. The mixture is hydrated overnight at room temperature. The catalyst is filtered off, and the filtrate is evaporated in vacuo to dryness.

Yield: 13 g (quantitative) of a colorless solid.

Elemental analysis:

c) 1,2-epoxy-4-oxa-6,6,6-tris-(2-oxa-1H,1H,3H.,3H,,4H,4H-perfluorodecyl)hexane

To a mixture of 12.5 g (10.64 mmol) of the title compound from example 14b) and 1 g (2.95 mmol) of tetrabutylammonium hydrogen sulfate in 150 ml of 60% aqueous potassium hydroxide/50 ml of toluene is added dropwise with vigorous stirring at 10 °C 3 .94 g (42.57 mmol) of epichlorohydrin, and it is ensured that the temperature in the reaction solution does not become higher than 20 °C. The mixture is stirred for 2 hours at 15 °C and then, as described above, 1.97 g (21.29 mmol) of epichlorohydrin is added dropwise. The mixture is then stirred overnight at room temperature. 100 ml of toluene and 100 ml of methyl tert-butyl ether are added, and the aqueous phase is separated. This is extracted twice with 50 ml of toluene. The organic phases are combined, dried over magnesium sulphate and evaporated in vacuo. The precipitate is chromatographed on silica gel (eluent: dichloroethane/hexane/acetone = 20/10/1).

Yield: 8.12 g (62% of the theoretical value) of a colorless solid.

Elemental analysis:

Calculated: C 31.24 H 2.05 F 60.22

Found: C 31.09 H 2.19 F 60.10.

d) 10-[2-hydroxy-4-oxa-6,6,6-tris-(2-oxa-1H,1H,3H,3H,4H,4H-perfluorodecyl)hexyl]-1,4,7-tris (carboxymethyl)- 1, 4, 7, 10-tetraazacyclododecane

To 2.25 g (6.50 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in 30 ml of water is added 2.08 g (52 mmol) of sodium hydroxide. A solution of 8.0 g (6.50 mmol) of the title compound from example 14c) dissolved in 50 ml n-butanol/30 ml 2-propanol is added dropwise to this mixture, and the solution is heated overnight at 100 °C in an autoclave. The mixture is evaporated in vacuo to dryness, the precipitate is dissolved in 200 ml of water and adjusted to pH 3 with 3 N hydrochloric acid. The mixture is then extracted twice with 100 ml of n-butanol. The combined butanol phases are evaporated in vacuo to dryness, and the precipitate is purified by RP chromatography (RP-18/eluent: gradient of water/n-butanol/acetonitrile).

Yield: 7.79 g (67% of the theoretical value) of. a colorless, glassy, solid.

Water content: 11.9%. Elemental analysis (with regard to anhydrous substance):

e) Gadolinium complex of 10-[ 2- hydroxy- 4-oxa- 6, 6, 6- tris-( 2-oxa- 1H, 1H, 3H, 3H, 4H, 4H- perfluorodecyl) hexyl]- 1, 4, 7 - tris-(carboxymethyl)-1,4,7,10-tetraazacyclododecane 7 g (4.44 mmol) of the title compound from example 14d) is dissolved in 30 ml water/50 ml ethanol/50 ml chloroform and 0.80 g is added (2.22 mmol) of gadolinium oxide. The mixture is stirred for 5 hours at 90°C in an autoclave. The solution is filtered and evaporated in vacuo to dryness.

Yield: 8.34 g (quantitative) of a colorless glassy solid.

Water content: 8.1%.

Elemental analysis (with regard to anhydrous substance): Calculated: C 31.94 H 2.74 F 42.83 Gd 9.09 N 3.24

Found: C 31.74 H 2.91 F 42.67 Gd 8.85 N 3.15.

Example 15

a) 1,7-bis[acetyl-(2-(N-ethyl-N-perfluorooctylsulfonylamino)3-1,4,7-triazaheptane 20 g (34.17 mmol) of the title compound from example 1b) and 4.33 g {37.59 mmol) of N-hydroxysuccinimide is dissolved in 150 ml of dimethylformamide. At 0 <*>C, 7.76 g (37.59 mmol) of dicyclohexylcarbodiimide are added, and the mixture is stirred for 3 hours at room temperature. Dicyclohexylurea is filtered off, and the filtrate is added dropwise to a solution of 1.76 g (17.09 mmol) diethylenetriamine and 13.83 g (136.7 mmol) triethylamine in 200 ml dimethylformamide at room temperature. The mixture is stirred overnight at room temperature. It is evaporated in vacuo to dryness, and the precipitate is dissolved in 200 ml of 5% aqueous soda solution. The mixture is extracted twice with 150 ml of dichloromethane, the combined organic phases are dried over magnesium sulfate and evaporated in vacuo to dryness. The precipitate is chromatographed on silica gel (eluent: dichloromethane/2-propanol = 20/1).

Yield: 16.5 g (78% of theory) of a waxy solid.

Elemental analysis:

b) 4-(3-carboxypropanoyl)-1,7-bis-{acetyl-[2-(N-ethyl-N-perfluorooctylsulfonylamino)1}-1,4,7-triazaheptane

To 16 g (12.93 mmol) of the title compound from example 15a) in 100 ml of methylene chloride is added 3.92 g (38.78 mmol) of triethylamine, and the solution is cooled to 0 °C. 2.59 g (25.86 mmol) of succinic anhydride are then added, and the mixture is stirred for 3 hours at 0 °C and overnight at room temperature. Add 200 ml of .5% aqueous hydrochloric acid to the mixture and stir well. The organic phase is separated and dried over magnesium sulfate. The mixture is evaporated in vacuo to dryness, and the precipitate is chromatographed on silica gel (eluent: dichloromethane/2-propanol = 15/1).

Yield: 15.74 g (91% of the theoretical value) of a colorless solid.

Elemental analysis:

c) 10-[7-hydroxy-5-aza-4-oxooctanoic acid-N,N-bis-(3-aza-4-oxo-6-aza-6-(perfluorooctylsulfonyl)octyl)amide]- 1,4, 7-tris-(carboxymethyl)-1,4,7,10-tetraazacyclododecane 15 g (11.21 mmol) of the title compound from example 15b) and 1.42 g (12.33 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 80 ml of dimethylformamide and 30 ml of chloroform. At 0 °C, 2.54 g (12.33 mmol) of dicyclohexylcarbodiimide are added, and the mixture is stirred for 1 hour at 0 °C, followed by 3 hours at room temperature. The mixture is cooled again to 0 °C and 4.05 g (40 mmol) of triethylamine/50 ml of 2-propanol are added. 7.07 g (12.33 mmol) gadolinium complex of 10-[2-hydroxy-3-aminopropyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane dissolved in 30 ml is then added water, and the mixture is stirred for 3 hours at room temperature. The mixture is evaporated to dryness, the precipitate is dissolved in a mixture of 100 ml of methanol and 50 ml of chloroform, and dicyclohexylurea is filtered off. The filtrate is evaporated to dryness and purified by RP chromatography {RP-18/eluent: gradient of water/n-propanol/acetonitrile).

Yield: 17.76 g (78% of theory) of a colorless glassy solid.

Water content: 6.8%.

Elemental analysis (with regard to anhydrous substance):

Example 16

Gadolinium complex of 1, 4, 7- tris(carboxylatomethyl)- 10-( 2-hydroxy- 19, 19, 20, 20, 21, 21, 22, 22, 23, 23, 24, 24, 25, 25, 26, 26, 26-heptadecafluoro- 4, 7, 10, 13, 16- pentaoxahexacosane)- 1, 4, 7, 10-tetraazacyclododecane

a) 16, 16, 17, 17, 18, 18, 19, 19, 20, 20, 21, 21, 22 , 22 , 22-heptadecafluoro-3, 6, 9, 12- tetraoxadocosan-l-ol

A mixture of 20 g (32.35 mmol) of 1-p-toluenesulfonyloxy-1H,1H,2H„,2H-'perfluorododecane [see Example 7a)], 1 g of tetra-butyla*mm'onium hydrogen sulfate, 62.83 g ( 323.5 mmol) tetraethylene glycol, 300 ml dichloromethane and 100 ml 50% caustic soda are stirred intensively for 24 hours at approx. 5 °C. The mixture is then diluted with 200 ml dichloromethane, the phases are separated, and the dichloromethane phase is washed with water. The organic phase is dried over magnesium sulfate and evaporated in vacuo. 1.8.5 g of the desired title compound are obtained as a pale yellow oil.

b) 1, 2- epoxy- 19~, 19, 20, 20, 21, 21, 22, 22, 23, 23., 24, 24, 25,-. 25, 26, 26, 26- heptadecafluoro- 4, 7, 10, 13, 16- pentaoxahexacosane

A mixture of 17 g (26.5 mmol) of 16,16,17,17,18,18,-19,19,20,20,21,21,22,22,22-heptadecafluoro-3,6,9, 12-tetraoxa-docosan-1-ol, 0.5 g of tetrabutylammonium hydrogen sulfate, 2.94 g of epichlorohydrin, 200 ml of dichloromethane and 50 ml of 50% caustic soda are stirred intensively for 8 hours at room temperature. The phases are separated, the aqueous phase is shaken with 100 ml of dichloromethane, the organic phases are combined, shaken with 50 ml of water, dried over magnesium sulphate and evaporated in vacuo. The precipitate is chromatographed on silica gel with hexane/5-50% ethyl acetate, and 12.92 g of the title compound is obtained as an oil.

Elemental analysis:

c) 1, 4, 7- tris(carboxylatomethyl)- 10-( 2- hydroxy- 19, 19, 20, 20, 21-, 21, 22, 22, 23, 23, 2- 4, 2. 4, 25 , 25, 26, 26, 26- heptadecafluoro-4, 7, 10, 13, 16- pentaoxahexacosane)- 1, 4, 7, 10- tetraazacyclododecane

A solution of 12.05 g (17 .3 mmol) 1,2-epoxy-19,19,20,20,21,21,22,22,23,23,24,24, - 25,25,26,26,26-heptadecafluoro-4,7 ,10,13,16-pentaoxahexacosane in 50 ml of tetrahydrofuran. The mixture is stirred overnight at 70 °C, evaporated in vacuo, the precipitate is dissolved in 150 ml of water and adjusted with 6 N hydrochloric acid to pH 3 and extracted several times with n-butanol. The combined extracts are evaporated in vacuo, and the precipitate is purified by chromatography on RP-18 with a gradient of water/n-butanol/acetonitrile. 13.71 g of the title compound are obtained as a yellow, viscous oil.

Elemental analysis:

d) Gadolinium complex of 1, 4, 7- tris(carboxylatomethyl)- 10-( 2-hydroxy- 19, 19, 20, 20, 21, 21, 22, 22, 23, 23, 24, 24, 25, 25, 26, 26, 26-heptadecaluor- 4, 7, 10, 13, 16- pentaoxahexacosane) - 1, 4, 7, 10-tetraazacyclododecane

A mixture of 5 g (4.79 mmol) of 1,4,7-tris(carboxylatomethyl)-10-(2-hydroxy-19,19,20,20,21,21,22,22,23,23, 24,25,25,26,26,26-heptadecafluoro-4,7,10,13,16-pentaoxahexacosane)-1,4,7,10-tetraazacyclododecane, 50 ml of water and 30 ml of ethanol are added 869 mg (2.397 mmol) gadolinium oxide. and refluxed for 5 hours. The hot solution is filtered and evaporated in vacuo. 5.60 g of the title compound are obtained as a glassy solid with a water content of 4.1%. Elemental analysis (with regard to anhydrous substance):

Example 17

Gadolinium complex of 1, 4, 7- tris( carboxylatomethyl)- 10-( 4- aza-2- hydroxy- 2' 6, 26, 26, 25, 25, 24, 24, 23, 23, 22, 22, 21, 21, 20, 20, 19, 19-heptadecafluoro- 5- oxo- 16- thiahexacosyl)- 1, 4, 7, 10- tetraazacyclododecane

a) 22, 22, 22, 21, 21, 20, 20, 19, 19, 18, 18, 17, 17, 16, 16, 15, 15-heptadecafluoro-12-thiadocosanoic acid

A mixture of 10 g (37.71 mmol) of 11-bromodecanoic acid in 150 ml of dichloromethane is added to 11.43 g of triethylamine and 18.11 g (37.71 mmol) of 1H,1H,2H,2H-perfluorodecyl mercaptan and stirred overnight at room temperature . The solution is extracted several times with 2 N hydrochloric acid, washed with sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. 21.5 g of the title compound are obtained as a yellow oil.

