DE19731300C1 - Triiodoaromatics containing perfluoroalkyl groups, process for their preparation and their use as contrast agents - Google Patents

Abstract

The invention relates to novel triiodine aromates containing perfluoroalkyl groups, to a method for the production thereof, and the use of said aromates as contrast agents for x-ray diagnosis, in addition to magnetic resonance diagnosis and magnetic resonance spectroscopy by fluorometry. The invention also relates to diagnostic agents containing said novel compounds.

Description

The invention relates to the objects characterized in the claims, that means new, perfluoroalkyl group-containing triiodoaromatics, process for their Manufacture, its use as a contrast agent for X-ray diagnostics and for magnetic resonance diagnostics and spectroscopy using fluorine measurement. The invention also relates to diagnostic agents containing these new ones Links.

There are a variety of iodinated organic compounds that are considered X-ray contrast agents can serve as the iodine atom effectively eliminates the x-rays absorbed. Such X-ray contrast media are e.g. B. in US 2,786,055, US 3,795,698, US 4,735,795 and US 5,047,228. Also in DE 43 44 464 A1 X-ray contrast media containing iodine are described, in particular for Representation of the vessels are suitable. In those described in DE 43 44 464 A1 Compounds are iodine-containing dendrimeric polymers that unite imaging residues containing nitrogen-containing core and triiodoaromatics exhibit.

Furthermore, X-ray contrast media containing iodine aromatics are used Examination of the gastrointestinal tract in US 5,422,114 and US 5,326,553 described. Example 4 in US 5,326,553 discloses as X-ray contrast agents Compound (2,4,6-triiodophenoxy) -1H, 1H, 2H, 2H-perfluorooctane, which is a triiodoaromatic containing perfluoroalkyl groups.

WO 94 5335 A1 discloses triiodoaromatics with a -COCF ₃ group as a group which generates nuclear magnetic resonance, in particular N-trifluoroacetyl iopanoic acid and α-fluoro-N-trifluoroacetyl iopanoic acid. The compounds are described as X-ray contrast agents as well as contrast agents for ¹⁹ F imaging (see amended claims 9 and 10).

However, it has been shown that the contrast media of the prior art are not for all applications are to be used satisfactorily. The object of the invention was therefore, to find new contrast agents that are suitable both for X-ray diagnostics and also for magnetic resonance diagnostics using fluorine measurement, in particular for Magnetic resonance imaging are very suitable.

The object of the invention is achieved with the perfluoroalkyl group-containing tri-aromatic compounds of general formula I according to claim 1 and dependent claims 2 to 10 solved.

Of the compounds of the general formula I, those are preferred according to the invention in which L ^{1 is} a direct bond or a C ₁ -C ₁₅ -alkyl radical, preferably a C ₁ -C ₁₀ -alkyl radical, which, as stated in claim 1, optionally can be interrupted or substituted. L ¹ particularly preferably means:
a direct bond

The radicals L ^{1 of} the compounds mentioned in the examples are very particularly preferred according to the invention.

Of the compounds of the general formula I according to the invention, preference is furthermore given to those in which R ^{F is} -C _n F _{2n + 1} , where n is preferably the numbers 4-15. The radicals -C ₄ F ₉ , -C ₆ F ₁₃ , -C ₈ F ₁₇ , -C ₁₂ F ₂₅ and -C ₁₄ F ₂₉ and the radicals of the compounds mentioned in the examples are very particularly preferred.

In the general formula I, A is preferably a triiodoaromatic general formula II.

R ³ in the general formulas II, III, IV and V is preferably hydrogen or a C ₁ -C ₁₀ -alkyl radical which is optionally interrupted by 1-3 oxygen atoms and / or 1-2 CO or SO ₂ groups and / or is substituted by 1-3 hydroxy groups. In particular, R ^{3 can} also denote the radical R ^F -L ¹ -L ² -, preferably C ₄ F ₉ CO-, C ₈ F ₁₇ SO ₂ - or C _n F _{2n + 1} CH ₂ CH ₂ , where n is the number 4-15 stands.

R ³ very particularly preferably means:
Hydrogen, C ₁ -C ₁₀ alkyl, in particular C ₁ -C ₄ alkyl, -CH ₂ CH (OH) CH ₂ OH, -CO-CH ₂ OCH ₃ , C ₆ H ₅ CH ₂ -, -CH ₂ CH (OH) CH (OH) CH ₂ OH, -CH ₂ -CH (OH) CH (OH) CH ₂ OH, -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ OH, -COCH ₂ OH, -COCH ( OH) CH ₃ , -COCH (OH) CH ₂ OH, - COCH (CH ₂ OH) ₂ and the radicals listed in the examples.

X in general formulas II, IV and V and Y in general formula II independently of one another preferably have the following meanings:

R ⁸ in the general formulas III and V particularly preferably denotes hydrogen, C ₁ -C ₅ -alkyl, in particular methyl, -CH ₂ CH ₂ OH, -CH ₂ CH (OH) CH ₂ OH, -CH ₂ CH ₂ OCH ₃ , -CH (CH ₂ OH) CH (OH) CH ₂ OH, -CH ₂ CH (OH) CH (OH) CH ₂ OH, -CH ₂ CH ₂ - [OCH ₂ CH ₂ ] - _u OCH ₃ , -CH ₂ CH ₂ O- [CH ₂ CH ₂ O] - _n -H where u = 1-5, (-CH ₂ -) _t COOH, where t = 1-5.

R ⁹ in the general formulas III and V particularly preferably denotes hydrogen, C ₁ -C ₅ -alkyl, in particular methyl, CH ₂ OH, CH ₃ CH (OH) -, CH (OH) CH ₂ OH, -CH (CH ₂ OH) ₂ and -CH (CH ₂ OH) CH (OH) CH ₂ OH.

The compounds of the general formula I according to the invention are prepared by performing the functional groups on the corresponding triiodoaromatic alkylating or acylating reaction derivatized with a perfluoroalkyl radical become.

Compounds of the general formula I with A in the meaning of the general formula II and l = 1 are obtained by reacting compounds of the general formula 10

wherein R ³ , X and Y have the meaning given above, with compounds of the general formula 11

wherein R ^F and L ^{1 have} the meaning given above and Nu is a nucleofug.

If the radicals R ⁴ , R ⁵ , R ⁶ , R ⁷ contain hydroxyl groups, they can optionally be protected by acetyl or isopropylidene groups. The protection group technology is familiar to the specialist.

The residues advantageously serve as nucleofug:

The reaction is carried out in organic solvents or their mixtures such as:
Isopropanol, ethanol, methanol, butanol, dioxane, tetrahydrofuran, dimethylformamide, dimethylacetamide, formamide, dichloromethane, dichloroethane, toluene, benzene, ethyl acetate.

The reaction is carried out in a temperature interval between -10 ° C-100 ° C preferably carried out between 0 ° C-30 ° C.

Inorganic and organic bases such as triethylamine, Pyridine, N-methylmorpholine, diisopropylethylamine, dimethylaminopyridine. Alkali and Alkaline earth metal hydroxides, their carbonates or hydrogen carbonates such as lithium hydroxide, Sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, Potassium hydrogen carbonate.

The compounds of general formula 11 are obtained from compounds of general formula 12:

HO ₂ CL ¹ -R ^F (12)

in the
R ^F , L ^{1 have} the meaning given above, according to the acid activation processes generally known to the person skilled in the art, such as:
by reacting the acid with dicyclohexylcarbodiimide, thionyl chloride N-hydroxysuccinimide / dicyclohexylcarbodiimide, carbonyldiimidazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, oxalic acid dichloride or chloroformic acid isobutyl ester in the manner described in the literature:

• - Activation of carboxylic acids. Overview in Houben-Weyl, Methods of Organic Chemistry, Volume XV / 2, Georg Thieme Verlag Stuttgart, 19.
• - Activation with carbodiimides. R. Schwyzer u. H. Kappeler, Helv. 46: 1550 (1963).
• - E. Wünsch et al., B. 100: 173 (1967).  
• Activation with carbodiimides / hydroxysuccinimide: J. Am. Chem. Soc. 86: 1839 (1964) and J. Org. Chem. 53: 3583 (1988). Synthesis 453 (1972).
• - Anhydride method, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline: B. Belleau et al., J. Am. Chem. Soc., 90: 1651 (1986), H. Kunz et al., Int. J. Pept. Prot. Res., 26: 493 (1985) and J.R. Voughn, Am. Soc. 73: 3547 (1951).
• - Imidazolid method: B.F. Gisin, R.B. Merrifield, D.C. Tosteon, Am. Soc. 91: 2691 (1969).
• - Acid chloride methods, thionyl chloride: Helv., 42: 1653 (1959).
• - Oxalyl chloride: J. Org. Chem., 29: 843 (1964).

The compounds of general formula 12 are commodities or are made by reacting compounds of general formula 13

HQL ¹ -R ^F (13)

in which R ^F and L ^{1 have} the meaning given above and
Q in the meaning of

with a bond from the nitrogen atom to the hydrogen atom, or

obtained with compounds of general formula 14

Hal-CH ₂ -CO-OR ¹⁰ (14)

in the
Hal Cl, Br, I means and
R ^{10 has} the meaning of H, methyl, ethyl, t-butyl, benzyl, isopropyl, shown for example according to CF Ward, Soc. 121, 1161 (1922), using the methods known to those skilled in the art, such as alkylation of alcohols with alkyl halides [Houben-Weyl, methods of organic chemistry, oxygen compounds I, part 3, methods for the preparation and conversion of ethers, Georg Thieme Verlag, 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, Methods of Organic Chemistry, XI / 2 nitrogen compounds, Georg Thieme Verlag Stuttgart, 1957, p. 680; JE Rickman and T. Atkins, Am. Chem. Soc., 96: 2268, 1974, 96: 2268; F. Chavez and AD Sherry, J. Org. Chem. 1989, 54: 2990].

In the event that Q is the group

means the reaction with a Wittig reagent of the structure

where r means the numbers 0-16. The resulting -CH = CH double bond can be retained as part of the structure or converted into a -CH ₂ -CH ₂ grouping by catalytic hydrogenation (Pd 5% / C).

The compounds of the general formula 14 are commodities (Fluorochem, ABCR, Aldrich, Fluka, Merck).

Compounds of the general formula 10, in which X denotes the hydroxyl group, are obtained by the process described in EP 0 308 364 A2.

Compounds of the formula 10 with X = NR ⁴ R ⁵ , one of the radicals R ⁴ or R ^{5 being} a polyhydroxyalkyl group, are obtained analogously to the processes described in EP 0 308 364 A2 and subsequent reaction of the benzoic acid radical with the corresponding polyhydroxyalkylamines.