Elemental analysis:

b) Gadolinium complex of 1, 4, 7- tris(carboxylatomethyl) 10-( 4-aza- 2- hydroxy- 26, 26, 26, 25, 25, 24, 24, 23, 23, 22, 22, 21-, 21, 20, 20, 19, 19-heptadecafluoro-5-oxo-16-thiahexacosyl)-1,4,7,10-tetraazacyclododecane 5 g (7.52 mmol) of the title compound from example 17a) and 0.95 g N -hydroxysuccinimide is dissolved in a mixture of 25 ml of dimethylformamide and 15 ml of chloroform. At 0 °C, 1.71 g of dicyclohexylcarbodiimide is added, and the mixture is stirred for 1 hour at 0 °C and then for 3 hours at room temperature. The mixture is cooled to 0 °C and 3 ml of triethylamine and 20 ml of 2-propanol are added. Then 4.75 g (8.27 mmol) of the gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane dissolved in in 25 ml of water, and it is stirred for 3 hours at 20 °C. The mixture is evaporated to dryness, the precipitate is dissolved in a mixture of 55 ml of methanol and 20 ml of chloroform, and the dicyclohexylurea is filtered off. The filtrate is evaporated to dryness and purified by chromatography on RP-18 with a gradient of water/n-propanol/acetonitrile. 6.15 g of the title compound are obtained as a glassy solid with a water content of 2.3%.

Elemental analysis (with regard to anhydrous substance):

Example 18

Gadolinium complex of 1, 4, 7- tris(carboxylatomethyl)- 10-[ 1-( 1, 2- dihydroxyethyl)- 3- oxa- 6, 6, 7, 7, 8, 8, 9, 9, 10, 10, 11, 11, 11-tridecafluoro] undecane- 1, 4, 7, 10- tetraazacyclododecane

a) 1- p- toluenesulfonyloxy- 1H, 1H, 2H, 2H- perfluorooctane

To a solution of 25 g (68.7 mmol) of 1H,1H,2H,2H-perfluorooctan-1-ol in 300 ml of dichloromethane, 20 ml of pyridine is added at 0 °C, and while stirring, 13.49 g (70, 76 mmol) p-toluenesulfonic acid chloride. The mixture is stirred for a further 3 hours at 0 °C, and dichloromethane is removed in vacuo at room temperature. Ice water is added to the remaining pyridine solution, whereby the desired product is precipitated. The mixture is decanted, and the precipitate is dissolved in dichloromethane, the solution is washed with water, dried over magnesium sulphate and evaporated in vacuo. The precipitate is purified by chromatography on silica gel with hexane/5-40% ethyl acetate. 12.92 g of the title compound are obtained as a tough precipitate.

Elemental analysis:

b). 1,4,7-tris(benzyloxycarbonyl)-10-[1-(2,2-dimethyl- i,3-dioxolan-4-yl)-6,6,7,7,8,8,9,9, 10, 10, 11, 11,. 11- tridecafluoro- 3-oxa] undecane- 1, 4, 7, 10- tetraazacyclododecane

To 7.33 g (10 mmol) 1,4,7-tris(benzyloxycarbonyl)-10-[2-hydroxy-1-(2,2-dimethyl-1,3-dioxolan-4-yl)]ethyl-1 ,4,7,-10-tetraazacyclododecane [J. With. Res. Imag., 5:7-10 (1955)] dissolved in 100 ml of dichloromethane, 20 ml of 50% caustic soda, 0.5 g of tetrabutylammonium hydrogen sulfate and 5.18 g (10 mmol) of 1-p-toluenesulfonyloxy-lH,1H, are added in order. 2H,2H-perfluorooctane [see example 18a)], and the mixture is stirred intensively overnight at room temperature. The phases are separated, the organic phase is washed several times with water, dried over magnesium sulphate and evaporated in vacuo. The precipitate is purified by chromatography on silica gel with dichloromethane/1-10% ethanol. 8.02 g of the title compound are obtained as a viscous oil.

Elemental analysis:

c) l-[l-(2,2- dimethyl-1,3-dioxolan-4-yl)-6, 6, 7, 7, 8, 8, 9, 9,-10, 1010H, 10H, 11, 11, 11- tridecafluoro- 3- oxa]- undecane- 1, 4, 7, 10-tetraazacyclododecane

A solution of 7 g (6.57 mmol) of 1,4,7-tris(benzyloxycarbonyl)-10-[1-(2,2-dimethyl-1,3-dioxolan-4-yl)-6,6,7 . carbon (10%), and it is stirred for 3 hours under a hydrogen atmosphere. The catalyst is filtered off, and the solution is evaporated in vacuo. 4.20 g of the title compound are obtained as a glassy foam.

Elemental analysis:

d) 1, 4, 7-tris(carboxylatomethyl)-10-[ 1-{ 1, 2- dihydroxyethyl)-3-oxa- 6, 6, 7, 7, 8, 8, 9, 9, 10, 10, 11, 11, 11- tridecafluoro] undecane-1, 4, 7, 10- tetraazacyclododecane

3.36 g (24.15 mmol) of bromoacetic acid are dissolved in 50 ml of water and 6 N caustic soda is added to pH 7. At 40 °C, a solution of 4 g {6.04 mmol) 1-[1-( 2,2-dimethyl-1,3-dioxolan-4-yl)-6,6,7,7,8,8,9,9,10,10,11,11,-11-tridecafluoro-3-oxa] undecane-1,4,7,10-tetraazacyclododecane dissolved in 20 ml of isopropyl alcohol, and enough 6 N caustic soda to keep the pH at 9-10. Semi-concentrated hydrochloric acid is then added to pH 1, and the mixture is stirred for a further 3 hours at 60 °C. The mixture is cooled to room temperature, and the solution is extracted several times with n-butanol. The organic extract is evaporated, and the precipitate is purified by chromatography on RP-18 with a gradient of water/n-butanol/acetonitrile. 3.85 g of the title compound are obtained as a yellow oil with a water content of 3.9%.

Elemental analysis:

e) Gadolinium complex of 1, 4, 7- tris(carboxylatomethyl)- 10-[ 1-{ 1, 2- dihydroxyethyl)- 3- oxa- 6, 6, 7, 7, 8, 8, 9, 9, 10, 10, 11, 11, 11-

tridecafluoro] undecane- 1, 4, 7, 10- tetraazacyclododecane

A mixture of 1.59 g (2 mmol) of 1,4,7-tris(carboxylatomethyl)-10-[1-(1,2-dihydroxyethyl)-3-oxa-6,6,7,7,8,8 ,9,9,-10,10,11,11,11-tridecafluoro]undecane-1,4,7,10-tetraazacyclododecane, 25 ml of water and 15 ml of ethanol are added to 363 mg (1 mmol) of gadolinium oxide and heated for 5 hours during reflux. The hot solution is filtered and evaporated in vacuo to give 1.85 g of the title compound as a glassy solid with a water content of 4.2%.

Elemental analysis (taking account of anhydrous substance):

Example 19

Gadolinium complex of 1,4,7-tris(carboxylatomethyl)-10-{2-hydroxy-4-oxa-4-[4-(2H,2H,3H,3H-l-oxaperfluoroundec-l-yl)]-phenyl> but-l-yl-l,4,7,10-tetraazacyclododecane

a) l-hydroxy-4-(2H,2H,3H,3H-l-oxaperfluoroundec-l-yl)benzene

5 g (45.41 mmol) of hydroquinone are added to 100 ml of acetone

and 13.8 g of potassium carbonate and 14.04 g (22.7 mmol) of 1-p-toluenesulfonyl bxy-1H,1H,2H,2H-perfluorodecane [see example 7a] are added in sequence while stirring. The mixture is heated for 6 hours under reflux, evaporated in vacuo, diluted with 200 ml of water, adjusted with citric acid to pH 3 and extracted several times with dichloromethane. The organic extract is dried over magnesium sulfate and evaporated in vacuo. The precipitate is purified by chromatography on silica gel with hexane/5-30% ethyl acetate. 8.20 g of the desired title compound are obtained as a viscous oil.

Elemental analysis:

b) 1-(3,4-epoxy-l-oxabutyl-l-vl)-4-(2H,2H,3H,3H-l-oxaperfluoroundec-l-yl)benzene

A mixture of 8 g (14.38 mmol) of 1-hydroxy-4-(2H,2H,3H,3H-1-oxaperfluoroundec-1-yl)benzene, 0.4 g of tetrabutylammonium hydrogen sulfate, 1.60 g (17.26 mmol) of epichlorohydrin, 150 ral of dichloromethane and 30 ml of 50% caustic soda are stirred intensively for 30 minutes in an ice bath and then for 5 hours at room temperature. The phases are separated, the organic phase is washed with water, dried over magnesium sulphate and evaporated in vacuo. The precipitate is purified by chromatography on silica gel with hexane/5-30% ethyl acetate, and 6.60 g of the title compound is obtained as a viscous oil.

Elemental analysis:

c) 1,4,7-tris(carboxylatomethyl)-10-{2-hydroxy-4-oxa-4-[4-(2H,2H,3H,3H-1-oxaperfluoroundec-1-yl)]-phenyl} but-l-yl-l, 4, 7, -

10- tetraazacyclododecane

A solution of 6.12 g (10 mmol) of 1-(3,4-epoxy-1-oxabut-1-yl)-4-(2H,2H,3H,3H-1-oxaperfluoroundec-1-yl)benzene in 25 ml of tetrahydrofuran, and the heated for 24 hours under reflux, then evaporated in vacuo, the precipitate dissolved in 100 ml of water, adjusted with 6 N hydrochloric acid to pH 3 and extracted several times with n-butanol. The combined extracts are evaporated in vacuo. The precipitate is purified by chromatography! on RP-18 with a gradient of water/n-butanol/acetonitrile. 6.71 g of the title compound are obtained as a viscous oil.

Elemental analysis:

d) Gadolinium complex of 1,4,7-tris(carboxylatomethyl)-10-{2-hydroxy-4-oxa-4-[4-(2H,2H,3H,3H-1-oxaperfluoroundec-1-yl)]- phenyl} but- l- yl- l, 4, 7, 10- tetraazacyclododecane

A mixture of 4.79 g (5 mmol) of 1,4,7-tris(carboxylatomethyl)-10-{2-hydroxy-4-oxa-4-[4-(2H,2H,3H,3H-1-oxaperfluoroundec -l-yl)]-phenyl}but-l-yl-1,4,7,10-tetraazacyclododecane, 50 ml of water and 30 ml of ethanol are added to 906 mg (2.5 mmol) of gadolinium oxide and heated for 5 hours under backflow cooking. The hot solution is filtered and evaporated in vacuo. 5.50 g of the title compound are obtained as a glassy solid with a water content of 4.9%. Elemental analysis (with regard to anhydrous substance):

Example 20

Gadolinium complex, disodium salt of 3, 9- bis(carboxymethyl)- 6-[( 1- carboxy)- 1H, 2H, 2H, 4H, 4H, 5H, 5H- 3-oxaperfluorotridecyl]- 3, 6, 9- triazaundecanedioic acid

a) N-t-butoxycarbonylserine-(1H, 1H, 2H, 2H- perfluorodecyl)-ether benzyl ester

In a solution of 2.953 g (10 mmol) of N-t-butyloxycarbonylserine benzyl ester (commercial product, Bachem) in 30 ml of dry dimethylformamide, 300 mg (10 mmol) of sodium hydride (80% in oil) is added portionwise. After the solution, 6.0.72 g (10 mmol) of the tosylate prepared under 7a) are added. The mixture is stirred for 12 hours at room temperature. The mixture is then poured into 500 ml of ice water, the product is dissolved in dichloromethane, the organic solution is washed with water, dried over sodium sulphate and evaporated to dryness. The precipitate is purified by chromatography on silica gel. A mixture of dichloromethane with increasing methanol addition is used as the elution phase. The title compound is obtained as a syrup.

Yield: 5.902 g (79.6% of the theoretical value). Elemental analysis:

b) Serine-(1H, 1H, 2H, 2H- perfluorodecyl) ether benzyl ester (as salt of trifluoroacetic acid)

In 50 ml of a mixture of trifluoroacetic acid and dichloromethane in the ratio 2:1, 7.414 g (10 mmol) of the N— protected compound prepared under 20a) are dissolved, and it is stirred overnight at room temperature. The mixture is evaporated to dryness, and residues of trifluoroacetic acid are removed by distillation together with ethanol. The title compound is isolated as a salt of

trifluoroacetic acid.

Yield: 7.418 g {98.2% of the theoretical value). Elemental analysis:

c) 3, 9- bis( t- butoxycarbonylmethyl)- 6-[( 1- benzyloxycarbonyl)- 1H, 2H, 2H, 4H, 4H, 5H, 5H- 3- oxaperfluorotridecyl)- 3, 6, 9- triazaundecanedic acid- di (t-butyl ester)

To a mixture of 10 ml of acetonitrile and 20 ml of phosphate buffer with a pH value of 8.0 are added 3.777 g (5 mmol) of the amine trifluoroacetate prepared under 20b) and 3.523 g (10 mmol) of N,N-bis(t-butyloxycarbonylmethyl )-2-(bromomethyl)amine, and it is stirred intensively for 2 hours at room temperature. The buffer phase is removed, extracted with 10 ml of acetonitrile and added to the organic phase. After adding 20 ml of fresh buffer, the mixture is stirred for a further 20 hours at room temperature. The organic phase is separated, evaporated, and the precipitate is distributed between 100 ml of phosphate buffer (pH 8.0) and <1>100 ml of acetic acid. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The compound is purified by chromatography on silica gel. As eluent, dichloromethane is used with increasing addition of methanol. The title compound is obtained as a glassy solid.