Compounds of the formula 10 in which X is NR ⁴ R ⁵ and Y is NR ⁶ R ⁷ and one of the radicals R ⁴ or R ⁵ and one of the radicals R ⁶ or R ^{7 are} a polyhydroxyalkyl group can be prepared according to the method described in EP 0 015 867 A1 described method can be obtained.

Compounds of the general formula I with A in the meaning of the general Formula II and I = 2 are obtained analogously to the above. Method. The procedure is described in detail in Example 9.

Compounds of the general formula I with A in the meaning of the general formula III and I = 1 are obtained by reacting compounds of the general formula 15

where Hal means chlorine
R ⁸ , R ^{9 has} the meaning given above, with compounds of the general formula 18

HR ³ NL ¹ -R ^F (18)

wherein
R ^F , L ¹ and R ^{3 have} the meaning given above.

If the radicals R ⁸ , R ⁹ contain hydroxyl groups, they can optionally be protected by acetyl or isopropylidene groups. The protection group technology is familiar to the specialist.

Compounds of the general formula 15 are obtained starting from 2,4,6-triiodine 3,5-diaminobenzoic acid (DE 19 61 289 A1) and its derivatization on nitrogen and preparation of the as described in Example 7 or analogous to those in DE 20 31 724 A1, DE 34 07 473 C2, US 5,191,119, WO 84 01727 A1, EP 0406992 A2 described method.

Compounds of the general formula I with A in the meaning of the general formula IV and I = 1 are obtained by reacting compounds of the general formula 16

wherein Hal, X, R ⁶ and R ^{7 have} the meaning given above with compounds of the general formula 18

HR ³ NL ¹ -R ^F (18)

wherein R ^F , L ¹ , and R ^{3 have} the meaning given above
If the radicals R ⁴ , R ⁵ , R ⁶ , R ⁷ contain hydroxyl groups, they can optionally be protected by acetyl or isopropylidene groups. The protection group technology is familiar to the specialist.

Compounds of the general formula 16 are obtained by reacting the appropriate acid made accessible with thionyl chloride. The representation of the  Acid occurs in accordance with EP 0032388 A1 and DE 30 01 293 A1 Method.

Compounds of the general formula I with A in the meaning of the general formula V and I = 1 are obtained by reacting compounds of the general formula 17

wherein Hal, X, R ⁸ and R ^{9 have} the meaning given above with compounds of the general formula 18

HR ³ NL ¹ -R ^F (18)

wherein R ^F , L ¹ and R ^{3 have} the meaning given above
If the radicals R ⁴ , R ⁵ , R ⁸ , R ⁹ contain hydroxyl groups, they can optionally be protected by acetyl or isopropylidene groups. The protection group technology is familiar to the specialist.

The compounds of the general formula 17 are based on those according to DE 39 37 118 A1, EP 0406992 A2, EP 0015867 A1, DE 28 05 928 A1, DE 25 23 567 A1, US 4954348, WO 9310825 A1, DE 29 26 428 A1, EP 0033426 A2, Invest. Radiol. 92, p.51-p.53 (1994), JOC 59 1344 (1994) obtained acid chlorides (e.g. 5-acetoxyyacetylamino-2,4,6-triiodoisophthalic acid [N- (2,3-diacetoxypropyl) amide chloride ) obtained by reaction with the corresponding polyfluoroalkylamine. (5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid- [N- (2,3-diacetoxypropyl) amide chloride),
Compounds of the general formula I with A in the meaning of the general formula V and I = 2 are also obtained starting from those according to DE 39 37 118 A1, EP 0406992 A1, EP 0015867 A1, DE 28 05 928 A1, DE 25 23 567 A1 , US 4954348, WO 9310825 A1, DE 29 26 428 A1, EP 0033426 A2, Invest. Radiol. 92, p.51-p.53 (1994), JOC 59 1344 (1994) obtained acid chlorides (e.g. 5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid- [N- (2,3-diacetoxypropyl) amide chloride ) by reaction with triamines, as described in Tetrahedron Letters 36 3451 (1995) and subsequent reaction with the corresponding polyfluoroalkylamine. After the protective groups have been removed, the compounds according to the invention are obtained.

It has been shown that the perfluoroalkyl group-containing triiodoaromatics of the general formula I are very suitable as contrast agents for X-ray diagnostics, for ¹⁹ F-NMR diagnostics and spectroscopy and in particular for combined X-ray and NMR diagnostics. They can preferably be used as contrast agents for imaging the intravascular space (including vascular leakage), the liver and the bile duct, the gastrointestinal tract and the lymphatic system. The compounds according to the invention can also be applied in combination with the contrast media based on heavy metal chelates (eg Magnevist®, Dotarem®, ProHance®). In addition, the agents according to the invention can be used as ultrasound contrast agents.

The invention therefore also relates to diagnostic agents which at least one of the compounds according to the invention and optionally physiological contain compatible auxiliaries and / or additives that are used in galenics for Formulation of pharmaceutical agents are common. The invention Agents are intended for enteral or parenteral administration. Suitable additives are, for example, physiologically harmless buffers (such as tromethamine, Bicarbonate, phosphate, citrate), stabilizers (such as DTPA, sodium edetate, Calcium disodium edetate), or - if necessary - electrolytes (such as Sodium chloride) or - if necessary - antioxidants (such as ascorbic acid) or also substances to adjust the osmolality (such as mannitol, glucose). Are suspensions or for enteral administration or other purposes Solutions of the agents according to the invention in water or physiological saline if desired, they are made with one or more auxiliary agents commonly used in galenics (e.g. methyl cellulose, lactose, mannitol) and / or surfactants (e.g. lecithins,  Tweens®, Myrj® and / or flavoring agents for taste correction (e.g. essential oils) mixed.

The concentration of the new X-ray contrast media in the aqueous medium is directed according to the X-ray diagnostic method. The usual concentrations range from 2 to 250 mmol / l, preferably 5 to 150 mmol / l. The iodine content of the solutions is usually in the range between 50 to 450 mg / ml, preferably 100 to 350 mg / ml.

The resulting agents are then heat sterilized if desired. she are dependent on the iodine content and the X-ray diagnostic used Method or question usually in a dose of 5 mg iodine / kg to 2000 mg iodine / kg and applied in amounts of 1 to 1000 ml.

The application of the aqueous X-ray contrast medium solution can be enteral or parenteral, so oral, rectal, intravenous, intraarterial, intravascular, intracutaneous, interstitial, subcutaneously (lymphography), subarachnoidally (myelography).

The agents according to the invention show the high effectiveness that is necessary to to burden the body with the smallest possible amount of foreign substances and the good tolerance, which is necessary to the non-invasive nature of the Maintain investigations.

Embodiments example 1 a) 9,9,9,8,8,7,7-nonafluoro-3-oxa-nonanoic acid tert-butyl ester

To a mixture of 20 g (75.73 mmol) of 1H, 1H, 2H, 2H-perfluorohexan-1-ol and 2.57 g (7.57 mmol) of tetrabutylammonium hydrogen sulfate in 300 ml of 60% aqueous potassium hydroxide solution / 200 ml of toluene is added dropwise with vigorous stirring at 0 ° C 29.54 g (151.5 mmol) tert-butyl bromoacetate (100.0 mmol, 19.51 g). The mixture is stirred for one hour at 0 ° C., the organic phase is separated off 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 residue is chromatographed on silica gel (mobile phase: dichloromethane).
Yield: 21.48 g (75% of theory) of a colorless oil.
Elemental analysis:
calc .: C 38.11; H 4.00; F 45.21;
Found: C 37.98; H 4.18; F 45.03.

b) 9,9,9,8,8,7,7-nonafluoro-3-oxa-nonanoic acid

20 g (52.88 mmol) of the title compound from Example 1a) are dissolved in 300 ml of trifluoroacetic acid and stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is recrystallized from hexane / diethyl ether.
Yield: 14.82 g (87% of theory) of a colorless crystalline solid.
Elemental analysis:
calc .: C 38.11; H 4.00; F 45.21;
Found: C 37.98; H 4.18; F 45.03.

c) 3- (2,3-Diacetoxypropanaminocarbonyl) -5- (2H, 2H, 4H, 4H, 5H, 5H-perfluoro-3-oxa- nonanoylamino) -2,4,6-triiodobenzoic acid

The title compound from Example 1b) (71.4 mmol, 23.0 g) and oxalyl chloride (74.0 mmol, 9.39 g) in 100 ml of 1,2-dichloroethane are stirred at 60 ° C. for 2 h. 5-Amino-3- (2,3-diacetoxypropanaminocarbonyl) -2,4,6-triiodobenzoic acid (23.7 mmol, 17.0 g, EP 0308364) is added and the mixture is heated to boiling for 20 h. The mixture is concentrated to dryness in vacuo and the residue is purified by column chromatography on silica gel (mobile solvent: dichloromethane / methanol; 2/1).
Yield: 20.34 g (84% of theory) of a colorless, crystalline solid.
Elemental analysis:
calc .: C 27.08; H 1.98; N 2.75; I 37.32; F 16.76;
Found: C 27.28; H 2.17; N 2.56; I 37.15; F 16.60.

d) 3- (2,3-Dihydroxypropanaminocarbonyl) -5- (2H, 2H, 4H, 4H, 5H, 5H-perfluoro-3-oxa- nonanoylamino) -2,4,6-triiodobenzoic acid

The title compound from Example 1c) (10.0 mmol, 10.20 g) is heated to boiling in 50 ml of 2N sodium hydroxide solution and 50 ml of methanol for 15 min. It is concentrated in vacuo, the residue is dissolved in distilled water, the acid is released with ion exchanger (Amberlite 120 IR, H,-form), filtered and the filtrate is evaporated to dryness. The residue is purified by column chromatography on silica gel (mobile phase: acetone / methanol; 4/1).
Yield: 8.89 g (95% of theory) of a colorless solid.
Elemental analysis:
calc .: C 24.38; H 1.72; N 2.99; I 40.67; F 18.27;
Found: C 24.51; H 1.90; N 2.75; I 40.51; F 18.20.

e) Sodium-3- (2,3-dihydroxypropanaminocarbonyl) -5- (2H, 2H, 4H, 4H, 5H, 5H-perfluoro- 3-oxanonanoylamino) -2,4,6-triiodobenzoate

The title compound from Example 1d) (5.0 mmol, 4.68 g) is dissolved in 100 ml of distilled water and a pH of 7.2 is set with 0.1 N sodium hydroxide solution. The solution is filtered through a membrane filter and the sodium benzoate is isolated by ge freeze-drying.
Yield: 4.74 g (99% of theory) of a colorless solid.
Elemental analysis:
calc .: C 23.82; H 1.58; N 2.92; I 39.74; F 17.85; Na 2.40;
Found: C 23.63; H 1.44; N 2.83; I 39.70; F 18.01; Na 2.30.