Yield: 3.162 g (53.4% of the theoretical value).-Elemental analysis:

d) 3, 9- bis(carboxymethyl)- 6-[( 1- carboxy)- 1H, 2H, 2H, 4H, 4H, 5H, 5H-3- oxaperfluorotridecyl]- 3, 6, 9- triazaundecanedioic acid

To a mixture of 25 ml of trifluoroacetic acid and dichloromethane in the ratio 2:1 is added 5.920 g (5 mmol) of the compound prepared under 20c). The mixture is stirred overnight at room temperature, evaporated to dryness, the precipitate dissolved in 100 ml of 3 N hydrochloric acid, refluxed for 3 hours, then evaporated in vacuo to dryness and dissolved in 160 ml of a mixture of water, ethanol and chloroform (10:5: 1). The solution is adjusted to a constant pH value (approx. 3) by adding ion exchanger IRA-67 (OH~ form). The mixture is quickly filtered off, evaporated, and the title compound is obtained as a glassy solid.

Yield: 3.080 g (71.3% of the theoretical value).

Water content: 11.3%.

Elemental analysis (with regard to anhydrous substance):

e) Gadolinium complex, disodium salt of 3, 9- bis(carboxymethyl)-6-[( 1- carboxy)- 1H, 2H, 2H, 4H, 4H, 5H, 5H- 3- oxaperfluorotridecyl]-3, 6, 9- triazaundecanedioic acid

To a mixture of 60 ml of distilled water and 30 ml of ethanol is added 2.941 g (3.0 mmol, calculated on 11.3% water content) of the acid prepared under 2Od). While stirring and heating to 50 °C, 543.8 mg (1.5 mmol) of gadolinium oxide are added in portions. After the addition, the mixture is stirred until a single solution is present. The pH value in the solution is then adjusted to 7.2 by adding caustic soda. The solution is then evaporated, whereby a strong foaming is observed. The precipitate is distilled with distilled water. The title compound is obtained as a glassy solid.

Yield: 3.489 g (quantitative).

Water content: 8.2%.

Elemental analysis (with regard to anhydrous substance):

Example 21

Gadolinium complex, monosodium salt of 3, 6, 9- tris( carboxymethyl) - 3, 6, 9- triazaundecanedioic acid- mono- N-( ethyl- 2- amino[ carbonylmethylamino-( N- ethyl- N- perfluorooctylsulfonyl)]} amide

a) 3, 6, 9- tris( carboxylatomethyl)- 3, 6, 9- triazaundecanedic acid-mono- N-( ethyl- 2- amino[ carbonylmethylamino-( N- ethyl- N-perfluorooctylsulfonyl) ]} amide

In 200 ml of a mixture of dimethylformamide and dichloromethane in a ratio of 4:1, 17.87 g (50 mmol) of diethylene-triaminepentaacetic acid-bisanhydride are suspended and, with vigorous stirring, the mixture 3.137 g (5 mmol) [N-{2-aminoethyl )-N-perfluorooctylsulfonyl]aminoacetic acid-N-(2-aminoethyl)amide and 6.50 g (64.2 mmol) of triethylamine. The mixture is stirred for 5 hours, evaporated to dryness, 300 ml of ice water is added, and the pH value in the mixture is adjusted with 3 N hydrochloric acid to approx. 3. The mixture is extracted twice with 200 ml of n-butanol, the organic solutions are combined and evaporated. The product is purified by chromatography on silica gel RP-18. Water and tetrahydrofuran are used as eluents. The title compound is obtained as a glassy solid.

Yield: 2.722 g (54.3% of the theoretical value).

Water content: 9.7%.

Elemental analysis (with regard to anhydrous substance):

b) Gadolinium complex, monosodium salt of 3, 6, 9- tris( carboxymethyl) - 3, 6, 9- triazaundecanedioic acid- mono- N- { ethyl- 2- amino[ carbonylmethylamino-( N- ethyl- N- perfluorooctylsulfonyl)] } amide

To 90 ml of a mixture of distilled water and ethanol (2:1) is added 3.259 g (3 mmol, calculated on 9.7% water content) of the compound prepared under 21a). While stirring, 543.8 mg (1.5 mmol) of gadolinium oxide is added in portions. The mixture is stirred until a solution is present, the pH value in the solution is set to 7.2 by adding caustic soda, and the solution is evaporated, whereby a strong foaming occurs. The precipitate is distilled together with distilled water. The title compound is obtained as a glassy solid.

Yield: 3.861 g (quantitative).

Water content: 8.4%.

Elemental analysis (with regard to anhydrous substance):

Example 22

Gadolinium complex, monosodium salt of 3, 9- bis(carboxymethyl)-6- 1H, 1H, 4H, 4H, 5H, 5H, 8H, 8H, 10H, 1QH, 11H, 11H- 2, 7- dioxo- 3, 6- diaza - 9- oxaperfluoromonodecyl)- 3, 6, 9- triazaundecanedioic acid

a) Glycolic acid-(1H, 1H, 2H, 2H-per£luordecyl) ether- N-(2- aminoethyl) amide

10.44 g (20 mmol) of compound 2b) are dissolved in 80 ml of dichloromethane and 2.30 g (20 mmol) of N-hydroxysuccinimide and 4.13 g (20 mmol) of dicyclohexylcarbodiimide are added. The mixture is stirred overnight, dicyclohexylurea is filtered off, and the filtrate is stirred in a solution of 60.1 g (1000 mmol) of ethylenediamine in 100 ml of dichloromethane. The mixture is stirred overnight, 1.5 1 of water is added, and the organic phase is separated. The dichloromethane solution is washed with water, dried over sodium sulfate, evaporated to dryness, and the precipitate is purified by chromatography on silica gel. A mixture of dichloromethane with increasing addition of isopropanol is used as eluent.

Yield: 9.615 g (85.2% of the theoretical value). Elemental analysis:

b) Glycolic acid-(1H, 1H, 2H, 2H- perfluorodecyl) ether- M-[ ethyl- 2-( benzyloxycarbonylaminoethylcarbonylamino)] amide

2.092 g (10 mmol) of benzyloxycarbonylglycine are dissolved in 15 ml of dichloromethane and 1.151 g (10 mmol) of N-hydroxysuccinimide and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are added. The mixture is stirred overnight, dicyclohexylurea is filtered off, and the mixture is evaporated to dryness. The precipitate is purified on silica gel by column chromatography. A mixture of dichloromethane and ethanol is used as eluent. The title compound is obtained as a glassy solid.

Yield: 6.905 g (91.4% of the theoretical value). Elemental analysis:

c) Glycolic acid-( 1H, 1H, 2H, 2H- perfluorodecyl) ether- N-[ ethyl-( 2-aminomethylcarboxylamino) 1 amide

In 100 ml of a mixture of tetrahydrofuran and ethanol in the ratio 2jl, 3.777 g (5 mmol) of the compound prepared under 22b) are hydrogenated in the presence of 0.2 g of Pearlman catalyst (Pd 20%/C)' until 112 ml of hydrogen is busy The catalyst is filtered off, washed well with ethanol, and the mixture is evaporated to dryness. The title compound is obtained as a glassy solid. " • .

Yield: 3.097 g (99.7% of the theoretical value). Elemental analysis:.

d) 3, 9- bis(t- butoxycarbonylmethyl)- 6- 1H, 1H, 4H, 4H, 5H, 5H, -8H, 8H, 10H, 10H, 11H, 11H- 2, 7- dioxo- 3, 6- diaza- 9- oxa-perfluorononadecyl)- 3, 6, 9- triazaundecanedioic acid- bis(t-butyl ester)

To a mixture of 10 ml of acetonitrile and 20 ml of phosphate buffer with a pH value of 8, 3.107 g (5 mmol) of the amine prepared under 22c) and 3.523 g (10 mmol) of N,N-bis(t-butyloxy-carbonylmethyl) are added - 2-(bromomethyl)amine, and it is stirred intensively for 2 hours at room temperature. The buffer phase is separated, extracted with 10 ml of acetonitrile and added to the organic phase. After adding 20 ml of fresh buffer, the mixture is stirred for a further 20 hours at room temperature. The organic phase is separated, evaporated, and the precipitate is distributed between 100 ml of phosphate buffer (pH 8.0) and 100 ml of acetic acid. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The compound is purified by chromatography on silica gel. As eluent, dichloromethane is used with increasing addition of methanol. The title compound is obtained as a glassy solid.

Yield: 3.044 g (52.3% of the theoretical value). Elemental analysis:

e) 3, 9- bis(carboxymethyl)- 6-( 1H, 1H, 4H, 4H, 5H, 5H, 8H, 8H, 10H, 1-OH, 11H, 11H- 2, 7- dioxo- 3, 6- diaza- 9- oxaperfluoromonodecyl)-3, 6/ 9- triazaundecanedioic acid

5.820 g (5 mmol) of the compound prepared under 22d) are added to a mixture of 120 ml of trifluoroacetic acid and dichloromethane in a ratio of 2:1. The mixture is stirred overnight at room temperature, evaporated to dryness, residues of trifluoroacetic acid are removed by distillation together with ethanol and dissolved in 240 ml of a mixture of water, ethanol and chloroform. The solution is adjusted to a constant pH value (about 3) by the addition of ion exchanger IRA-67 (OH" form). The mixture is rapidly suctioned off, evaporated, and the title compound is obtained as a glassy, solid substance.

Yield: 3.214 g (68.4% of the theoretical value).

Water content: 10.3%.

Elemental analysis (with regard to anhydrous substance):

f) Gadolinium complex, monosodium salt of 3, 9- bis-(carboxymethyl)- 6-( 1H, 1H, 4H, 4H, 5H, 5H, 8H, 8H, 10H, 10H, 11H, 11H-2, 7- dioxo- 3 , 6- diaza- 9- oxaperfluorononadecyl)- 3, 6, 9- triazaundecanedioic acid

To a mixture of 60 ml of distilled water and 30 ml of ethanol is added 3.143 g (3.0 mmol, calculated on 10.3% water content) of the acid prepared under 22e). While stirring and heating to 50 °C, 543.8 mg (1.5 mmol) of gadolinium oxide are added in portions. After the addition is complete, the mixture is stirred until a solution is present. The pH value in the solution is then adjusted to 7.2 by adding caustic soda, the solution is evaporated, whereby strong foaming is observed. The precipitate is distilled together with distilled water. The title compound is obtained as a glassy solid.

Yield: 3.635 g (quantitative).

Water content: 7.9%.

Elemental analysis (with regard to anhydrous substance):

Calculated: C 30.14 H 2.71 F 28.95 Gd 14.09 N 6.28

Now 2.06

Found: C 30.21 H 2.78 F 29.03 Gd 14.16 N 6.22

Now 2.11.

Example 23

Gadolinium complex of 3, 6, 9- tris(carboxymethyl)- 3, 6, 9- triazaundecanedioic acid- bis( N-[ 2- aminoethyl-( N- ethyl- N- perfluorooctylsulfonyl)] amide)

a) N-ethyl-(2-benzyloxycarbonylaminoethyl)perfluorooctylsulfonic acid amide 30 ml of dimethylformamide is dissolved in 5.272 g (10 mmol) perfluorooctylsulfonic acid N-ethylamide. While excluding moisture, 330 mg (11 mmol) of sodium hydride (80% in oil) are added. After gas evolution has ended, a solution of 2.093 g (10 mmol) of N-benzyloxycarbonylaziridine is added dropwise. The mixture is poured into 300 ml of ice water, extracted with dichloromethane, the organic solution is washed with water, dried over sodium sulphate and evaporated to dryness. The precipitate is chromatographed on silica gel with dichloromethane/methanol. The title compound is a glassy solid.

Yield: 6.149 g (87.3% of the theoretical value). Elemental analysis:

b) N-ethyl-N-2-(aminoethyl) perfluorooctylsulfonamide

In 100 ml of a mixture of tetrahydrofuran and ethanol

in the ratio 2:1, 3.522 g (5 mmol) of the compound prepared under 23a) are hydrogenated in the presence of 0.2 g of Pearlman catalyst

(Pd 20%/C) until 112 ml of hydrogen is taken up. The catalyst is filtered off, washed well with ethanol, and the mixture is evaporated to dryness. The title compound is obtained as an amorphous solid.

Yield: 2.814 g (98.7% of the theoretical value). Elemental analysis:

c) 3, 6, 9- tris( carboxymethyl)- 3 , 6 , 9- triazaundecanedioic acid- bis{ N-[ 2- aminoethyl-( N- ethyl- N- perfluorooctylsulfonyl)] amide}

Dissolve 5.073 g in 30 ml of dry dimethylformamide

(10 nimol) of the compound prepared under 23b) and 1.518 g (15 mmol) of triethylamine and 1.787 g (5 mmol) of diethylenetriamine-pentaacetic acid-bisanhydride are added in portions while stirring and exclusion of moisture. The mixture is stirred overnight,

is then evaporated, water is added, the pH value is adjusted with 3 N hydrochloric acid at approx. 3, and the mixture is extracted twice with 100 ml of n-butanol. The organic solutions are combined, evaporated and

is subjected to a chromatography on silica gel RP-18. Water and tetrahydrofuran are used as eluents. The title connection

is obtained as a glassy solid.

Yield: 6.172 g (82.4% of the theoretical value).

Water content: 9.8%.

Elemental analysis (with regard to anhydrous substance):

d) Gadolinium complex of 3, 6, 9- tris(carboxymethyl)- 3, 6, 9-triazaundecanedioic acid- bis fN-[ 2- aminoethyl-(N- ethyl- N- perfluorooctylsulfonyl) amide)

To a mixture of 120 ml of distilled water, 60 ml of ethanol and 20 ml of chloroform, 6.570 g (4 mmol, calculated on 9.8% water content) of the compound prepared under 23c are added. While stirring and heating to 50 °C, 725 are added in portions mg (82.0 mmol) gadolinium oxide The mixture is stirred until

a solution is present, then evaporated, whereby a strong foaming occurs, and the precipitate is distilled together with distilled water. The distillation is repeated twice. The title compound is obtained as a glassy solid.

Yield: 7.191 g (quantitative).

Water content: 8.1%.

Elemental analysis (with regard to anhydrous substance):

Example 24

Gadolinium complex of 3, 6, 9- tris(carboxymethyl)- 3, 6, 9- triazaundecanedioic acid- bis{ N- <2- aminoethyl-[ glycolic acid-( 1H, 1H, 2H, 2H- perfluorodecyl ether) amide] >- amide) a) 3, 6/ 9- tris(carboxymethyl)- 3, 6, 9- triazaundecanedioic acid- bis{ N-<2- aminoethyl-[ glycolic acid-(1H, 1H, 2H, 2H- perfluorodecyl ether)-amide] >- amide )

Dissolve 6.771 g in 40 ml of dry dimethylformamide

(12 mmol) of the compound prepared under example 22a) and 1.821 g (18 mmol) of triethylamine and 2.144 g (6 mmol) of diethylene-triaminepentaacetic acid-bisanhydride are added in portions while stirring and excluding moisture. The mixture is stirred overnight, then evaporated, 20 ml of water is added, the pH value is set to approx. 3, and the mixture is extracted with 3 N hydrochloric acid and twice with 150 ml of butanol. The organic solutions are combined, evaporated, and the precipitate subjected to chromatography on silica gel RP-18. Water and tetrahydrofuran are used as eluents. The title compound is obtained as a glassy solid.

Yield: 6.989 g (78.4% of the theoretical value).

Water content: 7.1%.

Elemental analysis (with regard to anhydrous substance):

b) Gadolinium complex of 3, 6, 9- tris(carboxymethyl)- 3, 6, 9-triazaundecanedioic acid- bis{ N- <2- aminoethyl-[ glycolic acid-( 1H, 1H, 2H, 2H- perfluorodecyl ether) amide] >- amide)

To a mixture of 100 ml of distilled water, 50 ml of ethanol and 20 ml of chloroform is added 4.798 g (3 mmol, calculated on 7.1% water) of the compound prepared under 24a). While stirring and heating to 50 °C, 543.8 mg (1.5 mmol) of gadolinium oxide are added in portions. The mixture is stirred until a solution is present, then evaporated, whereby a strong foaming occurs. The precipitate is distilled several times together with distilled water. The title compound is obtained as a glassy solid.

Yield: 5.285 g (quantitative).

Water content: 6.9%.

The elemental analysis is calculated based on anhydrous substance:

Example 25

Gadolinium complex, sodium salt of 3, 9- bis(carboxymethyl)- 6-[ N-( 1H, 1H, 2H, 2H- perfluorodecyl) aminocarbonylImethyl- 3, 6, 9- triazaundecanedioic acid

a) N-benzyloxycarbonylglycine-N-(1H, 1H, 2H, 2H- perfluorodecyl) amide In 70 ml of dichloromethane dissolve 7.877 g (15 mmol)

1H,1H,2H,2H-perfluorodecylamine (J. Fluor. Chem., 55, 85 (1991)) and 1.726 g (15 mmol) of N-hydroxysuccinimide, 3.095 g (15 mmol) of dicyclohexylcarbodiimide and 3.138 g (15 mmol) are added. N-benzyloxycarbonylglycine (commercial product, Bachem). The mixture is stirred overnight, the dicyclohexylurea is filtered off, the mixture is evaporated, and the precipitate is subjected to column chromatography on silica gel. Mixtures of dichloromethane are used as eluent. and ethanol. The title compound is obtained as a solid.

Yield: 8.951 g (91.2% of the theoretical value). Elemental analysis:

b) Glycine- N-( 1H, 1H, 2H, 2H- perfluorodecylamide

In 150 ml of a mixture of tetrahydrofuran and ethanol

in the ratio 2:1, 7.594 g (10 mmol) of the compound prepared under 28a) are dissolved and hydrogenated in the presence of 0.25 g of Pearlman catalyst (Pd 20%/C) until 224 ml of hydrogen is taken up. The catalyst is filtered off, washed well with ethanol, and the mixture is evaporated to dryness. The title compound is obtained as an amorphous solid.

Yield: 6.21 g (99.3% of the theoretical value). Elemental analysis:

c) 3/9-bis(t-butoxycarbonylmethyl)-6-N-(1H, 1H, 2H, 2H- perfluorodecyl) aminocarbonylmethyl- 3, 6? 9- triazaundecanedioic acid- di(t-butyl ester)

To a mixture of 10 ml acetonitrile and 20 ml phosphate buffer with a pH value of 8.0, 2.841 g (5 mmol) of the amine prepared under 25b) and 3.875 g (11 mmol) N,N- bis(t-butyloxycarbonylmethyl)-2-(bromomethyl)amine; and it is stirred intensively for 2 hours at room temperature. The buffer phase is separated, extracted with -10 ml of acetonitrile, which is added to the organic phase. After adding 20 ml of fresh buffer, the mixture is stirred for a further 20 hours at room temperature. The organic phase is separated, evaporated, and the precipitate is distributed between 100 ml of phosphate buffer (pH 8.0) and 100 ml of acetic acid. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The title compound is purified by chromatography on silica gel. As eluent, dichloromethane is used with increasing addition of methanol. The title compound is obtained as a glassy solid.

Yield: 4.161 g (78.3% of the theoretical value). Elemental analysis:

d) 3, 9- bis( carboxymethyl)- 6- N-( 1H, 1H, 2H, 2H- perfluorodecyl) aminocarbonylmethyl- 3, 6, 9- triazaundecanedioic acid

To a mixture of 100 ml of trifluoroacetic acid and dichloromethane in the ratio -2:1 is added 4.783 g (4.5 mmol) of the compound prepared under 25c). The mixture is stirred overnight at room temperature, then evaporated to dryness, residues of trifluoroacetic acid are removed by distillation together with ethanol, and the mixture is dissolved in 160 ml of a mixture of water, ethanol and chloroform (10:5:1). By adding the ion exchanger IRA-67 (OH" form), a pH value of about 3 (pH constant) is set. The mixture is quickly suctioned off, evaporated, and the title compound is obtained as a glassy, solid substance.

Yield: 3.007 g (79.7% of the theoretical value).

Water content: 10.9%.

Elemental analysis (with regard to anhydrous substance):

e) Gadolinium complex, monosodium salt of 3, 9- bis (carboxymethyl)- 6- N-( 1H, 1H, 2H, 2H- perfluorodecyl) amino-carbonylmethyl- 3, 6, 9- triazaundecanedioic acid

To a mixture of 60 ml of distilled water and 30 ml of ethanol, 2.823 g (3.0 mmol, calculated on a 10.9% water content) of the acid prepared under example 25d) is added. While stirring and heating to 50 °C, 543.8 mg (1.5 mmol) of gadolinium oxide are added in portions. After the addition is complete, the mixture is stirred until a solution is obtained. The pH value in the solution is then adjusted to 7.2 by adding caustic soda. The solution is evaporated, a strong foaming occurs. The precipitate is distilled twice with distilled water. The title compound is obtained as a glassy solid.

Yield: 3.353 g (quantitative).

Water content: 9.2 The elemental analysis is calculated based on anhydrous substance:

Example 26

Gadolinium complex, disodium salt of 3, 6, 9- tris(carboxymethyl) - 4- [N- ( 1H, 1H, 2H, 2H- perfluorodecyloxy) benzyl]- 3, 6, 9- triazaundecanedioic acid a) 3, 6, 9- tris ( t-butyloxycarbonylmethyl)- 4-[ 4-( 1H, 1H, 2H, 2H-perfluorodecyloxy) benzyl]- 3, 6, 9- triazaundecanedioic acid- di( t-butyl ester)

6.131 g are added to 50 ml of dry dimethylformamide

(5 mmol) 3,6,9-tris(t-butyloxycarbonylmethyl)-4-(4-hydroxy-benzyl)-3,6,9-triazaundecanedioic acid di(t-butyl ester), prepared according to PCT WO 88/07521, and 150 g (5 mmol) sodium hydride (80% in oil) are added in portions while stirring and excluding moisture. After dissolution, 3.092 g (5 mmol) of tosy-

dummy produced under example 7a). The mixture is stirred for 12 hours at 40 °C. The mixture is then poured into 500 ml of ice water, the product is extracted with dichloromethane, the organic solution is washed with water, dried over sodium sulphate and evaporated to dryness. The precipitate is purified by chromatography on silica gel. A mixture of dichloromethane, isopropanol and hexane in the ratio 20:1:5 is used as eluent. The title compound is obtained as an amorphous solid.

Yield: 5.015 g (81.8% of the theoretical value). Elemental analysis:

b) 3, 6, 9- tris(carboxymethyl)- 4-[ N-( 1H, 1H, 2H, 2H- perfluorodecyloxy) benzyl]- 3, 6, 9- triazaundecanedioic acid

In 100 ml of a mixture of trifluoroacetic acid and dichloromethane in a ratio of 2:1, dissolve 3.678 g (3 mmol) of the compound prepared under example 26a), and it is stirred overnight at room temperature. The mixture is evaporated to dryness, and residues of trifluoroacetic acid are removed by distillation together with ethanol. The precipitate is dissolved in 160 ml of a mixture of water, ethanol and chloroform (10:5:1). By adding the ion exchanger IRA-67 (OH" form), a pH value of about 3 (pH constant) is set. The mixture is quickly suctioned off, evaporated, and the title compound is obtained as a glassy, solid substance.

Yield: 2.357 g (83.1% of the theoretical value).

Water content: 11.3%.

The elemental analysis is calculated with regard to anhydrous substance:

c) Gadolinium complex, disodium salt of 3, 6, 9- tris (carboxymethyl)- 4-[ N-( 1H, 1H, 2H, 2H- perfluorodecyloxy) benzyl]-3, 6, 9- triazaundecanedioic acid

To a mixture of 60 ml of distilled water and 30 ml of ethanol is added 3.145 g (3.0 mmol, calculated on 11.3% water content) of the acid prepared under example 26b). While stirring and heating to 50 °C, 543.8 mg is added in portions

(1.5 mmol) gadolinium oxide. After the addition is complete, the mixture is stirred until a solution is present. The pH value in the solution is then adjusted to 7.2 by adding caustic soda and evaporated. This results in a strong foaming effect. The precipitate is distilled twice with distilled water. The title compound is obtained as a glassy solid.

Yield: 3.804 g (quantitative).

Water content: 9.8%.

Elemental analysis (with regard to anhydrous substance):

Example 27

Gadolinium complex of 10-[(perfluorooctylsulfonyl)piperazin-1-ylcarbonylmethyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

a) 1-perfluorooctylsulfonylpiperazine

34.39 g (398.3 mmol) piperazine, 50 g (99.6 mmol) per-fluorooctylsulfonyl fluoride and 10.12 g (100 mmol) triethylamine are heated for 24 hours at 85 °C. The mixture is added to 500 ml of water and extracted two times with 200 ml of dichloromethane. The organic phase is dried over magnesium sulfate and evaporated in vacuo to dryness. The precipitate is chromatographed on silica gel (eluent: dichloromethane/2-propanol = 25:1).

Yield: 17.55 g (31% of the theoretical value) of a colorless, amorphous solid.

Elemental analysis:

b) 1-(2-'bromoacetyl)-4-perfluorooctylsulfonylpiperazine

17 g (29.9 mmol) of the title compound from example

27a) and 5.1 g (50 mmol) of triethylamine are dissolved in 100 ml of dichloromethane. At -10 °C, 9.1 g (44.9 mmol) of bromoacetyl bromide are added dropwise over 60 minutes, and the mixture is stirred for 2 hours at 0 °C. The solution is poured into 200 ml of 2 N hydrochloric acid and

stir well. The organic phase is separated, dried over magnesium sulphate and evaporated in vacuo. The precipitate is chromatographed on silica gel (eluent: dichloromethane/acetone = 20/1).