Example 2 a) N ¹ , N ³ bis (2,3-diacetoxypropane) -N ¹ -methyl-5- (2H, 2H, 4H, 4H, 5H, 5H-perfluoro-3-oxanonanoylamino) -2,4,6- triiodo-1,3-benzenedicarboxamide

The title compound from Example 1c) (10.0 mmol, 10.20 g) is heated to boiling with 50 ml of thionyl chloride for 2 h. The mixture is concentrated in vacuo, the residue was dissolved in 100 ml of 1,4-dioxane and with N-methylamino-2,3-propanediol (20.0 mmol, 2.10 g) and anhydrous sodium carbonate (20.0 mmol, 2.12 g) for 3 h 80 ° C stirred. The salts are filtered off, the fitrate is concentrated in vacuo and the residue is purified by column chromatography on silica gel (mobile solvent: dichloromethane / methanol; 4/1).
Yield: 9.41 g (79% of theory) of a colorless oil that gradually solidifies.
Elemental analysis:
calc .: C 31.25; H 2.79; N 3.53; I 31.96; F 14.35;
found: C 31.07; H 2.71; N 3.68; I 32.12; F 14.50.

b) N ¹ , N ³ -bis (2,3-dihydroxypropyl) -N ¹ -methyl-5- (2H, 2H, 4H, 4H, 5H, 5H-perfluoro-3-oxanonanoylamino) -2,4,6- triiodo-1,3-benzenedicarboxamide

The title compound from Example 2a) (5.0 mmol, 5.96 g) is heated to boiling for 15 min with 30 ml of 2N sodium hydroxide solution and 30 ml of methanol. The mixture is concentrated in vacuo and the residue is purified by column chromatography on silica gel (mobile solvent: tert-butyl methyl ether / methanol / 25% ammonia; 4/2/1).
Yield: 4.71 g (92% of theory) of a colorless solid.
Elemental analysis:
calc .: C 27.00; H 2.46; N 4.11; I 37.21; F 16.71;
Found: C 26.83; H 2.40; N 4.30; I 37.50; F 16.55.

Example 3 a) N-ethyl-N- (perfluorooctylsulfony) amino acetic acid t-butyl ester

20 g (37.94 mmol) N-ethylperfluorooctylsulfonamide and 15.73 g (113.8 mmol) Potassium carbonate is suspended in 200 ml acetone and 14.80 g (75.87 mmol) tert-butyl bromoacetate was added dropwise. The mixture is stirred at 60 ° C. for 3 hours.

The salts are filtered off and the filtrate is evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: hexane / dichloromethane / acetone = 10/10/1). After evaporation of the product-containing fractions, the residue is recrystallized from methanol / ether.
Yield: 21.66 g (89% of theory) of a waxy, colorless solid.
Elemental analysis:
calc .: C 29.96; H 2.51; F 50.36; N 2.18; S 5.00;
Found: C 29.81; H 2.70; F 50.15; N 2.30; S 4.83.

b) N-ethyl-N- (perfluorooctylsulfonyl) amino acetic acid

20 g (31.18 mmol) of the title compound from Example 3a) are dissolved in 200 ml of trifluoroacetic acid and stirred overnight at room temperature. It is evaporated to the dry state in a vacuum. The residue is recrystallized from methanol / ether.
Yield: 17.34 g (95% of theory) of a colorless crystalline solid.
Elemental analysis:
calc .: C 24.63; H 1.38; F 55.19; N 2.39; S 5.48;
Found: C 24.48; H 1.50; F 55.01; N 2.17; S 5.59.

c) N ¹ , N ³ -Bis (2,3-diacetoxypropane) -N ¹ -methyl-5- (N-ethyl-N-perfluorooctanesulfonylglycylamino) -2,4,6-triiodo-1,3-benzenedicarboxamide

The title compound from Example 3b) (30.0 mmol, 17.56 g) and oxalyl chloride (30.0 mmol, 3.81 g) in 150 ml of 1,2-dichloroethane are stirred at room temperature overnight. 5-Amino-N ¹ , N ³ -bis (2,3-diacetoxypropanamino) -N ¹ -methyl-2,4,6-triiodo-1,3-benzenedicarboxamide (10.0 mmol, 8.87 g, obtained in accordance with EP 0) 015867) and heated to boiling for 20 hours. The mixture is concentrated in vacuo and the residue is purified by column chromatography on silica gel (mobile solvent: dichloromethane / methanol; 9/1).
Yield: 12.94 g (89% of theory) of a slightly yellowish oil, which he gradually stares at.
Elemental analysis:
calc .: C 28.90; H 2.36; N 3.85; S 2.21; I 26.18; F. 22.21;
Found: C 28.74; H 2.21; N 3.68; S 2.26; I 26.40; F 22.48.

d) N ¹ , N ³ bis (2,3-dihydroxypropyl) -N ¹ -methyl-5- (N-ethyl-N-perfluorooctanesulfonylglycylamino) -2,4,6-triiodo-1,3-benzenedicarboxamide

The title compound from Example 3c) (5.0 mmol, 7.27 g) is stirred with 30 ml of 2N sodium hydroxide solution and 30 ml of methanol overnight at room temperature. 20 ml of 2N hydrochloric acid are added dropwise and the mixture is concentrated in vacuo. The residue is purified by column chromatography on silica gel (mobile phase: dichloromethane / methanol; 3/1).
Yield: 5.85 g (91% of theory) of a slightly yellowish oil which gradually solidifies.
Elemental analysis:
calc .: C 25.21; H 2.04; N 4.36; S 2.49; I 29.60; F 25.11;
Found: C 25.25; H 1.98; N 4.50; S 2.38; I 29.76; F 24.87.

Example 4 5-N- (3,3,4,4,5,5,6,6,6-nonafluorohexyl) -5-methoxyacetylamino-2,4,6- triiodisophthalic acid- [N, N'-bis (-2,3-dihydroxypropyl) -N-methyl] diamide a) 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - [(2,2-dimethyl-1,3-dioxolane-4- ylmethyl) - (2,2-dimethyl-1,3-dioxolan-4-ylmethyl) -N-methyl] diamide

90.25 g (114.1 mmol) of isopromide (Ultravist®) are suspended in 90 ml of acetone, 94 ml (684.6 mmol) of 2,2-dimethoxypropane and 217 mg (1.1 mmol) of para-toluenesulfonic acid are added, and Stirred for 16 hours at room temperature. The mixture is then neutralized with 570 mg (2 mmol) of sodium carbonate, the solution is concentrated and the residue is taken up in ethyl acetate. It is washed with half-concentrated sodium chloride solution, dried over sodium sulfate and, after filtration, evaporated to dryness.
Yield: 97 g (97.6% of theory) of a colorless solid.
Analysis (based on solvent-free substance):
calc .: C 33.09; H 3.70; I 43.70; N 4.82; O 14.69;
Found: C 32.87; H 3.84; I 43.86; N 4.70.

b) 5-N- (3,3,4,4,5,5,6,6,6-nonafluorohexyl) -5-methoxyacetylamino-2,4,6- triiodisophthalic acid - [(2,2-dimethyl-1,3-dioxolan-4-ylmethyl) - (2,2-dimethyl-1,3- dioxolan-4-ylmethyl) -N-methyl] diamide

4.35 g (5 mmol) of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - ((2,2-dimethyl-1,3-dioxolan-4-ylmethyl) - (2,2-dimethyl-1,3- dioxolan-4-ylmethyl) -N-methyl] -diamide are dissolved in 22 ml of anhydrous dioxane, with 0.76 g (5.5 mmol) of potassium carbonate (anhydrous) and 2.06 g (5.5 mmol) of 1-iodine -3,3,4,4,5,5,6,6,6-nonafluorohexane are added, the reaction mixture is allowed to stir at 60 ° C. and after nine hours 0.76 g (5.5 mmol) of potassium carbonate and 2 , 06 g (5.5 mmol) of 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexane The reaction mixture is stirred overnight at 60 ° C. After the reaction has ended, the mixture is filtered The residue is taken up in ethyl acetate, washed with water and then the organic phase is dried over sodium sulfate. After filtration and evaporation, a yellow oil is obtained which is chromatographed on silica gel for purification.
Yield: 3.2 g (52.1% of theory) of a yellowish oil.
Analysis (based on solvent-free substance):
calc .: C 32.25; H 3.16; F 15.30; I 34.07; N 3.76; O 11.46;
Found: C 32.04; H 3.11; F 15.08; I 33.93; N 3.85.

c) 5-N- (3,3,4,4,5,5,6,6,6-nonafluorohexyl) -5-methoxyacetylamino-2,4,6- triiodisophthalic acid- [N, N'-bis (-2,3-dihydroxypropyl) -N-methyl] diamide

3.0 g (2.7 mmol) 5-N- (3,3,4,4,5,5,6,6,6-nonafluorohexyl) -5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - [( 2,2-dimethyl-1,3-dioxolan-4-ylmethyl) - (2,2-dimethyl-1,3-dioxolan-4-ylmethyl) -N-methyl] -diamide are dissolved in a solution of 5 ml. 1 N aqueous hydrochloric acid and 15 ml of methanol dissolved and heated to 55 ° C for four hours. The reaction solution is treated with a weakly basic ion exchanger to remove the hydrochloric acid and evaporated to dryness.
Yield: 2.35 g (83.9% of theory) of a colorless, amorphous solid.
Analysis (based on solvent-free substance):
calc .: C 27.79; H 2.62; F 16.48; I 36.71; N 4.05; O 12.34;
Found: C 27.91; H 2.53; F 16.30; I 36.58; N 3.92.

Example 5 a) N ¹ , N ³ -bis (2,3-diacetoxypropanamino) -N ¹ -methyl-5- [N- (9,9,9,8,8,7,7-nonaflu-or-3-oxa- nonanoyl) -N- (2,3-dihydroxypropyl) amino] -2,4,6-triiodo-1,3-benzenedicarbox amide

To 20 g (16.79 mmol) of the title compound from Example 2a) in 200 ml of dimethylformamide are added in portions at 0 ° C with stirring 0.48 g (20.15 mmol) of sodium hydride. After the evolution of hydrogen has ended, 2.23 g (20.15 mmol) of 3-chloro-1,2-propanediol are added dropwise and the mixture is stirred at 80 ° C. for 10 hours. 10 ml of 1 N acetic acid are added and the mixture is evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 4/1).
Yield: 16.63 g (83% of theory) of a pale yellow, glassy solid.
Elemental analysis:
calc .: C 32.27; H 3.11; N 3.32; I 30.08; F 13.51;
Found: C 32.07; H 2.98; N 3.19; I 30.35; F 13.60.

b) N ¹ , N ³ -bis (2,3-dihydroxypropanamino) -N ¹ -methyl-5- [N- (9,9,9,8,8,7,7-nonafluoro-3-oxa-nonanoyl) -N- (2,3-dihydroxypropyl) amino] -2,4,6-triiodo-1,3-benzenedicarbox amide

40 ml of 2N sodium hydroxide solution are added to 10 g (7.90 mmol) of the title compound from Example 5a) in 100 ml of methanol and the mixture is stirred overnight at room temperature. 60 ml of water are added and the conductivity minimum is set by adding ion exchanger IRA 67 (OH⁻ form) and IRC 50 (H⁺ form). It is filtered off from the ion exchanger and washed twice with methanol. The combined filtrates are concentrated and freeze-dried.
Yield: 8.58 g (99% of theory) of a colorless amorphous solid.
Elemental analysis:
calc .: C 28.46; H 2.85; N 3.83; I 34.69; F 15.58;
Found: C 28.33; H 2.73; N 3.90; I 34.80; F 15.40.