Yield: 18.55 g (90% of theory) of a light yellow waxy solid.

Elemental analysis:

c) 10-[(perfluorooctylsulfonyl)piperazin-1-ylcarbonylmethyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

To 17.78 g (20 mmol) of the title compound from example 27b) in 180 ml of methanol is added 4.63 g (13.36 mmol) of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (SD03A) and 18.5 g (133.6 mmol) of potassium carbonate. The mixture is refluxed for 12 hours. The inorganic salts are filtered off, and the filtrate is evaporated to dryness. The precipitate is dissolved in 100 ml of water and adjusted to pH 3 with 5 N hydrochloric acid. The mixture is extracted twice with 150 ml of n-butanol. The combined organic phases are evaporated in vacuo to dryness, and the precipitate is purified by RP chromatography (RP-18/eluent = gradient of water/n-butanol/acetonitrile).

Yield: 12.79 g (67% of the theoretical value) of a colorless solid.

Water content: 8.5%.

Elemental analysis (with regard to anhydrous substance):

d) Gadolinium complex of 10-[(perfluorooctylsulfonyl)piperazin-1-ylcarbonylmethyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetra

azacyclododecane

10 g (10.47 mmol) of the title compound from example 27c) are dissolved in a mixture of 50 ml of water and 20 ml of ethanol and 1.90 g (5.23 mmol) of gadolinium oxide are added. The mixture is stirred for 4 hours at 80 °C. The solution is filtered and evaporated in

vacuum to dryness.

Yield: 12.2 g (quantitative).

Water content: 5.1%.

Elemental analysis (with respect to anhydrous substance) :

Example 28

Gadolinium complex, monosodium salt of 3,9-bis(carboxymethyl)-6-[(4-perfluorooctylsulfonyl)piperazine-1-carbonylmethyl]-3,6,9-triazauhdecanedioic acid

a) 1-( 2- benzyroxycarbonylamino) methylcarbonyl- 4-( per fluorooctylsulfonyl) piperazine

8.524 g (15 mmol) of the piperazine derivative prepared under 27a) are dissolved in 80 ml of dichloromethane and 1.726 g (15 mmol) of N-hydroxysuccinimide, 3.095 g (15 mmol) of dicyclohexylcarbodiimide and 3.138 g (15 mmol) of N-benzyloxycarbonylglycine (commercial product, Bachem) are added. ). The mixture is stirred overnight, the dicyclohexylurea is filtered off, the mixture is evaporated, and the precipitate is subjected to column chromatography on silica gel. Mixtures of dichloromethane and ethanol are used as eluent. The title compound is obtained as a solid.

Yield: 10.16 g (89.2% of the theoretical value). Elemental analysis:

b) 1-(2-amino)-acetyl-4-(perfluorooctyl)sulfonylpiperazine

In 150 ml of a mixture of tetrahydrofuran and ethanol

in the ratio 2:1, 7.594 g (10 mmol) of the compound prepared under 28a) are dissolved and hydrated. in the presence of 0.25 g of Pearlman catalyst (Pd 20%/C) until 224 ml of hydrogen is taken up. The catalyst is filtered off, washed well with ethanol, and the mixture is evaporated to dryness. The title compound is obtained as an amorphous solid.

Yield: 6.21 g (99.3% of the theoretical value). Elemental analysis: Calculated: C 26.89 H 1.93 F 51.65 N 6.72 S 5.13

Found: C 27.03 H 1.97 F 51.77 N 6.58 S 5.20.

c) 3,9-bis(t-butyloxycarbonylmethyl)-6-[(4-perfluorooctylsulfonyl)piperazine-1-carbonylmethyl]-3,6,9-triazaundecane

dicarboxylic acid- di(t-butyl ester)

To a mixture of 10 ml of acetonitrile and 20 ml of phosphate buffer with a pH value of 8.0, 3.127 g (5 mmol) of the amine prepared under 28b) and 3.875 g (11 mmol) of N,N-bis(t-butyloxycarbonylmethyl)- 2-(bromomethyl)amine, and it is stirred intensively for 2 hours at room temperature. The buffer is removed, extracted with 10 ml of acetonitrile, and this is added to the organic phase. After adding 20 ml of fresh buffer, the mixture is stirred for a further 20 hours at room temperature. The organic phase is separated, evaporated, and the precipitate is distributed between 100 ml of phosphate buffer (pH 8.0) and 100 ml of acetic acid. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The title compound is purified by chromatography on silica gel. As eluent, dichloromethane is used with increasing addition of methanol. The title compound is obtained as a glassy solid.

Yield: 4.481 g (76.3% of the theoretical value). Elemental analysis:

d) 3,9-bis(carboxymethyl)-6-[(4-perfluorooctylsulfonyl)piperazine-1-carbonylmethyl]-3,6,9-triazaundecanedoic acid

To a mixture of 100 ml of trifluoroacetic acid and dichloromethane in a ratio of 2:1 is added 5.193 g (4.5 mmol) of the compound prepared under 28c). The mixture is stirred overnight at room temperature and then evaporated to dryness, residues of trifluoroacetic acid are removed by distillation together with ethanol, and the mixture is dissolved in 160 ml of a mixture of water, ethanol and chloroform (10:5:1). By adding the ion exchanger IRA-67 (OH" form), a pH value of approx. 3 (pH constant) is set. The mixture is quickly suctioned off, evaporated, and the title compound is obtained as a glassy, solid substance.

Yield: 3.718 g (79.2% of the theoretical value).

Water content: 10.9%.

Elemental analysis (with regard to anhydrous substance):

e) Gadolinium complex, monosodium salt of 3, 9- bis (carboxymethyl)- 6-[( 4- perfluorooctylsulfonyl) piperazine-1-carbonylmethyl] - 3, 6, 9- triazaundecanedioic acid

To a mixture of 60 ml of distilled water and 30 ml of ethanol is added 3.13 g (3.0 mmol, calculated on 10.9% water content) of the acid prepared under example 28d). With stirring and heating to 50 °C, 543.8 mg (1.5 mmol) of gadolinium oxide are added in portions. After the addition is complete, the mixture is stirred until a solution is present. The pH value in the solution is then adjusted to 7.2 by adding caustic soda, and the mixture is evaporated. This results in a strong foaming effect. The precipitate is distilled twice with distilled water. The title compound is obtained as a glassy solid.

Yield: 3.678 g (quantitative).

Water content: 9.2%.

The elemental analysis (with regard to anhydrous substance):

. Example 29

Gadolinium complex of 3, 6, 9- tris(carboxymethyl)- 3, 6, 9- triazaundecanedioic acid- bis[( 4- perfluorooctylsulfonyl) piperazine] amide

a) 3, 6, 9- tris(carboxymethyl)- 3, 6, 9- triazaundecanedioic acid- bis[( 4-perfluorooctylsulfonyl) piperazine] amide

5.683 g are added to 30 ml of dry dimethylformamide

(10 mmol) of the compound prepared under 27a), as well as 1.518 g (15 mmol) of triethylamine and 1.787 g (5 mmol) of diethylenetriamine-pentaacetic acid-bisanhydride are added in portions while stirring and excluding moisture. The mixture is stirred overnight, evaporated, water is added, the pH value is adjusted with 3 N salt-

acid of approx. 3, and the mixture is extracted twice with 100 ml of n-butanol. The organic solutions are combined, evaporated and chromatographed on silica gel RP-18. Water and tetrahydrofuran are used as eluents. The title compound is obtained as a glassy solid.

Yield: 6.741 g {81.4% of the theoretical value).

Water content: 9.8%. '

Elemental analysis {with respect to anhydrous substance):

b) Gadolinium complex of 3, 6, 9- tris( carboxymethyl)- 3, 6, 9-triaza undecadiacid- bis[{ 4- perfluorooctylsulfonyl) pipera-

zin] amide

To a mixture of 120 ml of distilled water, 60 ml of ethanol and 20 ml of chloroform is added 6.570 g (4 mmol, calculated on 9.8% water content) of the compound prepared under 23c). While stirring and heating to 50 °C, 725 mg (82.0 mmol) of gadolinium oxide are added in portions. The mixture is stirred until a solution is formed, the solution is evaporated, whereby a strong foaming occurs, and the precipitate is subjected to distillation together with distilled water. The distillation is repeated twice. The title compound is obtained as a glassy solid.

Yield: 7.191 g (quantitative).

Water content: 8.1%.

The elemental analysis (with regard to anhydrous substance):

Example 30 a) 11-[N-ethyl-N-(perfluorooctylsulfonyl)amino]undecane acid benzyl ester 20 g (37.94 mol) of N-ethyl-N-perfluorooctylsulfonamide and 15.73 g (113.8 mmol) of potassium carbonate are suspended in 200 ml of acetone and add dropwise at 60 °C 26.96 g (75.87 mmol) of 11-bromo-undecanoic acid benzyl ester. The mixture is stirred for 3 hours at 60 °C. The salts are filtered off, and the filtrate is evaporated in vacuo to dryness. The precipitate is chromatographed on silica gel (eluent: hexane/dichloromethane/acetone = 10/10/1). After evaporation of the product-containing fractions, the precipitate is recrystallized from methanol/ether.

Yield: 26.46 g (87% of the theoretical value) of a colorless crystalline powder.

Elemental analysis:

b) 11-[N-ethyl-N-(perfluorooctylsulfonyl)aminoundecanoic acid

20 g (24.95 mmol) of the title compound from example

30a) is dissolved in 300 ml of isopropanol/200 ml of dichloromethane and 3 g of palladium catalyst (10% Pd/C) are added. The mixture is hydrated overnight at room temperature. The catalyst is filtered off, and the filtrate is evaporated in vacuo to dryness. The precipitate is recrystallized from ether/hexane.

Yield: 16.69 g (94% of the theoretical value) of a colorless crystalline solid.

Elemental analysis:

c) Gadolinium complex of 10-[ 2- hydroxy- 4- aza- 5- oxo- 16- aza- 16-( perfluorooctylsulfonyl) octadecyl]- 1, 4, 7- tris( carboxymethyl)-1, 4, 7, 10- tetraazacyclododecane

12.16 g (17.09 mmol) of the title compound from example 30b) and 1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 ml of dimethylformamide and 50 ml of chloroform. At 0 °C, 3.88 g (18.79 mmol) of dicyclohexylcarbodiimide are added, and the mixture is stirred for 1 hour at 0 °C, followed by 3 hours at room temperature. The mixture is cooled again to 0 °C and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol are added. 10.78 g (18.79 mmol) gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (WO 95/ 17451) dissolved in 50 ml

water, and the mixture is stirred for 3 hours at room temperature. The mixture is evaporated to dryness, the precipitate is dissolved in a mixture of 200 ml of methanol and 100 ml of chloroform, and the dicyclohexylurea is filtered off. The filtrate is evaporated to dryness and purified by RP chromatography (RP-18/eluent: gradient of water/n-propanol/acetonitrile).

Yield: 16.82 g (71% of theory) of a colorless glassy solid.

Water content: 8.6%.

Elemental analysis (with regard to anhydrous substance):

d) 10-[2-hydroxy-4-aza-5-oxo-16-aza-16-(perfluorooctylsulfonyl)octadecyl]-1,4,7-tris (carboxymethyl)'-!, 4, 7, 10-tetraazacyclododecane

11.1 g (8.76 mmol) of the title compound from example 30c) are dissolved in a mixture of 100 ml of water and 100 ml of ethanol and 1.73 g (13.71 mmol) of oxalic acid dihydrate are added. The mixture is heated for 8 hours at 80 °C. It is cooled to 0 °C, and precipitated gadolinium oxalate is filtered off. The filtrate is evaporated to dryness, and the precipitate is purified on RP-18 (RP-18/eluent: gradient of water/i-propanol/acetonitrile).

Yield: 9.80 g (92% of the theoretical value) of a glassy solid.

Water content: 8.5%.

Elemental analysis (with regard to anhydrous substance):

Calculated: C 41.01 H 5.16 F 29.02 N 7.55 S 2.88

Found: C 40.87 H 5.31 F 28.85. N 7.40 S 2.73.

e) Ytterbium complex of 10-[ 2- hydroxy- 4- aza- 5- oxo- 16- aza- 16-( perfluorooctylsulfonyl) octadecyl]- 1, 4, 7- tris( carboxymethyl) -

1, 4, 7, 10- tetraazacyclododecane

To 5.64 g (5.07 mmol) of the title compound from example 30d) in 100 ml of water/50 ml of ethanol, 1.33 g (2.53 mmol) of ytterbium carbonate is added, and the mixture is stirred for 3 hours at 80 °C. The solution is filtered, and the filtrate is evaporated in vacuo to dryness.

Yield: 7.08 g (quantitative) of a glassy solid.

Water content: 8.1%.

Elemental analysis (with regard to anhydrous substance):

f) Dysprosium complex of 10-[ 2- hydroxy- 4- aza- 5- oxo- 16- aza- 16-( perfluorooctylsulfonyl) octadecyl]- 1, 4, 7- tris( carboxymethyl)-1, 4, 7, 10- tetraazacyclododecane

To 5.64 g (5.07 mmol) of the title compound from example 30d) in 100 ml of water/50 ml of ethanol is added 0.95 g (2.53 mmol) of dysprosium oxide, and the mixture is stirred for 3 hours at 80 °C. The solution is filtered, and the filtrate is evaporated in vacuo to dryness.

Yield: 7.10 g (quantitative) of a colorless glassy solid.

Water content: 9.1

Elemental analysis (with regard to anhydrous substance):

Example 31

a) 11, 11, 11, 10, 10, 9, 9, 8, 8, 7, 7- tridecafluoro- 3- oxanedecanoic acid tert-butyl ester

To a mixture of 27.57 g (75.73 mmol) 1H,1H,2H,2H-perfluorooctan-1-ol and 2.57 g (7.57 mmol) tetrabutylammonium hydrogen sulfate in 300 mL 60% aqueous potassium chloride/200 mL toluene 19.51 g (100.0 mmol) of bromoacetic acid tert-butyl ester are added dropwise with vigorous stirring at 0 °C. The mixture is stirred for 1 hour at 0 °C, the organic phase is separated, and the aqueous phase is extracted twice with 50 ml of toluene. The combined organic extracts are dried over sodium sulfate and evaporated in vacuo. The precipitate is chromatographed on silica gel (eluent: dichloro-

methane).

Yield: 28.97 g (80% of the theoretical value) of a colorless oil.

Elemental analysis:

b) 11, 11, 11, 10, 10, 9, 9, 8, 8, 7, 7-tridecafluoro-3-oxaundecanoic acid 25.29 g (52.88 mmol) of the title compound from

example la) is dissolved in 300 ml of trifluoroacetic acid and stirred overnight at room temperature. The mixture is evaporated in vacuo to dryness, and the precipitate is recrystallized from hexane/diethyl ether.

Yield: 20.54 g (92% of theory) of a colorless crystalline solid.

Elemental analysis:

c) Gadolinium complex of 10-[ 2- hydroxy- 4- aza- 5- oxo- 7- oxa-10, 10, 11, 11, 12, 12, 13, 13, 14, 14, 15, 15, 15- trideca -fluoropentadecyl]- 1, 4, 7- tris(carboxymethyl)- 1, 4, 7, 10-tetraazacyclododecane

7.21 g (17.09 mmol) of the title compound from example 31b) and 1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 ml of dimethylformamide and 50 ml of chloroform. At 0 °C, 3.88 g (18.79 mmol) of dicyclohexylcarbodiimide are added, and the mixture is stirred for 1 hour at 0 °C, followed by 3 hours at room temperature. The mixture is cooled again to 0 and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol are added. 10.78 g (18.79 mmol) gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (WO 95/ 17451) dissolved in 50 ml of water, and it is stirred for 3 hours at room temperature. The mixture is evaporated to dryness, the precipitate is dissolved in a mixture of 200 ml of methanol and 100 ml of chloroform, and the dicyclohexylurea is filtered off. The filtrate is evaporated to dryness and purified by RP chromatography (RP-18/eluent: gradient of water/n-propane

ol/acetonitrile).

Yield: 12.68 g {71% of theory) of a colorless glassy solid.

Water content: 6.4%.

Elemental analysis (with regard to anhydrous substance):

Example 32

a) 15, 15, 15, 14, 14, 13, 13, 12, 12, 11, 11, 10, 10, 9, 9, 8, 8, 7, 7-henicosafluoro-3-oxapentadecanoic acid-tert-butyl ester

To a mixture of 42.72 g (75.73 mmol) 1H,1H,2H,2H-perfluorooctan-1-ol and 2.57 g (7.57 mmol) tetrabutylammonium hydrogen sulfate in 300 mL 60% aqueous potassium chloride/200 mL toluene 19.51 g (100.0 mmol) of bromoacetic acid tert-butyl ester are added dropwise with vigorous stirring at 0 °C. The mixture is stirred for 1 hour at 0 °C, the organic phase is separated, and the aqueous phase is extracted twice with 50 ml of toluene. The combined organic extracts are dried over sodium sulfate and evaporated in vacuo. The precipitate is chromatographed on silica gel (eluent: dichloromethane).

Yield: 42.12 g (82% of the theoretical value) of a colorless oil.

Elemental analysis:

b) 15, 15, 15, 14, 14, 13, 13, 12, 12, 11, 11, 11, 10, 10, 9, 9, 8, 8, 7, 7-henicosafluoro-3-oxapentanedecanoic acid tert. - butyl ester

35.87 g (52.88 mmol) of the title compound from example la) are dissolved in 300 ml of trifluoroacetic acid and stirred overnight at room temperature. The mixture is evaporated in vacuo to dryness, and the precipitate is recrystallized from hexane/diethyl ether.

Yield: 30.60 g (93% of theory) of a colorless crystalline solid.

Elemental analysis:

Calculated: C 27.03 H 1.13 F 64.12

Found: C 26.91 H 1.20 F 64.02.

c) Gadolinium complex of 10-[ 2- hydroxy- 4- aza- 5- oxo- 7- oxa-10, 10, 11, 11, 12, 12, 13, 13, 14, 14, 15, 15, 16, 16 , 17, -

17, 18 ^ 18, 19, i' 9, i9- henicosafluorononadecyl]- 1, 4, 7- tris ( carboxymethyl) - 1, 4, 7- tris ( carboxymethyl) 1, 4, 7, 10- tetraazacyclododecane

10.63 g (17.09 mmol) of the title compound from example 32b) and 1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 ml of dimethylformamide and 50 ml of chloroform. At 0 °C, 3.88 g (18.79 mmol) of dicyclohexylcarbodiimide are added, and it is stirred for 1 hour at 0 °C, followed by 3 hours at room temperature. The mixture is cooled again to 0 °C and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol are added. 10.78 g (18.79 mmol) gadolinium complex of 10-(3-araino-2-hydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (WO 95/ 17451) dissolved in 50 ml of water, and it is stirred for 3 hours at room temperature. The mixture is evaporated to dryness, the precipitate is dissolved in a mixture of 200 ml of methanol and 100 ml of chloroform, and the dicyclohexylurea is filtered off. The filtrate is evaporated to dryness and purified by RP chromatography (RP-18/eluent: gradient of water/n-propanol/acetonitrile).

Yield: 14.73 g (69% of theory) of a colorless glassy solid.

Water content: 5.7%.

Elemental analysis. (with regard to anhydrous substance):

Example 33

a) N-(2-bromopropionyl) glycine benzyl ester

55.9 g (326.1 mmol) of 2- bromo-propionic acid chloride. The temperature is not allowed to rise above 5 °C. After the addition is complete, the mixture is stirred for 1 hour at 0 °C and then for 2 hours at room temperature. 500 ml of ice water is added to the mixture, and the aqueous phase is adjusted with 10% aqueous hydrochloric acid to pH 2. The organic phase is separated and washed once with 300 ml of 5% aqueous soda solution and 400 ml of water. The organic phase is dried over magnesium sulfate and evaporated in vacuo to dryness. The precipitate is recrystallized from diisopropylethyl ether.

Yield: 68.51 g (75% of the theoretical value) of a colorless crystalline powder.

M.p.: 69-70 °C.

Elemental analysis:

b) 1-[ 4-( benzyloxycarbonyl)- 1- methyl- 2- oxo- 3- azabutyl]-1, 4, 7, 10- tetraazacyclododecane

To 55.8 g (324.4 mmol) of 1,4,7,10-tetraazacyclododecane dissolved in 600 ml of chloroform is added 50 g (162.2 mmol) of the title compound from example 1a), and it is stirred overnight at room temperature. 500 ml of water is added to the mixture, the organic phase is separated and washed a further two times with 400 ml of water. The organic phase is dried over magnesium sulphate and evaporated in vacuo to dryness. The precipitate is chromatographed on silica gel (eluent: chloroform/methanol/aqueous 25% ammonia = 10/5/1).

Yield: 40.0 g [63% of the theoretical value calculated on added la)] of a slightly yellow, viscous oil. Elemental analysis:

c) 10-[4-(benzyloxycarbonyl)-1-methyl-2-oxo-3-azabutyl]-1,4,7-tris(tert.-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane

(sodium bromide complex)

To 20 g (51.08 mmol) of the title compound from example 1b) and 17.91 g (169 mmol) of sodium carbonate in 300 ml of acetonitrile is added 33 g (169 mmol) of bromoacetic acid tert-butyl ester, and it is stirred for 24 hours at 60 °C. The mixture is cooled to 0 °C, the salts are filtered off, and the filtrate is evaporated to dryness. The precipitate is chromatographed on silica gel (eluent: ethyl acetate/ethanol = 15/1). The fractions containing the product are evaporated, and the precipitate is recrystallized from diisopropyl ether.

Yield: 34.62 g (81% of the theoretical value) of a colorless crystalline powder.

M.p.: 116-117 °C.

Elemental analysis:

d) 10-( 4- carboxyl- l- methyl- 2- oxo- 3- azabutyl)- 1, 4, 7- tris( tert. - butoxycarbonylmethyl)- 1, 4, 7, 10- tetraazacyclododecane-( sodium bromide complex) 30 g (35.85 mmol) of the title compound from example le) are dissolved in 500 ml of isopropanol and 3 g of palladium catalyst (10% Pd/C) are added. The mixture is hydrated overnight at room temperature. The catalyst is filtered off, the filtrate is evaporated in vacuo to dryness and recrystallized from acetone.

Yield: 22.75 g (85% of the theoretical value) of a colorless crystalline powder.

Melting point: 225 °C (decomposition).

Elemental analysis:

e) 10-[1-methyl-2-oxo-3-aza-5-oxo-5-{4-perfluorooctyl-sulfonylpiperazin-1-yl}pentyl]-1,4,7-tris{carboxymethyl)-1 , 4, 7, 10- tetraazacyclododecane 10 g (13.39 mmol) of the title compound from example 33d) and 7.61 g (13.39 mmol) of the title compound from example 27a) are dissolved in 150 ml of tetrahydrofuran. At 0 °C, 3.97 g (16.07 mmol) of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) are added / stirred for 3 hours at 0 °C and then for 12 hours at room temperature. The mixture is evaporated in vacuo to dryness. The precipitate is dissolved in 150 ml of trifluoroacetic acid and stirred for 12 hours at room temperature. The mixture is evaporated to dryness, the precipitate is dissolved in water and adjusted with 10% aqueous caustic soda to pH 3.2. The product is purified by RP-18 chromatography (gradient of water/acetonitrile/tetrahydrofuran).

Yield: 9.67 g (63% of the theoretical value) of a hygroscopic solid.

Water content: 10.5%.

Elemental analysis (with regard to anhydrous substance):

f) Gadolinium complex of 10-[1-methyl-2-oxo-3-aza-5-oxo-5-{4-perfluorooctylsulfonylpiperazin-1-yl}pentyl-1,4,7-tris-(carboxymethyl)-1, 4, 7, 10-tetraazacyclododecane 5 g (4.87 mmol) of the title compound from example 33e) are dissolved in 60 ml of water and 0.883 g (2.44 mmol) of gadolinium oxide are added. The mixture is stirred for 3 hours at 90 °C. The solution is filtered, and the filtrate is freeze-dried.

Yield: 6.47 g (quantitative) of a bulky, amorphous powder.

Water content: 11.3%.

Elemental analysis (with regard to anhydrous substance):

Example 34

a) 4-perfluorooctansulfonylpiperazin-1-ylpentanediamic acid

A solution of 10.62 g (105.0 mmol) of triethylamine and 59.67 g (105 .0 mmol) of the title compound from example 27a) in 50 ml of tetrahydrofuran, and the mixture is allowed to stand overnight at room temperature. The reaction mixture is acidified with 100 ml of 2 N HCl and extracted three times with 100 ml of tetrahydrofuran. The combined organic extracts are dried with sodium sulfate, filtered and evaporated. The precipitate is recrystallized from 2-propanol/ethyl acetate.

Yield: 52.30 g (73% of theory) of a colorless crystalline solid.

Elemental analysis:

b) 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- tris(carboxymethyl)- 1, 4, 7, 10- tetraazacyclododecane

11.66 g (17.09 mmol) of the title compound from example 34a) and 1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 ml of dimethylformamide and 50 ml of chloroform. At 0 °C, 3.88 g (18.79 mmol) of dicyclohexylcarbodiimide are added, and the mixture is stirred for 1 hour at 0 °C and then for 3 hours at room temperature. The mixture is cooled again to 0 °C and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol are added. 10.78 g (18.79 mmol) gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4, 7, 10-tetraazacyclododecane (WO 95/ 17451) dissolved in 50 ml of water, and it is stirred for 3 hours at room temperature. The mixture is evaporated to dryness, the precipitate is dissolved in a mixture of 200 ml of methanol and 100 ml of chloroform, and the dicyclohexylurea is filtered off. The filtrate is evaporated to dryness and purified by RP chromatography (RP-18/eluent: gradient of water/n-propanol/acetonitrile).