Example 6 5- (N-Dihydroxypropyl) -hydroxyacetylamino-2,4,6-triiodoisophthalic acid- [N- (2.3 dihydroxypropyl) -N- (6,6,7,7,8,8,9,9,9-nonafluoro-3-oxanonyl)] diamide a) 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid- [N- (2,3-diacetoxypropyl) -N'- hydroxyethyl] diamide

16.7 g (20 mmol) of 5-acetoxyacetylamino-2,4,6-triiodisophthalic acid- [N- (2,3-diacetoxypropyl) amide chloride (DE 39 37 118) are dissolved in 110 ml of anhydrous dioxane, with 1.5 ml (20 mmol) triethylamine and 1.22 g (20 mmol) ethanolamine were added. The mixture is stirred at 60 ° C. overnight, allowed to cool to room temperature, the reaction mixture is filtered and the filtrate is evaporated. The residue is dried under high vacuum and gives a firm foam.
Yield: 14.1 g (82.1% of theory) of a yellowish solid.
Analysis (based on solvent-free substance):
calc .: C 29.36; H 2.82; I 44.31; N 4.89; O 18.62;
Found: C 29.51; H 2.59; I 44.19; N 5.01.

b) 5- [N- (2,2-Dimethyl-1,3-dioxolan-4-ylmethyl)] - acetoxyacetylamino-2,4,6- triiodisophthalic acid- [N '- (2,3-diacetoxypropyl) -N' '- hydroxyethyl] diamide

13.7 g (16 mmol) of 5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid- [N- (2,3-diacetoxypropyl) -N'-hydroxyethyl] diamide are dissolved in 100 ml of anhydrous dioxane, with 2.21 g (16 mmol) of potassium carbonate and 2.41 g (16 mmol) of 4-chloromethyl-2,2-dimethyl-1,3-dioxolane were added. The mixture is stirred at 60 ° C. overnight and the amount of potassium carbonate and chlorine compound given above is added again. After a further six hours at 60 ° C, the reaction mixture is filtered and evaporated. The residue is dried under high vacuum and gives a firm foam. The amorphous solid is stirred with 350 ml of hexane / tert-butyl methyl ether, the yellowish precipitate is filtered off with suction after 15 hours and dried in vacuo.
Yield: 11.8 g (75.8% of theory) of a yellow solid.
Analysis (based on solvent-free substance):
calc .: C 33.32; H 3.52; I 39.12; N 4.32; O 19.73;
Found: C 33.24; H 3.60; I 38.99; N 4.21.

c) 5- [N- (2,2-Dimethyl-1,3-dioxolan-4-ylmethyl)] - acetoxyacetylamino-2,4,6- triiodisophthalic acid- [N '- (2,3-diacetoxypropyl) -N' '- (6,6,7,7,8,8,9,9,9-nonafluoro-3- oxanonyl)] - diamide

To 11.6 g (12 mmol) of 5- [N- (2,2-dimethyl-1,3-dioxolan-4-ylmethyl)] - acetoxyacetylamino-2,4,6-triiodoisophthalic acid- [N '- (2, 3-diacetoxypropyl) -N '' - hydroxyethyl] -diamide in 85 ml of N, N-dimethylformamide are added 0.44 g (14.7 mmol) of sodium hydride (80% in mineral oil) and stirred for 20 min. at -10 ° C. Then 3.92 g (12 mmol) of 1H, 1H, 2H, 2H-perfluorohexyl bromide are added and the mixture is stirred for 12 hours at room temperature. 350 ml of ice water are carefully added, the mixture is extracted several times with ethyl acetate and the combined organic phases are dried over sodium sulfate. The product can be chromatographed on silica gel for purification.
Yield: 10.4 g (71.1% of theory) of a colorless solid.
Analysis (based on solvent-free substance):
calc .: C 32.51; H 3.06; F 14.02; I 31.22; N 3.45; O 15.74;
Found: C 32.42; H 3.24; F 13.88; I 31.08; N 3.37.

d) 5- (N-Dihydroxypropyl) -hydroxyacetylamino-2,4,6-triiodoisophthalic acid- [N- (2,3- dihydroxypropyl) -N- (6,6,7,7,8,8,9,9,9-nonafluoro-3-oxanonyl)] diamide

9.8 g (8 mmol) of 5- [N- (2,2-dimethyl-1,3-dioxolan-4-ylmethyl)] - acetoxyacetylamino-2,4,6-triiodoisophthalic acid [N '- (2.3 -diacetoxypropyl) -N '' - (6,6,7,7,8,8,9,9,9-nonafluoro. 3-oxanonyl)] - diamide are suspended in dilute sodium hydroxide solution and stirred at 60 ° C. for three hours. The mixture is then adjusted to pH 1 with concentrated hydrochloric acid and stirred for two hours. After the protective groups have been completely removed, the product solution is desalted using cationic and anionic exchangers. To isolate the product, the aqueous solution is concentrated and freeze-dried.
Yield: 7.6 g (90.2% of theory) of colorless lyophilisate.
Analysis (based on solvent-free substance):
calc .: C 27.37; H 2.58; F 16.24; I 36.15; N 3.99; O 13.67;
Found: C 27.24; H 2.73; F 16.07; I 36.09; N 3.87.

Example 7 3,5-bis - [(N-2,3-dihydroxypropyl) hydroxyacetylamino] -2,4,6-triiodobenzoic acid- [N- (6,6,7,7,8,8,9,9,9-nonafluoro-3-oxanonyl)] - amide a) N, N-Dibenzyl-6,6,7,7,8,8,9,9,9-nonafluoro-3-oxanonylamine

15 g (60 mmol) N, N-dibenzylaminoethanol in 150 ml abs. Submitted diethyl ether and mixed with 1.44 g (60 mmol) sodium hydride (80%). After 20 minutes, 22.44 g (60 mmol) of 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexane are added and the mixture is stirred at room temperature for 18 hours. The reaction mixture is filtered and the filtrate is evaporated to dryness. The residue obtained is used in the next reaction without further purification.
Yield: 23.7 g (81% of theory) of a pale yellow oil.

b) 6,6,7,7,8,8,9,9,9-nonafluoro-3-oxanonylamine, hydrochloride

21 g (43.1 mmol) of N, N-dibenzyl-6,6,7,7,8,8,9,9,9-nonafluoro-3-oxanonylamine are dissolved in 300 ml of methanol, with 2 g of palladium on activated carbon (10%) and hydrogenated at normal pressure with the addition of hydrochloric acid. When the hydrogenation is complete, the catalyst is filtered off and the filtrate is evaporated. The solid obtained is stirred with tert-butyl methyl ether, filtered and dried.
Yield: 13.2 g (89.1% of theory) of a yellowish oil.
Analysis (based on solvent-free substance):
calc .: C 27.96; H 3.23; Cl 10.32; F 49.76; N 4.08; O 4.66;
Found: C 27.81; H 3.09; Cl 10.45; F 49.64; N 3.92.

c) 2,4,6-triiodo-3,5-diacetoxyacetylaminobenzoic acid

54.8 g (10 mmol) of 2,4,6-triiodo-3,5-diaminobenzoic acid monohydrate (DE 19 61 289 A) are dissolved in 55 ml of N, N-dimethylacetamide and added dropwise with cooling at a maximum of 10 ° C 53 ml (480 mmol) of acetoxyacetyl chloride were added. The mixture is stirred overnight at room temperature. Then 750 ml of water are added, the mixture is stirred overnight and the precipitate is filtered off, washed with water and the product is dried in vacuo.
Yield: 65.1 g (89.2% of theory) of a colorless solid.
Analysis (based on solvent-free substance):
calc .: C 24.68; H 1.80; I 52.15; N 3.84; O 17.53;
Found: C 24.49; H 1.87; I 52.01; N 3.68.

d) 2,4,6-triiodo-3,5-diacetoxyacetylaminobenzoic acid chloride

51.1 g (70 mmol) of 2,4,6-triiodo-3,5-diacetoxyacetylaminobenzoic acid are suspended in 255 ml of ethyl acetate and 2.7 ml of N, N-dimethylformamide, and 15.2 ml (210 mmol) of thionyl chloride are added. The mixture is stirred at 80 ° C for 10 hours. The solid is then filtered off, washed with ethyl acetate and dried in vacuo.
Yield: 48.4 g (92.2% of theory) of a pale yellow solid.
Analysis (based on solvent-free substance):
calc .: C 24.07; H 1.62; Cl 4.74; I 50.87; N 3.74; O 14.96;
Found: C 23.88; H 1.76; Cl 4.88; I 50.63; N 3.59.

e) 3,5-bis - [(N-2,3-dihydroxypropyl) acetoxyacetylamino] -2,4,6-triiodobenzoic acid chloride

Under an argon atmosphere, 23.95 g (32 mmol) of 2,4,6-triiodo-3,5-diacetoxyacetyl aminobenzoic acid chloride are dissolved in 200 ml of anhydrous dioxane, with 8.84 g (64 mmol) of anhydrous potassium carbonate and 7.74 g (70 mmol) 1-chloropropanediol added. The mixture is stirred at 60 ° C. overnight, the reaction mixture is filtered and the filtrate is evaporated. The residue is dried under high vacuum and gives a firm foam. The solid is stirred with 600 ml of hexane / tert-butyl methyl ether, the pale yellow precipitate is filtered off with suction after 18 hours and dried in vacuo.
Yield: 24.3 g (84.7% of theory).
Analysis (based on solvent-free substance):
calc .: C 28.13; H 2.70; Cl 3.95; I 42.46; N 3.12; O 19.63;
Found: C 28.30; H 2.87; Cl 3.81; I 42.22; N 3.06.

f) 3,5-bis - ((N-2,3-dihydroxypropyl) -hydroxyacetylamino] -2,4,6-triiodobenzoic acid- [N- (6,6,7,7,8,8,9,9,9-nonafluoro-3-oxanonyl)] amide

8.97 g (10 mmol) of 3,5-bis - [(N-2,3-dihydroxypropyl) acetoxyacetylamino] -2,4,6-triiodobenzoic acid chloride are dissolved in 90 ml of anhydrous dioxane and, with the addition of 3, 1 ml of triethylamine, reacted with 3.44 g (10 mmol) of 6,6,7,7,8,8,9,9,9-nonafluoro-3-oxanonylamine, hydrochloride. The reaction mixture is stirred for five hours at 70 ° C., the precipitate is then filtered off and the filtrate is evaporated to dryness. The residue is dissolved in methanol and a normal sodium hydroxide solution is added. After complete saponification, the mixture is neutralized with hydrochloric acid, evaporated to dryness and the solid is stirred out several times with ethanol. The combined ethanol extracts are evaporated. The crude product can be chromatographed for purification on an RP-HPLC.
Yield: 9.2 g (84.9% of theory) of a colorless solid.
Analysis (based on solvent-free substance):
calc .: C 27.72; H 2.70; F 15.78; I 35.15; N 3.88; O 14.77;
Found: C 27.55; H 2.61; F 15.94; I 35.03; N 3.69.