Yield: 16.7 g (73% of theory) of a colorless glassy solid.

Water content: 7.5%.

Elemental analysis (with regard to anhydrous substance):

Example 35

a) H-benzylperfluorooctanesulfonamide

To a mixture of 10.62 g (105.0 mmol) of triethylamine

and 10.72 g (100.0 mmol) of benzylamine are added dropwise at 80 °C with vigorous stirring to 50.21 g (100.0 mmol) of perfluorooctansulfonyl fluoride. The reaction mixture is stirred for 2 days at 80 °C

300 ml of water are added and extracted three times with ethyl acetate. The combined organic extracts are dried with sodium sulfate, filtered and evaporated. The precipitate is chromatographed on silica gel (eluent: dichloromethane/methanol = 4/1).

Yield: 45.96 g (78% of the theoretical value) of a colorless liquid.

Elemental analysis:

b) N-benzyl-N-(perfluorooctylsulfonyl)aminoacetic acid t-butyl ester

22.4 g (37.94 mmol) of the title compound from example 35a) and 15.73 g (113.8 mmol) potassium carbonate are suspended in 200 ml acetone and added dropwise at 60 °C 14.80 g (75.87 mmol) bromoacetic acid -tert-butyl ester. The mixture is stirred for 3 hours at 60 °C. The salts are filtered off, and the filtrate is evaporated in vacuo to dryness. The precipitate is chromatographed on silica gel (eluent: hexane/dichloromethane/acetbn = 10/10/1). After evaporation of the product-containing fractions, the precipitate is recrystallized from methanol/ether.

Yield: 24.02 g (90% of theory) of a waxy, colorless solid.

Elemental analysis:

c) N-benzyl-N-(perfluorooctylsulfonyl)aminoacetic acid

20 g (28.43 mmol) of the title compound from example

35b) is dissolved in 200 ml of trifluoroacetic acid and stirred overnight at room temperature. The mixture is evaporated in vacuo to dryness. The precipitate is recrystallized from methanol/ether.

Yield: 17.48 g (95% of theory) of a colorless crystalline solid.

Elemental analysis:

d) Gadolinium complex of 10-[ 2- hydroxy- 4- aza- 5- oxo- 7- aza- 7-( perfluorooctylsulfonyl)- 8- phenyloctyl}- 1, 4, 7- tris( carboxymethyl)- 1, 4, 7 , 10- tetraazacyclododecane

11.0'6'g (17.09 mmol) of the title compound from example 35c): and 1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 ml of dimethylformamide and 50 ml of chloroform. At 0 °C, 3.88 g (18.79 mmol) of dicyclohexylcarbodiimide are added, and the mixture is stirred for 1 hour at 0 °C and then for 3 hours at room temperature. The mixture is cooled again to 0°C and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol are added. 10.78 g (18.79 mmol) gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,'7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (WO 95 /17451) dissolved in 50 ml of water, and it is stirred for 3 hours at room temperature. The mixture is evaporated to dryness, the precipitate is dissolved in a mixture of 200 ml of methanol and 100 ml of chloroform, and the dicyclohexylurea is filtered off. The filtrate is evaporated to dryness and purified by RP chromatography (RP-18/eluent: gradient of water/n-propanol/acetonitrile).

Yield: 16.49 g (75% of theory) of a colorless glassy solid.

Water content: 6.5%.

Elemental analysis:

Example 36

a) N-decylperfluorooctanesulfonamide.

To a mixture of 10.62 g (105.0 mmol) of triethylamine

and 15.73 g (100.0 mmol) of decylamine are added dropwise at 80 °C with vigorous stirring to 50.21 g (100.0 mmol) of perfluorooctansulfonyl fluoride. The mixture is stirred for 2 days at 80 °C, 300 ml of water is added to the reaction mixture and extracted three times with ethyl acetate. The combined organic extracts are dried over sodium sulphate, filtered and evaporated. The precipitate chromato-

graphed on silica gel (eluent: dichloromethane/methanol = 4/1).

Yield: 43.48 g (68% of the theoretical value) of a colorless viscous liquid.

Elemental analysis:

b) N-decyl-N-(perfluorooctylsulfonyl)aminoacetic acid t-butyl ester 24.26 g (37.94 mmol) of the title compound from example 36a) and 15.73 g (113.8 mmol) of potassium carbonate are suspended in 200 ml of acetone and 14.80 g (75.87 mmol) of bromoacetic acid tert-butyl ester are added dropwise at 60 °C. The mixture is stirred for 3 hours at 60 °C. The salts are filtered off, and the filtrate is evaporated in vacuo to dryness. The precipitate is chromatographed on silica gel (eluent: hexane/dichloromethane/acetone = 10/10/1). After evaporation of the product-containing fractions, the precipitate is recrystallized from methanol/ether.

Yield: 24.87 g (87% of theory) of a waxy, colorless solid. Elemental analysis:

c) N-decyl-N-(perfluorooctylsulfonyl)aminoacetic acid

20 g (26.54 mmol) of the title compound from example

36b) is dissolved in 200 ml of trifluoroacetic acid and stirred overnight at room temperature. The mixture is evaporated in vacuo to dryness. The precipitate is recrystallized from methanol/ether.

Yield: 17.22 g (93% of theory) of a colorless crystalline solid.

Elemental analysis:

d) Gadolinium complex of 10-[, 2- hydroxy- 4- aza- 5- oxo- 7- aza- 7-( perfluorooctylsulfonyl) heptadecyl]- 1, 4, 7- tris(carboxymethyl)-1, 4, 7, 10 - tetraazacyclododecane

11.92 g (17.09 mmol) of the title compound from

example 36c) and 1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 ml of dimethylformamide and 50 ml of chloroform. At 0 °C, 3.88 g (18.79 mmol) of dicyclohexylcarbodiimide are added, and the mixture is stirred for 1 hour at 0 °C and then for 3 hours at room temperature. The mixture is cooled again to 0 °C and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol are added. 10.78 g (18.79 mmol) gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-tris(carboxymethyl)-1, 4, 7, 10-tetraazacyclododecane (WO 95/ 17451) dissolved in 50 ml of water, and it is stirred for 3 hours at room temperature. The mixture is evaporated to dryness, the precipitate is dissolved in a mixture of 200 ml of methanol and 100 ml of chloroform, and the dicyclohexylurea is filtered off. The filtrate is evaporated to dryness and purified by RP chromatography (RP-18/eluent: gradient of water/n-propanol/acetonitrile).

Yield: 16.76 g (71% of theory) of a colorless glassy solid.

Water content: 6.5%.

Elemental analysis:

Example 37

a) N-hexylperfluorooctanesulfonamide

To a mixture of 10.62 g (105.0 mmol) of triethylamine

and 10.12 g (100.0 mmol) of benzylamine are added dropwise at 80 °C with vigorous stirring to 50.21 g (100.0 mmol) of perfluorooctansulfonyl fluoride. The mixture is stirred for 2 days at 80 °C, 300 ml of water is added to the reaction mixture and extracted three times with ethyl acetate. The combined organic extracts are dried over sodium sulphate, filtered and evaporated. The precipitate is chromatographed on silica gel (eluent: dichloromethane/methanol = 4/1).

Yield: 45.50 g (78% of the theoretical value) of a colorless liquid.

Elemental analysis:

Calculated: C 28.83 H 2.42 N 2.40 S 5.50 F 55.37

Found: C 28.29 H 2.39 N 2.44 S 5.55 F 55.50.

b) N-hexyl-N-(perfluorooctylsulfonyl) aminoacetic acid t-butyl ester

22.13 g (37.94 mmol) of the title compound from example 37a) and 15.73 g (113.8 mmol) of potassium carbonate are suspended in 200 ml of acetone and 14.80 g (75.87 mmol) of bromoacetic acid are added dropwise at 60 °C -tert-butyl ester. The mixture is stirred for 3 hours at 60 °C. The salts are filtered off, and the filtrate is evaporated in vacuo to dryness. The precipitate is chromatographed on silica gel (eluent: hexane/dichloromethane/acetone = 10/10/1). After evaporation of the product-containing fractions, the precipitate is recrystallized from methanol/ether.

Yield: 23.02 g (87% of theory) of a waxy, colorless solid.

Elemental analysis:

c) N-hexyl-N-(perfluorooctysulfonyl)aminoacetic acid

20 g (28.43 mmol) of the title compound from example

37b) is dissolved in 200 ml of trifluoroacetic acid and stirred overnight at room temperature. The mixture is evaporated in vacuo to dryness. The precipitate is recrystallized from methanol/ether.

Yield: 16.74 g (91% of theory) of a colorless crystalline solid.

Elemental analysis:

d) Gadolinium complex of 10-[ 2- hydroxy- 4- aza- 5- oxo- 7- aza- 7-( perfluorooctylsulfonyl) tridecyl]- 1, 4, 7- tris( carboxymethyl)-1, 4, 7, 10- tetraazacyclododecane

10.96 g (17.09 mmol) of the title compound from example 37c) and 1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 ml of dimethylformamide and 50 ml of chloroform. At 0 °C, 3.88 g (18.79 mmol) of dicyclohexylcarbodiimide are added, and the mixture is stirred for 1 hour at 0 °C and then

after for 3 hours at room temperature. The mixture is cooled again to 0 °C and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol are added. 10.78 g (18.79 mmol) gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-tris(carboxymethyl)-1, 4, 7, 10-tetraazacyclododecane (WO 95/ 17451) dissolved in 50 ml of water, and the mixture is stirred for 3 hours at room temperature. The mixture is evaporated to dryness, the precipitate is dissolved in a mixture of 200 ml of methanol and 100 ml of chloroform, and the dicyclohexylurea is filtered off. The filtrate is evaporated to dryness and purified by RP chromatography (RP-18/eluent: gradient of water/n-propanol/acetonitrile).

Yield: 16.46 g (75% of theory) of a colorless glassy solid.

Water content: 6.8%.

Elemental analysis:

Example 38 a) 11-[N-ethyl-N-(perfluorooctylsulfonyl)aminohexanoic acid benz<y>ester 20 g (37.94 mmol) of N-ethyl-N-perfluorooctylsulfonylamide and 15.73 g (113.8 mmol) of potassium carbonate are suspended in 200 ml of acetone and at 60 °C 21.64 g (75.87 mmol) of 6-bromo-hexanoic acid benzyl ester are added dropwise. The mixture is stirred for 3 hours at 60 °C. The salts are filtered off, and the filtrate is evaporated in vacuo to dryness. The precipitate is chromatographed on silica gel (eluent: hexane/dichloromethane/acetone = 10/10/1}. After evaporation of the product-containing fractions, the precipitate is recrystallized from methanol/ether.

Yield: 25.26 g (91% of the theoretical value) of a colorless crystalline powder.

Elemental analysis:

b) 11-[N-ethyl-N-(perfluorooctylsulfonyl)amino]hexanoic acid

20 g (27.34 mmol) of the title compound from Example

38b) is dissolved in 300 ml of isopropanol/200 ml of dichloromethane and 3 g of palladium catalyst (10% Pd/C) are added. The mixture is hydrated overnight at room temperature. The catalyst is filtered off, and the filtrate is evaporated in vacuo to dryness. The precipitate is recrystallized from ether/hexane.

Yield: 16.13 g (92% of theory) of a colorless crystalline solid.

Elemental analysis:

c) Gadolinium complex of 10-[ 2- hydroxy- 4- aza- 5- oxo- ll- aza- ll-( perfluorooctylsulfonyl) tridecyl]- 1, 4, 7- tris( carboxymethyl)- 1, 4, 7, 10- tetraazacyclododecane

10.96 g (17.09 mmol) of the title compound from example 38b) and 1.97 g (18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 ml of dimethylformamide and 50 ml of chloroform. At 0 °C, 3.88 g (18.79 mmol) of dicyclohexylcarbodiimide are added, and the mixture is stirred for 1 hour at 0 °C and then for 3 hours at room temperature. The mixture is cooled again to 0 °C and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol are added. 10.78 g (18.79 mmol) gadolinium complex of 10-(3-amino-2-hydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7, 10-tetraazacyclododecane (WO 95/ 17451) dissolved in 50 ml of water, and the mixture is stirred for 3 hours at room temperature. The mixture is evaporated to dryness, the precipitate is dissolved in a mixture of 200 ml of methanol and 100 ml of chloroform, and the dicyclohexylurea is filtered off. The filtrate is evaporated to dryness and purified by RP chromatography (RP-18/eluent: gradient of water/n-propanol/acetonitrile).

Yield: 15.0 g (69% of theory) of a colorless glassy solid.

Water content: 5.9 Elemental analysis:

Example 39

From the compound according to "Example lc) a 100 mmol/l solution in water containing an addition of 100 mg J/ral "isovist" as an X-ray density marker was prepared. This solution" is transparently clear and has a gel-like solid consistency> but can however, administered by hand, or with an infusion pump, through a tube of length 20 cm and_ internal diameter 0.58 mm, at a rate of

160 ul"/min.