Example 8 N- (6,6,7,7,8,8,9,9,9-nonafluoro-3-oxanonyl) -N ', N' '- bis- (2,3-dihydroxypropyl) -N' '- methyl-2,4,6-triiodotrimesic acid triamide a) N, N'-bis (2,3-dihydroxypropyl) -N'-methyl-2,4,6-triiodotrimesic acid diamide

12.4 g (16.6 mmol) of 5-carbamoyl-2,4,6-triiodoisophthalic acid- [N, N'-bis- (2,3-dihydroxypropyl) -N-methyl] -diamide are dissolved in 66 ml of glacial acetic acid a mixture of. 1.4 g (20.2 mmol) of sodium nitrite in 10 ml of concentrated sulfuric acid were added within 25 minutes. The mixture is then stirred at room temperature for two hours and at 70 ° C. for two hours. After cooling to room temperature, the solution is stirred into 166 ml of water. After stirring overnight, the precipitate is filtered off, washed with a little water and dried at 50 ° C in a vacuum. The partially acetylated product is suspended in 25 ml of water and saponified on the steam bath within 30 minutes with the addition of concentrated sodium hydroxide solution at pH 10-11. The warm solution is acidified with concentrated hydrochloric acid, the precipitate is filtered off overnight with stirring, washed with water and dried at 50 ° C. in vacuo.
Yield: 7.3 g (58.8% of theory) of a yellowish solid.
Analysis (based on solvent-free substance):
calc .: C 25.69; H 2.56; I 50.89; N 3.75; O 17.11;
Found: C 25.42; H 2.68; I 50.91; N 3.63.

b) N, N'-bis (2,3-diacetoxypropyl) -N'-methyl-2,4,6-triiodotrimesic acid diamide chloride

7.1 g (9.5 mmol) of N, N'-bis (2,3-dihydroxypropyl) -N'-methyl-2,4,6-triiodotrimesic acid diamide are suspended in 30 ml of dioxane at room temperature, with 5.7 ml (60 mmol) of acetic anhydride and 12 mg (0.1 mmol) of DMAP were added. The mixture is stirred at 80 ° C. for 24 hours, 0.6 g of activated carbon is added to the solution and the mixture is stirred at room temperature for 30 minutes. It is filtered, the filtrate is evaporated to dryness and the residue is stirred with diethyl ether. The precipitate is filtered off, washed with ether and dried in vacuo. The substance can be crystallized from acetonitrile for purification. To prepare the acid chloride, the intermediate is suspended in 50 ml of ethyl acetate and mixed with 1.2 ml (16.4 mmol) of thionyl chloride. The mixture is refluxed overnight, concentrated a little and the precipitate is suctioned off.
Yield: 6.1 g (68.7% of theory) of a yellowish solid.
Analysis (based on solvent-free substance):
calc .: C 30.84; H 2.80; Cl 3.79; I 40.73; N 3.00; O 18.83;
Found: C 30.72; H 2.95; Cl 3.91; I 40.56; N 2.87.

c) N- (6,6,7,7,8,8,9,9,9-nonafluoro-3-oxanonyl) -N ', N' '- bis- (2,3-dihydroxypropyl) -N' ' - methyl-2,4,6-triiodotrimesic acid triamide

5.8 g (6.2 mmol) of N, N'-bis (2,3-diacetoxypropyl) -N'-methyl-2,4,6-triiodotrimesic acid diamide chloride are dissolved in 60 ml of anhydrous dioxane and, with the addition of 2.0 ml of triethylamine, reacted with 2.13 g (6.2 mmol) of 6,6,7,7,8,8,9,9,9-nonafluoro-3-oxanonylamine, hydrochloride. The reaction mixture is stirred for four hours at 75 ° C., the precipitate is then filtered off and the filtrate is evaporated to dryness. The residue is dissolved in methanol and a normal sodium hydroxide solution is added. After complete saponification, the mixture is neutralized with hydrochloric acid, evaporated to dryness and the solid is stirred out several times with ethanol. The combined ethanol extracts are evaporated. The crude product can be chromatographed for purification on an RP-HPLC.
Yield: 5.7 g (88.6% of theory) of a colorless solid.
Analysis (based on solvent-free substance):
calc .: C 27.79; H 2.62; F 16.48; I 36.71; N 4.05; O 12.34;
Found: C 27.61; H 2.49; F 16.27; I 36.52; N 3.80.

Example 9 a) 13,13,13,12,12,11,11,10,10,9,9,8,8,7,7,6,6-heptadecafluoro-3-oxa-tridecanoic acid- t-butyl ester

To a mixture of 10 g (21.55 mmol) of 1H, 1H, 2H, 2H-perfluorodecan-1-ol and 0.73 g (2.15 mmol) of tetrabutylammonium hydrogen sulfate in 100 ml of 60% potassium hydroxide solution / 50 ml of toluene are added dropwise 10.51 g (53.9 mmol) of tert-butyl bromoacetate are added with vigorous stirring at 0.degree. The mixture is stirred at 0 ° C. for 1 hour. 200 ml of toluene are added, the aqueous phase is separated off and extracted twice with 50 ml of toluene each time. The combined organic phases are dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel (eluent: hexane / dichloromethane / acetone = 20/10/1).
Yield: 9.72 g (78% of theory) of a colorless viscous oil.
Elemental analysis:
calc .: C 33.23; H 2.61; F 55.85;
Found: C 33.09; H 2.78; F 55.71.

b) 13,13,13,12,12,11,11,10,10,9,9,8,8,7,7,6,6-heptadecafluoro-3-oxa-tridecanoic 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. It is evaporated to the dry state in a vacuum. The residue is recrystallized from methanol / ether. Yield: 7.80 g (96% of theory) of a colorless solid.
Elemental analysis:
calc .: C 27.60; H 1.35; F 61.85;
Found: C 27.48; H 1.49; F 61.66.

c) 3- [13,13,13,12,12,11,11,10,10,9,9,8,8,7,7,6,6-heptafluoro-3-oxa-tridecanoyl amino] glutaric acid

1.71 g of oxalic acid dichloride are added to 7 g (13.41 mmol) of the title compound from Example 9b, dissolved in 35 ml of dichloromethane, and the mixture is stirred at 0 ° C. for 3 hours and then at room temperature for 2 hours. The solution thus prepared is added dropwise at 0 ° C. to a suspension consisting of 1.97 g of 12.07 mmol) of 3-aminoglutaric acid and 6.78 g (67 mol) of triethylamine in 40 ml of tetrahydrofuran. The mixture is stirred at 0 ° C. for one hour, then at room temperature for 2 hours. It is evaporated to the dry state in a vacuum and the residue is taken up in 150 ml of dichloromethane and 150 ml of 5% strength aqu. Hydrochloric acid. The organic phase is separated off and dried over magnesium sulfate, then evaporated to dryness in vacuo. The residue is recrystallized from diethyl ether.
Yield: 6.84 g (87% of theory) of a colorless solid.
Elemental analysis:
calc .: C 31.35; H 2.17; N 2.15; F 49.59;
Found: C 31.09; H 2.41; N 2.02; F 49.30.

d) 5-methylamino-2,4,6-triiodoisphthalic acid- {N, N'-di (5-hydroxy-2,2-dimethyl-1,3- dioxepan-6-yl)} diamide

To 36.1 g (60.4 mmol) of the title compound from Example 13a in 150 ml of tetrahydrofuran are added 42.7 g (265 mmol) of 5-amino-6-hydroxy-2,2-dimethyl-1,3-dioxepane and stir for 2 days at room temperature. The resulting precipitate is filtered off, the filtrate is evaporated to dryness in vacuo and the remaining solid is recrystallized from 100 ml of ethyl acetate. 42.36 g of crystalline material are obtained. The crystals are suspended in 120 ml of water and stirred for 2 hours. The crystals are filtered off, washed with a little water and dried at 50 ° C. in vacuo.
Yield: 31.14 g (60% of theory) of crystalline solid.
Elemental analysis:
calc .: C 32.15; H 3.75; N 4.89; I 44.31;
Found: C 32.01; H 3.98; N 4.72; I 44.18.

e) Dimeric diamide of 3- [13,13,13,12,12,11,11,10,10,9,9,8,8,7,7,6,6-heptafluoro-3- oxa-tridecanoylamino] -glutaric acid with 5-methylamino-2,4,6-triiodoisophthalic acid- {N, N'-di (5-hydroxy-2,2-dimethyl-1,3-dioxepan-6-yl)} diamide

6.0 g (9.21 mmol) of the title compound from Example 9c are dissolved in 200 ml of 1,2-dichloromethane and 3.84 g (18.42 mmol) of phosphorus pentachloride are added. The mixture is stirred at 50 ° C. for 2 hours. Then 31.65 g (36.84 mmol) of the title compound from Example 9d are heated at reflux for 2 days. It is cooled to room temperature and 300 ml of 5% aqu. Sodium carbonate solution. The organic phase is separated off and dried over magnesium sulfate. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / acetone = 20/1).
Yield: 5.80 g (27% of theory) of a colorless solid.
Elemental analysis:
calc .: C 32.42; H 3.20; N 4.20; F 13.84; I 32.62;
Found: C 32.17; H 3.39; N 4.01; F 13.70; I 32.47.

f) Dimeric diamide from 3- [13,13,13,12,12,11,11,10,10,9,9,8,8,7,7,6,6-heptafluoro-3- oxa-tridecanoylamino] -glutaric acid with 5-methylamino-2,4,6-triiodoisophthalic acid- {N, N'-di (1-hydroxymethyl-2,3-dihydroxypropyl)} diamide

5.0 g (2.14 mmol) of the title compound from Example 9e are dissolved in a mixture of 30 ml of dioxane / 40 ml of water and 5 ml of 25% aqu. Hydrochloric acid. The mixture is stirred at 60 ° C. for 12 hours. the solution is evaporated to dryness in vacuo. The residue is dissolved in water and placed on an ion exchange column filled with anion exchanger IRA 67 (OH⁻ form). You elute with water. The product-containing fractions are evaporated to dryness in vacuo. It is dissolved in 100 ml of water and 10 ml of cation exchanger IR 120 (H⁺ form), 110 ml of anion exchanger IRA 67 (OH⁻ form) are added and the mixture is stirred for one hour. The exchanger is filtered off. The filtrate is freeze-dried.
Yield: 4.50 g (90% of theory) of an amorphous solid.
Water content: 6.8%.
Elemental analysis (calculated on anhydrous substance):
calc .: C 28.18; H 2.69; N 4.51; F 14.86; I 35.03;
Found: C 27.95; H 2.81; N 4.38; F 14.61; I 34.85.

Example 10 a) 11,11,11,10,10,9,9,8,8,7,7,6,6-tridecafluoro-3-oxaundecanoic acid t-butyl ester

To a mixture of 10 g (27.46 mmol) of 1H, 1H, 2H, 2H-perfluorooctan-1-ol and 0.73 g (2.15 mmol) of tetrabutylammonium hydrogen sulfate in 100 ml of 60% potassium hydroxide solution / 50 ml of toluene are added dropwise 10.51 g (53.9 mmol) of tert-butyl bromoacetate are added with vigorous stirring at 0.degree. The mixture is stirred at 0 ° C. for 1 hour. 200 ml of toluene are added, the aqueous phase is separated off and extracted twice with 50 ml of toluene each time. The combined organic phases are dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel (eluent: hexane / dichloromethane / acetone = 20/10/1).
Yield: 10.38 g (79% of theory) of a colorless viscous oil.
Elemental analysis:
calc .: C 35.16; H 3.16; F 51.64;
Found: C 35.28; H 3.31; F 51.52.

b) 11,11,11,10,10,9,9,8,8,7,7,6,6-tridecafluoro-3-oxa-undecanoic acid

9.0 g (18.82 mmol) of the title compound from Example 10a) are dissolved in 180 ml of trifluoroacetic acid and stirred overnight at room temperature. It is evaporated to the dry state in a vacuum. The residue is recrystallized from methanol / ether. Yield: 7.63 g (96% of theory) of a colorless solid.
Elemental analysis:
calc .: C 28.45; H 1.67; F 58.51;
Found: C 28.38; H 1.75; F 58.37.

c) 11,11,11,10,10,9,9,8,8,7,7,6,6-tridecafluoro-3-oxa-undecanoylamino) -2,4,6-triiod isophthalic acid- {N-methyl-N- [2,3-bis (hydroxyacetyl) propyl) -N '- [2,3-bis (hydroxy acetyl]} - diamide

4.22 g (10 mmol) of 11,11,11,10,10,9,9,8,8,7,7,6,6-tridecafluoro-3-oxaundecanoic acid are dissolved in 50 ml of 1,2-dichloroethane and 1.269 g (10 mmol) of oxalyl chloride were added. The mixture is stirred for 5 hours at room temperature. Then 3.613 g (4 mmol) of 5-amino-2,4,6-triiodoisophthalic acid- {N-methyl-N- [2,3-bis (hydroxyacetyl) propyl] -N '- [2, 3-bis (hydroxyacetyl) propyl} diamide and refluxing with exclusion of moisture for 2 days, then concentrated to dryness in vacuo, taken up in dichloromethane and the product purified by column chromatography on silica gel. A mixture of dichloromethane / Acetone 20: 1. The title compound is obtained as a waxy solid.
Yield: 3.894 g (82% of theory).
Elemental analysis:
calc .: C 23.27; H 2.80; F 20.80; I 32.07; N 3.54;
Found: C 23.38; H 2.90; F 20.71; I 32.19; N 3.61.

d) 5- (11,11,11,10,10,9,9,8,8,7,7,6,6-tridecafluoro-3-oxa-undecanoylamino) -2,4,6- triiodoisophthalic acid- [N-methyl-N- [2,3-dihydroxy) propyl-N '- (2,3-dihydroxy) - propyl] diamide

3.562 g (3 mmol) of the amide produced under 10c are dissolved in 100 ml of methanol. 25 ml of 30% ammonia solution are added and the mixture is heated in an autoclave at 60 ° C. for 2 hours. After cooling, the mixture is evaporated to dryness and purified by column chromatography on silica gel RP-18. A gradient of water, tetrahydrofuran and acetonitrile is used as the eluent. The title compound is obtained as a waxy solid.
Yield: 3.156 g (79% of theory).
Elemental analysis:
calc .: C 15.69; H 2.53; F 24.82; I 38.26; N 4.22;
Found: C 15.56; H 2.60; F 25.91; I 38.13; N 4.29.

Example 11 5- (6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,13-heptadecafluoro-3- oxatridecanoylamino) -N, N'-bis- (2,3-dihydroxy-1-hydroxymethylpropyl) -2,4,6- triiodisophthalic acid diamide a) 5- (6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,13-heptadecafluoro-3- oxatridecanoylamino) -2,4,6-triiodoisophthalic acid dichloride

10.4 g (20 mmol) of 6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,13-heptadecafluoro-3-oxatridecanoic acid are in 20 ml of N, N-dimethylacetamide are introduced and 1.46 ml (20 mmol) of thionyl chloride are added dropwise at 0 ° C. The mixture is then stirred at 10 ° C for one hour. At this temperature, 11.9 g (20 mmol) of 5-amino-2,4,6-triiodisophthalic acid dichloride (DE 29 26 428 A1) are added in portions and the mixture is stirred for 12 hours at room temperature. The batch is poured into ice water and the precipitate is suctioned off. The solid is taken up in ethyl acetate, washed with saturated sodium bicarbonate solution and water. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. For cleaning, the product is stirred with hexane.
Yield: 18.3 g (83.3% of theory) of a colorless solid.
Analysis (based on solvent-free substance):
calc .: C 21.84; H 0.64; Cl 6.45; F 29.36; I 34.61; N 1.27; O 5.82;
Found: C 21.71; H 0.90; Cl 6.54; F 29.19; I 34.43; N 1.15.

b) 5- (6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,13-heptadecafluoro-3- oxatridecanoylamino) -N, N'-bis- (6-hydroxy-2,2-dimethyl-1,3-dioxepan-5- ylcarbamoyl) -2,4,6-triiodoisophthalic acid diamide

17.6 g (16 mmol) 5- (6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,13-heptadecafluoro-3-oxatridecanoylamino ) -2,4,6-triiodoisophthalic acid dichloride are dissolved in 70 ml of tetrahydrofuran and added in portions with 12.9 g (80 mmol) of 6-amino-2,2-dimethyl-1,3-dioxepan-5-ol (EP 0033426 A2) transferred. The reaction mixture is stirred overnight at room temperature. It is filtered, the filtrate is concentrated a little and the product is precipitated by adding 350 ml of tert-butyl methyl ether. The precipitate is filtered off, washed with tert-butyl methyl ether and dried.
Yield: 18.9 g (87.5% of theory) of a pale yellow solid.
Analysis (based on solvent-free substance):
calc .: C 30.26; H 2.61; F 23.93; I 28.22; N 3.11; O 11.86;
Found: C 30.05; H 2.66; F 23.78; I 28.21; N 3.02.

c) 5- (6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,13-heptadecafluoro-3 oxatridecanoylamino) -N, N'-bis- (2,3-dihydroxy-1-hydroxymethylpropyl) -2,4,6- triiodisophthalic acid diamide

18.5 g (13.7 mmol) 5- (6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,13-heptadecafluoro-3 - oxatridecanoylamino) -N, N'-bis- (6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-ylcarbamoyl) - 2,4,6-triiodisophthalic acid diamide are suspended in 450 ml of water and mixed with 4 ml concentrated sulfuric acid. The mixture is stirred for nine hours at room temperature and the yellowish solution is neutralized with concentrated sodium hydroxide solution. The aqueous product solution is stirred with 5 g of activated carbon at 50 ° C for two hours. After filtering, the solution is desalted with anion and cation exchangers. The aqueous eluate is concentrated and freeze-dried.
Yield: 12.1 g (69.6% of theory) of colorless lyophilisate.
Analysis (based on solvent-free substance):
calc .: C 26.50; H 2.14; F 25.45; I 30.00; N 3.31; O 12.61;
Found: C 26.32; H 2.30; F 25.36; I 29.84; N 3.19.

Example 12 5- [N-ethyl-N- (perfluorooctylsulfonyl) aminoacetylamino] -N, N'-bis- (2,3-dihydroxy-1- hydroxymethylpropyl) -2,4,6-triiodoisophthalic acid diamide

Using N-ethyl-N- (perfluorooctylsulfonyl) aminoacetic acid, the title compound is prepared in analogy to Example 11 as a colorless lyophilisate in 53.4% yield (starting from 5-amino-2,4,6-triiodisophthalic acid dichloride).
Analysis (based on solvent-free substance):
calc .: C 25.24; H 2.12; F 24.24; I 28.58; N 4.20; S 2.41; O 13.21;
Found: C 25.03; H 2.16; F 24.14; I 28.29; N 4.08; S 2.28.

Example 13 5- [N-Methyl- (6,6,7,7,8,8,9,9,9-nonafluoro-3-oxanonanoyl) amino] -N ', N' '- (2,3- dihydroxypropyl) -2,4,6-triiodoisophthalic acid diamide a) 5- [N-Methyl- (6,6,7,7,8,8,9,9,9-nonafluoro-3-oxanonanoyl) amino] -2,4,6- triiodisophthalic acid dichloride

3.2 g (10 mmol) of 6,6,7,7,8,8,9,9,9-nonafluoro-3-oxanonanoic acid are placed in 12 ml of N, N-dimethylacetamide and at 0-5 ° C with 0 , 75 ml (11 mmol) of thionyl chloride are added dropwise. The mixture is then stirred at 5 ° C for two hours. At this temperature, 6.1 g (10 mmol) of 5-methylamino-2,4,6-triiodisophthalic acid dichloride are added in portions and the mixture is stirred for 15 hours at room temperature. The batch is poured into ice water and the precipitate is suctioned off. The solid is taken up in ethyl acetate, washed with saturated sodium bicarbonate solution and water. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. For cleaning, the product is stirred with hexane.
Yield: 6.4 g (70% of theory) of a yellow solid.
Analysis (based on solvent-free substance):
calc .: C 22.34; H 0.99; Cl 7.76; F 18.71; I 41.66; N 1.53; O 7.00;
Found: C 22.50; H 0.84; Cl 7.62; F 18.67; I 41.42; N 1.38.

b) 5- [N-Methyl- (6,6,7,7,8,8,9,9,9-nonafluoro-3-oxanonanoyl) amino] -N ', N' '- (2,3- dihydroxypropyl) -2,4,6-triiodoisophthalic acid diamide

6.2 g (6.8 mmol) 5- [N-methyl- (6,6,7,7,8,8,9,9,9-nonafluoro-3-oxanonanoyl) amino] - 2,4, 6-triiodoisophthalic acid dichloride are dissolved in 45 ml of dioxane and 3.1 g (34 mmol) of amino-2,3-propanediol are added in portions. The reaction mixture is stirred overnight at room temperature. The hydrochloride is filtered off, washed with dioxane, the filtrate is concentrated a little and the product is precipitated by adding 120 ml of tert-butyl methyl ether. The precipitate is filtered off, washed with tert-butyl methyl ether and dried. For purification, the product can be chromatographed on an HPLC (eluent: water / methanol).
Yield: 6.0 g (86.2% of theory) of colorless lyophilisate.
Analysis (based on solvent-free substance):
calc .: C 27.00; H 2.46; F 16.71; I 37.21; N 4.11; O 12.51;
Found: C 26.87; H 2.53; F 16.60; I 37.04; N 4.26.