Example 40

Solubility of the qadolinium complex from example lc) in different solvents and with different additives and delivery forms

A 100 mmol/l solution in water was prepared from the compound from example lc). This solution is transparent and has a gel-like solid consistency, but it can still be easily applied by hand, or with an infusion pump, through a tube with a length of 20 cm and an inner diameter of 0.58 mm, at a rate of 160 pl/minute . In an amount below approx. 10-20 mmol/1, a free-flowing solution is formed.

Addition of 10 mmol/1 (final concentration) HC1 or NaOH or high salt concentrations (3 mol/l NaCl) has no influence on the consistency of the preparation.

Addition of 8 mol/l (final concentration) urea gives a free-flowing solution even at very high substance concentrations (400 mmol/1).

Addition of detergents to the aqueous formulation of the compound from example lc) has very different effects. "Tween" 80 (polyoxyethylene-sorbitanoleate, non-ionic detergent, HLB 15, 4.6% final concentration) does not change the consistency, while "Triton" X-100 (octylphenol-polyethylene glycol ether, non-ionic detergent, HLB 13, 5, 1.7%) causes the gel-like consistency to become liquid.

In bovine plasma, the substance is as soluble as in pure water and gives a solution with a comparable consistency.

In pure propylene glycol or DMSO, the compound from example lc) is practically insoluble. In 66% propylene glycol / water, respectively. 66% DMSO/water, the substance is however well soluble also in higher concentration {250 mmol/1, resp.

150 mmol/1) and gives a free-flowing solution.

In 96% ethanol, the solubility of the substance is higher than 500 mmol/1. A free-flowing solution is formed.

Example 41

Solubility of the dysprosium complex from example 30f) in different solvents and with different additives and delivery forms

A 100 mmol/l solution in water was prepared from the compound from example 30f). This solution is transparent and has a gel-like solid consistency, but it can still be applied by hand or with an infusion pump through a tube with a length of 20 cm and an inner diameter of 0.58 mm at a rate of 160 pl/minute. In one quantity under approx. 10-20 mmol/1, a free-flowing solution is formed.

Addition of 10 mmbl/1 (final concentration) HC1 or NaOH or high salt concentrations (3 mol/l NaCl) has no influence on the consistency of the preparation.

Addition of 8 mol/l (final concentration) urea gives a free-flowing solution even at very high substance concentrations (400 mmol/1).

Addition of detergents to the aqueous formulation of the compound from example 30f) produces very different effects. "Tween" 80 (polyoxyethylene sorbitanoleate, nonionic detergent, HLB 15, 4.6% final concentration) does not change the consistency, while "Triton" X-100 (octylphenol polyethylene glycol ether, nonionic detergent, HLB 13.5 , 1.7%) causes the gel-like consistency to become liquid.

In bovine plasma, the substance is as soluble as in pure water and gives a solution with a comparable consistency.

In pure propylene glycol or DMSO, the compound from example 30f) is practically insoluble. In 66% propylene glycol/water, resp. 66% DMSO/water, the substance is however well soluble also in higher concentration (250 mmol/1, respectively

150 mmol/1) and gives a free-flowing solution.

In 96% ethanol, the solubility of the substance is higher than 500 mmol/1. A free-flowing solution is formed.

Example 42

Incorporation of cytostatics in the solution of the compound from example lc)

The materials used for embolization of tumors are also, in principle, suitable for local application of cytostatics, which in this way are present in tumors in very high concentrations, but systemically in lower and thus well tolerated concentrations. The blood clot also provides a delayed release over several days, which further increases the effectiveness of the cytostatic agent.

For the treatment, HCC 5-fluorouracil, doxorubicin, mitomycin C or cisplatin are usually used, in addition to some other cytostatics. If an aqueous solution of the cytostatic agent is used to prepare the solution of the compound from example lc), this is incorporated homogeneously in the formulation. The concentration of the cytostatic agent used depends on the amount of the solution to be applied, so that the maximum tolerable dose in mg/kg KG or in mg/m<2> body surface is not exceeded. For the individual cytostatics, the following solutions can be used to prepare a formulation of compound lc):

Example 43

Demonstration of embolization in an animal model. As easily demonstrable blood vessels, the renal blood vessels in rats were embolized.

A catheter {20 cm long, 0.58 mm internal diameter) was inserted into the animal's A. mesenteric and pushed into the A. renalis of the left kidney. The solution of the compound from example lc)

{here 50 mmol/1 with 150 mg J/ml "Isovist") bee applied with a

speed of 160 ul/minute. Total volume 250 ul. The catheter was then withdrawn to the A. mesenterica so as not to prevent the kidney's blood supply in the further course. In the following X-ray images, the blood vessels in the left kidney were sharply demarcated opposite the renal parenchyma. Up to 45 minutes after administration of the compound from example 1c), the signal intensity from the blood vessels in the kidney decreased significantly. This can be traced back to a diffusion of the X-ray contrast agent "Isoyist" and its elimination from the kidneys. To control the blood flow through the kidneys, one hour after the local application of the compound from example 1c), 400 ul of the kidney-acceptable x-ray contrast agent "Ultravist", 300 mg J/ml, was introduced intravenously into the tail vein. Only the non-embolized right kidney with ureter showed a significant increase, an indication of the good blood flow and functionality in this kidney. The embolized left kidney and its ureter, on the other hand, showed no increase, indicating the still existing embolism.

The effectiveness of the procedure can be seen from picture 1

and 2:

Picture 1

Embolization of a rat kidney

Directly after intra-arterial, local administration of

250 µl of a solution of the compound from example lc)

(50 mmol/1 + 150 mg J/ml "Isovist") in the catheterized renal artery (left kidney, on the right of the picture).

Picture 2

Control experiment

5' p.a. "Ultravist", 400 pl i.v.

One hour after local administration of the compound from example lc), "Ultravist" was administered through the tail vein. The right kidney excreted the X-ray contrast agent, the treated (embolized) left kidney remained dark. The urinary bladder (below right) is also bright.

Example 44

Demonstration of embolization in a further animal model as a well demonstrable blood vessel, the hepatic blood vessels of rabbits were embolized

A catheter (60 cm long, 1.5 mm outer diameter) was inserted into the anesthetized animal through the femoral artery to the hepatic artery through the aorta. The solution of gadolinium complex from example 1c) (50 mmol/l with 150 mg J/ml "Isovist") was applied at a rate of 160 µl/minute. Total volume 800 ul. The catheter was then withdrawn into the aorta so as not to damage the arterial blood supply to the liver in the further course. In the following radiographs, the liver blood vessels were sharply demarcated opposite the liver parenchyma. During 60 minutes after the addition of the compound from example lc), the signal intensity in the liver blood vessels decreased only slowly, which points to continued embolization due to the substance. The reduction in signal intensity can partly be attributed to a diffusion of the X-ray contrast agent "Isovist".

Example 45

Therapy of a carcinoma of the liver in the rabbit

Five male Chincilla rabbits were given a tumor by injection of VX-2 tumor cells into the left lobe of the liver. In the anesthetized animal, a catheter (60 cm long, 1 mm outer diameter) was inserted through the femoral artery to the vicinity of the tumor. The solution of the title compound from example lc)

[75 mmol/1 with 50 mg Cisplatin (= "Carboplatin")] was then applied. Total volume 8 ml.

The catheter was then removed. After 7 days, the animals were examined using MRI. It turned out that the tumor had decreased in size (average growth factor 0.8 ± 0.2). In the control animals (3 animals), however, a growth ratio of 3.7 ± 1.5 was observed.

Claims (18)

1. Pharmaceutical agent, characterized in that they contain at least one perfluoroalkyl-containing compound of general formula I in which RF denotes a perfluorinated, straight chain or branched hydrocarbon chain with the formula -CnF2nX, in which X denotes a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n denotes the numbers 4-30, L denotes a direct bond, a methylene group, an -NHCO group, a group there p denotes the numbers 0-10, q and u denote independent of each other the number 0 or 1, and R<1> denotes a hydrogen atom, a methyl group, a -CH2-OH group, a -CH2-CO2H group or a C2-C15 chain which is optionally interrupted by 1-3 oxygen atoms . or denotes a straight-chain, branched, saturated or unsaturated C2-C30 hydrocarbon chain which optionally contains and/or is interrupted by 1-10 oxygen atoms, 1-3 -NR<1> groups, 1-2 sulfur atoms, a piperazine group, a - CONR<1> group, a -NR^O group, a -SO2 group, a -NR<1->CO2 group, 1-2 - CO groups, a group substituted aryl groups, and/or is optionally substituted with 1-3 -Om groups, 1-2 oxo groups, 1-2 -NH-COR<1> groups, 1-2 .'-CONHR^ groups, 1-2 - (CH2 ) p-CO2H groups, 1-2 groups -{CH2jp-(0)q-CH2CH2-R<r>, where- R<1>, RF and p and q have the above meanings, and T denotes a C2-Ci0 chain which is optionally interrupted by 1-2 oxygen atoms or 1-2 -NHCO groups, A denotes a metal complex, its salts of organic and/or inorganic bases or amino acids or amino acid amides, i.e. a complex of general formula II in which R<3>, Z1 and Y are independent of each other, and R<3> has the meaning given for R<1> or denotes -{CH2-}m-L-RF, where m is 0, 1 or 2, and Log RF has the above meaning, Z<1> denotes a metal ion equivalent with ordinal numbers 12, 20-30, 39, 42, 44 or 57-83, Y is -0Z<1> or where Z<1>, L, RF and R3 have the meanings given above, or denotes a complex of general formula III wherein R<3> and Z<1> have the meanings given above, and R<2> has the meaning given for R<1>, or denotes a complex of general formula IV where Z<1> has the above meaning, or denotes a complex with general formula V in which Z<1> has the above meaning, and o and q denote the numbers 0 or 1 and the sum o + q = 1, or denotes a complex of general formula VI in which Z<1> has the meaning given above, or denotes a complex of general formula VII where Z<1> and Y have the meanings indicated above, or denotes a complex of general formula VIII wherein R<3> and Z<1> have the meanings given above, and R<2> has the meaning given for R<1>, or denotes a complex of general formula IX where R<3> and Z<1> have the meanings given above, or denotes a complex of general formula X where R<3> and Z<1> have the meanings given above, or denotes a complex, of general formula XI where Z<1> has the meaning given above, and R<2> has the meaning given for R<1>, or denotes a complex of general formula XII where L, RF and Z<1> have the meanings given above, or denotes a complex of general formula XIII where Z<1> has the meaning given above, possibly with the usual additives in galenic pharmacy for tumor therapy. 2. Pharmaceutical agent, characterized in that it contains at least one perfluoroalkyl-containing compound of general formula I according to claim 1, possibly together with the usual additives in galenic pharmacy for the therapy of hepatocellular carcinoma (HCC). 3. Pharmaceutical agent, characterized in that it contains at least one perfluoroalkyl-containing compound of general formula I according to claim 1, possibly together with the usual additives in the galenic pharmacy for interventional radiology. 4. Pharmaceutical agent containing at least one compound according to one of claims 1 to 3, characterized in that nine the formula -CnF2nX denotes the numbers 4-15. 5. Pharmaceutical agent containing at least one compound according to one of claims 1 to 4, characterized by atXi the formula -CnF2nX denotes a fluorine atom. 6. Pharmaceutical agent according to claim 1, characterized in that it contains gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctylsulfonyl)-nonyl]-1,4,7-tris (carboxymethyl)-1,4,7,10-tetraazacyclododecane. 7. Pharmaceutical agent, characterized in that it contains at least one perfluorine-containing compound of general formula I according to one of claims 1 to 3 and at least one chemotherapeutic agent. 8. Pharmaceutical agent according to claim 7, characterized in that it contains 5-fluorouracil, cisplatin, doxorubicin and/or mitomycin C as a chemotherapeutic agent. 9. Pharmaceutical agent,' characterized in that it contains at least one perfluoroalkyl-containing compound of general formula I according to one of claims 1 to 3 and at least one contrast agent. for NMR or X-ray diagnostics. 10. ■ Pharmaceutical agent according to one of claims 7 or 8 and at least one contrast agent for NMR or X-ray diagnostics. 11. Use of at least one physiologically compatible compound with formula I according to claim 1 for the production of a drug for tumor therapy. 12. Use according to claim 11, where the drug is for the therapy of hepatocellular carcinoma (HCC). 13. Application according to claim 11, where the drug is for the radiology intervention. 14. Use of at least one physiologically compatible compound according to claim 5 for the production of a drug for tumor therapy or interventional radiology. 15. Application according to one of claims 11 to 13, where the drug is used together with. at least one chemotherapy drug. 16. Use according to claim 15, where 5-fluorouracil, cisplatin, doxorubicin and/or mitomycin C are used as chemotherapeutic agents. 17. Use according to one of claims 11 to 13, where the drug is used together with at least one contrast agent for NMR or X-ray diagnostics. 18. Use according to one of claims 11 to 13, where the drug is used together with at least one contrast medium for NMR or X-ray diagnostics and at least one chemotherapeutic agent.