Example 14 1,5-bis- [3-N- (2,3-dihydroxypropyl) hydroxyacetylamino-5- (2,3-dihydroxypropyl) - aminocarbonyl-2,4,6-triiodobenzoylamino] -N '- (perfluorooctylsulfonyl) -3-azapentane a) Perfluorooctylsulfonyl chloride

10 g (20 mmol) of perfluorooctanesulfonic acid are mixed with 20 g of phosphorus pentachloride mixed and heated to 120 ° C for 30 minutes. After cooling, 200 ml are added Toluene, filtered and the filtrate evaporated to dryness. That as a backlog remaining crude sulfonyl chloride is suitable for conversion into the sulfonamide.

b) N '- (Perfluorooctylsulfonyl) -1,5-bis- (trifluoroacetamido) -3-azapentane

9.85 g (19 mmol) of crude sulfonyl chloride are dissolved in 50 ml of methylene chloride, with 2.65 ml of triethylamine, 100 mg of DMAP and with 5.6 g of 1,5-bis (trifluoroacetamido) -3-azapentane (US 5514810) transferred. The reaction mixture is stirred for 20 hours at room temperature and the hydrochloride is filtered off. A further 100 ml of methylene chloride is added to the filtrate and washed with water. The organic phase is dried over sodium sulfate and evaporated. The crude product is chromatographed on a silica gel column (eluent: methylene chloride / methanol).
Yield: 10.7 g (72.5% of theory) of a colorless solid.
Analysis (based on solvent-free substance):
calc .: C 24.72; H 1.30; F 56.22; N 5.41; S 4.13; O 8.23;
Found: C 24.59; H 1.47; F 56.14; N 5.46; S 3.98.

c) N '- (Perfluorooctylsulfonyl) -3-azapentane-1,5-diamine

10.5 (13.5 mmol) N '- (perfluorooctylsulfonyl) -1,5-bis- (trifluoroacetamido) -3-azapentane are dissolved in 70 ml ethanol and with 1.08 g (27 mmol) sodium hydroxide in 12 ml water transferred. The mixture is stirred at 45 ° C. for three hours, concentrated to dryness in vacuo and the residue is taken up in methylene chloride. The precipitated salt is filtered off and the filtrate is evaporated.
Yield: 7.1 g (89.9% of theory) of a pale yellow solid.
Analysis (based on solvent-free substance):
calc .: C 24.63; H 2.07; F 55.18; N 7.18; S 5.48; O 5.47;
Found: C 24.74; H 1.80; F 55.28; N 6.97; S 5.29.

d) 3- (N-2,3-dihydroxypropyl) acetoxyacetylamino-2,4,6-triiodoisophthalic acid- [N'- (2,3-diacetoxypropyl)] amide chloride

13.3 g (16 mmol) of 5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid- [N- (2,3-diacetoxypropyl)] amide chloride (DE 39 37 118 A1) are dissolved in 100 ml of anhydrous dioxane, with 2 , 21 g (16 mmol) of potassium carbonate and 1.77 g (16 mmol) of 1-chloropropanediol were added. The mixture is stirred overnight at 50 ° C. and the amount of potassium carbonate and chlorine compound given above is added again. After a further four hours at 50 ° C., the reaction mixture is filtered and evaporated. The residue is dried in a high vacuum. The amorphous solid is stirred with 400 ml of hexane / tert-butyl methyl ether, the precipitate is filtered off with suction after 12 hours and dried in vacuo. The product can be chromatographed on silica gel for cleaning (eluent: ethyl acetate / acetone).
Yield: 13.1 g (90.1% of theory) of a colorless solid.
Analysis (based on solvent-free substance):
calc .: C 29.08; H 2.66; Cl 3.90; I 41.90; N 3.08; O 19.37;
Found: C 28.88; H 2.74; Cl 3.74; I 41.73; N 2.97.

e) 1,5-bis- [5-N- (2,3-dihydroxypropyl) acetoxyacetylamino-3- (2,3-diacetoxypropyl) - aminocarbonyl-2,4,6-triiodobenzoylamino] -N '- (perfluorooctylsulfonyl) -3-azapentane

10.9 g (12 mmol) of 3- (N-2,3-dihydroxypropyl) acetoxyacetylamino-2,4,6-triiodisophthalic acid (N'-2,3-diacetoxypropyl) amide chloride are dissolved in 20 ml of N, N- Dimethylformamide and 1.7 ml of triethylamine dissolved. At room temperature, 3.51 g (6 mmol) of N '- (perfluorooctylsulfonyl) -3-azapentane-1,5-diamine are added and the reaction mixture is stirred overnight. The mixture is then concentrated a little and the product is precipitated with water. The precipitate is filtered off, washed with water and dried at 50 ° C in a vacuum.
Yield: 12.0 g (85.8% of theory) of a yellowish solid.
Analysis (based on solvent-free substance):
calc .: C 28.87; H 2.51; F 13.86; I 32.69; N 4.21; S 1.38; O 16.48;
Found: C 28.93; H 2.69; F 13.67; I 32.51; N 4.30; S 1.22.

f) 1,5-bis- [3-N- (2,3-dihydroxypropyl) hydroxyacetylamino-5- (2,3-dihydroxypropyl) - aminocarbonyl-2,4,6-triiodobenzoylamino] -N '- (perfluorooctylsulfonyl) -3-azapentane

11.6 g (5 mmol) of 1,5-bis [5-N- (2,3-dihydroxypropyl) acetoxyacetylamino-3- (2,3-diacetoxypropyl) aminocarbonyl-2,4,6-triiodobenzoylamino] -N '- (Perfluorooctylsulfonyl) - 3-azapentane are mixed with 45 ml of 3N sodium hydroxide solution and stirred at 40 ° C for five hours. After cooling, the mixture is neutralized with concentrated hydrochloric acid, 1.2 g of activated carbon are added to the solution and the mixture is stirred at room temperature for two hours. The suspension is filtered and desalted over ion exchangers. The product can be purified by preparative HPLC.
Yield: 9.3 g (89.5% of theory) of colorless lyophilisate.
Analysis (based on solvent-free substance):
calc .: C 25.44; H 2.23; F 15.55; I 36.65; N 4.72; S 1.54; O 13.86;
Found: C 25.28; H 2.11; F 15.64; I 36.77; N 4.46; S 1.38.

Example 15 a) 5-Amino-N ¹ , N ³ -bis (1,3-diacetoxypropan-2-amino) -2,4,6-triiodo-1,3-benzenedi carboxamide

To a mixture of 10.39 g (14.74 mmol) 5-amino-N ¹ , N ³ -bis (1,3-dihydroxypro pan-2-amino) -2,4,6-triiodo-1,3-benzenedicarboxamide and 18 mg (0.15 mmol) 4-dimethylaminopyridine in 30 ml dimethylacetamide are added in portions at 0 ° C 8.99 g (88.06 mmol) acetic anhydride. The mixture is stirred overnight at room temperature, 10 ml of methanol are added and the mixture is stirred for one hour at room temperature. The mixture is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 9/1).
Yield: 10.81 g (84% of theory) of a pale yellow, glassy solid.
Elemental analysis:
calc .: C 30.26; H 3.00; N 4.81; I 34.60;
found: C 30.04; H 3.02; N 4.60; I 34.74.

b) N ¹ , N ³ bis (1,3-diacetoxypropan-2-amino) -5- (9,9,9,8,8,7,7-nonafluoro-3-oxa nonanoylamino) -2,4, 6-triiodo-1,3-benzenedicarboxamide

23.0 g (71.40 mmol) of the title compound from Example 1b) and oxalyl chloride (74.00 mmol, 9.39 g) in 100 ml of 1,2-dichloroethane are stirred at 60 ° C. for 2 h. Then 20.69 g (23.70 mmol) of the title compound from Example 15a) are added and the mixture is heated to boiling for 20 h. The mixture is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 9/1).
Yield: 24.27 g (87% of theory) of a pale yellow, glassy solid.
Elemental analysis:
calc .: C 30.60; H 2.65; N 3.60; I 32.33; F 14.52;
Found: C 30.40; H 2.57; N 3.67; I 32.40; F 14.69.

c) N ¹ , N ³ -Bis (1,3-diacetoxypropan-2-amino) -5- [N- (9,9,9,8,8,7,7-nonafluoro-3-oxa nonanoyl) -N - (2,3-dihydroxypropyl) amino] -2,4,6-triiodo-1,3-benzenedicarboxamide

To 19.77 g (16.79 mmol) of the title compound from Example 15b) in 200 ml of dimethylformamide, 0.48 g (20.15 mmol) of sodium hydride is added in portions at 0 ° C. with stirring. After the evolution of hydrogen has ended, 2.23 g (20.15 mmol) of 3-chloro-1,2-propanediol are added dropwise and the mixture is stirred at 80 ° C. for 10 hours. 10 ml of 1 N acetic acid are added and the mixture is evaporated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol = 4/1).
Yield: 17.02 g (81% of theory) of a pale yellow, glassy solid.
Elemental analysis:
calc .: C 31.67; H 2.98; N 3.36; I 30.42; F 13.66;
Found: C 31.83; H 3.03; N 3.19; I 30.35; F 13.60.

d) N ¹ , N ³ bis (1,3-dihydroxypropan-2-amino) -5- [N- (9,9,9,8,8,7,7-nonafluoro-3-oxa nonanoyl) -N - (2,3-dihydroxypropyl) amino] -2,4,6-triiodo-1,3-benzenedicarboxamide

40 ml of 2N sodium hydroxide solution are added to 9.89 g (7.90 mmol) of the title compound from Example 15c) in 100 ml of methanol and the mixture is stirred overnight at room temperature. 60 ml of water are added and the conductivity minimum is set by adding ion exchanger IRA 67 (OH⁻ form) and IRC 50 (H⁺ form). The ion exchanger is filtered off and washed twice with methanol. The combined filtrates are concentrated and freeze-dried.
Yield: 8.39 g (98% of theory) of a colorless amorphous solid.
Elemental analysis:
calc .: C 27.72; H 2.70; N 3.88; I 35.14; F 15.78;
Found: C 27.53; H 2.61; N 3.90; I 34.90; F 15.50.

Example 16 a) 5- (5,5,5,4,4,3,3,2,2-nonafluoropentanoylamino) -2,4,6-triiodoisophthalic acid- {N- methyl- [2,3-bis (hydroxyacetyl) propyl] -N '- [2,3-bis (hydroxyacetyl) propyl]} diamide

20 g (22.1 mmol) 5-amino-2,4,6-triiodoisophthalic acid- {N-methyl-N- [2,3-bis (hydroxyacetyl) propyl] -N '- [2,3 bis (hydroxjacetyl) propyl]} - diamide and 15.57 g (55.2 mmol) of perfluoropentanoic acid chloride are dissolved in 200 ml of 1,2-dichloroethane and heated under reflux for 2 days. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent = dichloromethane / acetone 20: 1).
Yield: 17.29 (68% of theory) of a solid foam.
Elemental analysis:
calc .: C 29.23; H 3.86; N 3.65; F 14.86; I 33.09;
Found: C 29.05; H 3.97; N 3.52; F 14.67; I 32.88.

b) 5- (5,5,5,4,4,3,3,2,2-nonafluoropentanoylamino) -2,4,6-triiodoisophthalic acid - {[N- methyl-N- [2,3-dihydroxy) propyl-N '- (2,3-dihydroxy) propyl]} - diamide

15.0 g (13.04 mmol) of the title compound from Example 16a are dissolved in 200 ml of methanol and 80 ml of 25% aqu. Ammonia solution added. The mixture is heated in an autoclave at 60 ° C. for 12 hours. It is evaporated to dryness and the residue is chromatographed on RP-18 (eluent = gradient from water / tetrahydrofurnn / acetonitrile).
Yield: 13.06 g (91% of theory) of a colorless solid.
Water content: 6.2%.
Elemental analysis:
calc .: C 23.27; H 3.71; N 4.07; F 16.56; I 36.88;
Found: C 23.10; H 3.89; N 3.95; F 16.47; I 36.68.

Claims (22)

1. Compounds of the general formula (I)
R ^F -L ¹ - (L ² -A) ^l (I)
in which mean:
R ^{F is} a perfluorinated straight or branched carbon chain, with the formula
-C _n F _2n G
in the
G for a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and
n stands for the numbers 4-30,
L ^{1 is} a direct bond, a straight-chain, branched, saturated or unsaturated C ₁ -C ₃₀ carbon chain, which is optionally interrupted by 1-10 oxygen atoms, 1-3 sulfur atoms, 1-5 SO ₂ groups, 1-5 NHCSNH- Groups, 1-5 NR ¹ groups, where
R ^{1 is} hydrogen or C ₁ -C _{20 is} an alkyl radical which is optionally interrupted by 1-6 oxygen atoms, 1-5 -CO groups, 1-5 -CS groups, 1-6 -NH groups and / or optionally is substituted with 1-6 hydroxy groups, 1-3 - (CH ₂ ) _p -CO ₂ H groups,
where p stands for the numbers from 0-10,
1-3 phenylene groups, 1-3 phenyleneoxy groups, which are optionally substituted with 1-6 hydroxy groups or 1-6 C ₁ -C ₂₀ alkoxy groups, 1-3 piperazine groups, 1-3 phenyl groups, which are optionally substituted with 1-5 NR ¹ R ² groups, where
R ² independently of R ^{1 has} the meaning of R ¹ , 1-3 (CH ₂ ) _p -CO ₂ H groups, 1-5 R ^F groups, 1-5 -C = O groups, 1-5 - C = S groups, 1-5 C ₁ - C ₂₀ alkyl groups, 1-3 groups [(CH ₂ ) _m O] _p -R ¹ , where m stands for the numbers 2-3 and p and R ¹ the above Have meaning
L ^{2 is} a direct bond, -CO-, -SO ₂ -,
I the numbers 1 or 2
A a triiodoaromatic of the general formula II
being independent of each other
R ^{3 has} the same meaning as R ¹ or R ^{F represents} -L ¹ -L ²
the bond to L ² means
X represents OH, -O⁻Na⁺, -O⁻ meglumin⁺ or NR ⁴ R ⁵ ,
Y represents OH, -O⁻Na⁺, -O⁻ meglumin⁺ or NR ⁶ R ⁷ ,
in which
R ⁴ , R ⁵ , R ⁶ , R ^{7 can be} identical or different from one another and R ³ , - (CH ₂ ) _p COOH, where p stands for the numbers from 0-10, hydrogen, a straight-chain or branched C ₁ -C ₂₀ - represent alkyl group, where the alkyl group can be interrupted by 1-6 oxygen atoms and / or can be substituted by 1-6 hydroxy groups or the radicals R ⁴ and R ⁵ and R ⁶ and R ⁷ with, the nitrogen atom to which they are attached, form a heterocyclic ring which may optionally be substituted with 1-3 hydroxy groups or
A a triiodoaromatic of the general formula III
being independent of each other
R ^{3 has} the same meaning as R ¹ or R ^F -L ¹ -L ² ,
the bond to L ² means
R ⁸ , R ^{9 can be} identical or different from one another and R ³ , - (CH ₂ ) _p COOH,
where p stands for the numbers from 0-10, represent hydrogen, a straight-chain or branched C ₁ -C ₂₀ alkyl group, where the alkyl group can be interrupted by 1-6 oxygen atoms and / or substituted by 1-6 hydroxy groups
or
A is a triiodoaromatic of the general formula IV
being independent of each other
R ^{3 has} the same meaning as R ¹ or R ^F -L ¹ represents
the bond to L ² means
X represents OH, -O⁻Na⁺, -O⁻ meglumin⁺ or NR ⁴ R ⁵ ,
R ⁴ , R ⁵ , R ⁶ , R ^{7 have} the meaning given above or
A a triiodoaromatic of the general formula V
being independent of each other
R ^{3 has} the same meaning as R ¹ or R ^F -L ¹ represents
the bond to L ² means
X represents OH, -O⁻Na⁺, -O⁻ meglumin⁺ or NR ⁴ R ⁵ ,
R ⁴ , R ⁵ , R ⁸ , R ^{9 have} the meaning given above. 2. Compounds according to claim 1, characterized in that G in the formula -C _n F _2n G represents a fluorine atom. 3. Compounds according to claim 1 or 2, characterized in that n in the formula -C _n F _2n G represents the numbers 4-15. 4. Compounds according to any one of claims 1 to 3, characterized in that L ^{1 is} a direct bond or a straight-chain C ₁ -C ₁₅ alkyl radical, preferably a C ₁ -C ₁₀ alkyl radical, which, as indicated in claim 1, optionally can be interrupted or substituted. 5. Compounds according to claim 4, characterized in that the alkyl radical is interrupted by 1-4 oxygen atoms, 1-2 sulfur atoms, 1-3 SO ₂ groups and / or 1-3 NR ¹ groups. 6. Compounds according to one of claims 1 to 5, characterized, that A is a triiodoaromatic of the general formula II. 7. Compounds according to any one of claims 1 to 6, characterized in that R ^{1 is} hydrogen or a C ₁ -C ₁₀ alkyl radical which may optionally be interrupted or substituted as indicated in claim 1. 8. Compounds according to any one of claims 1 to 7, characterized in that R ^{3 is} hydrogen or a C ₁ -C ₁₀ alkyl radical which is optionally interrupted by 1-3 oxygen atoms and / or 1-2 CO or SO ₂ - Groups and / or is substituted by 1-3 hydroxy groups. 9. Compounds according to any one of claims 1 to 7, characterized in that R ³ R ^F -L ¹ -L ² -means, preferably C ₄ F ₉ CO-, C ₈ F ₁₇ SO ₂ - or C _n F _{2n + 1} CH ₂ CH ₂ -, where n is 4 to 15. 10. Compounds according to any one of claims 1 to 9, characterized in that R ⁴ -R ⁹ independently of one another represent hydrogen or C ₁ -C ₁₀ alkyl, the alkyl group being interrupted by 1-6 oxygen atoms and / or by 1-6 hydroxy groups is substituted. 11. A process for the preparation of compounds of general formula I with A in the meaning of general formula II, characterized in that compounds of general formula 10
where R ³ , X and Y have the meaning given above,
with compounds of general formula 11
wherein R ^F and L ¹ the above. Have meaning and Nu means a nucleofug,
reacted in an organic solvent or solvent mixture. 12. The method according to claim 11, characterized, that the reaction in the organic solvent or solution medium mixture with the addition of bases. 13. A process for the preparation of compounds of general formula I with A in the meaning of general formula III, characterized in that compounds of general formula 15
where Hal is chlorine and R ⁸ , R ^{9 are} as defined above,
with compounds of the general formula 18
HR ³ NL ¹ -R ^F (18)
where R ^F , L ¹ and R ^{3 have} the meaning given above, implemented in a manner known per se. 14. A process for the preparation of compounds of general formula I with A in the meaning of general formula IV, characterized in that compounds of general formula 16th
wherein Hal, X, R ⁶ and R ^{7 have} the abovementioned meaning, with compounds of the general formula 18
HR ³ NL ¹ -R ^F (18)
where R ^F , L ¹ and R ^{3 have} the meaning given above, implemented in a manner known per se. 15. A process for the preparation of compounds of general formula I with A in the meaning of general formula V, characterized in that compounds of general formula 17th
where Hal, X, R ⁸ and R ^{9 have} the abovementioned meaning,
with compound of the general formula 18
HR ³ NL ¹ -R ^F (18)
where R ^F , L ¹ and R ^{3 have} the meaning given above, implemented in a manner known per se. 16. The method according to any one of claims 11 to 15, characterized, that existing protective groups are split off after the implementation. 17. Use of at least one physiologically compatible compound according to claims 1 to 10 as a contrast agent in X-ray diagnostics. 18. Use of at least one physiologically compatible compound according to claims 1 to 10 as a contrast agent for ¹⁹ F-NMR diagnostics or spectroscopy. 19. Use according to one of claims 17 and 18 for the combined x-ray and NMR diagnostics. 20. Use according to one of claims 17, 18 or 19 for illustration the intravascular space, the liver, the bile duct, the Gastrointestinal tract or the lymphatic system. 21. Use of at least one physiologically compatible compound according to claims 1 to 10 as a contrast agent in ultrasound Diagnosis. 22. Use according to one of claims 17 to 20 of at least one physiologically compatible compound according to claims 1 to 10 together with contrast agents based on heavy metal chelates.