DE19521945A1 - Cascade polymers with iodoaromatics - Google Patents

Abstract

Iodine-containing dendritic polymers are useful as radiological diagnostic agents.

Description

The invention relates to those characterized in the claims Objects, that is new iodine-containing dendrimeric polymers, these ver compounds containing bonds, the use of the polymeric compounds as Contrast agents and methods for producing these compounds and agents.

X-ray contrast media are indispensable tools for diagnosis numerous diseases such as B. arteriosclerotic vascular processes, Tumors, infarcts, diseases of the kidneys and urinary tract and Perfusion disorders, e.g. B. on the heart (ischemia, and inflammation).

The requirements to be placed on such contrast media relate to everything:

• a) a sufficiently high iodine concentration
  the solution used. As long as the agent is not diluted, the X-ray density of a contrast agent depends on it as the only parameter. This is particularly the case in angiography when the contrast agent is injected into blood vessels at high speed via catheters and thus displaces the blood.

A number of other studies are highly concentrated Contrast agents also desirable, e.g. B. when thinning in the body otherwise it becomes too strong (injection into the heart chambers, the aorta or at the Intravenous digital subtraction angiography) or in the case of unfavorable Recording conditions (so the beam path through the body of a heavy patients become very long);

• b) chemotoxicity,
  an inherent property of the contrast medium solutions, which is linked among other things to the lipophilicity of the molecules, their protein affinity and electron density. In clinical application, it manifests itself in the occurrence of side effects such as nausea, vomiting, certain circulatory reactions, urticaria, bronchospasm and other symptoms up to shock and death. Chemotoxic effects are pharmacologically z. B. measurable as LD₅₀ after intravenous injection;
• c) the viscosity,
  a size that is important for the process of applying the contrast agents, e.g. B. if larger volumes (30-100 ml) of highly concentrated and therefore more viscous solutions should be injected quickly. In addition to the poor injectability, higher-viscosity contrast media also have the disadvantage of poor miscibility with blood (streak formation instead of homogeneous filling of the cardiac cavity or blood vessels) and the obstruction of the passage by capillaries, e.g. B. the lungs;
• d) osmolality
  of contrast media solutions. In the case of the application of solutions that are very hypertonic to the blood and tissue (the physiological value is 310 m osm / kg), water is driven out of the cells, which, among other things, destroys cell membranes and disturbs the overall electrolyte balance. As a result, a large number of sometimes serious side effects, such as. B. drop in blood pressure, bradycardia to cardiac arrest, disorders of the blood-brain barrier, vascular pain, etc. caused;
• e) solubility,
  which must be sufficiently high for the practical use of the contrast media at physiological pH values in water, without, however, at the same time impairing the tolerance and iodine content of the molecule too much;
• f) chemical stability
  the contrast agent solutions, which allow heat sterilization and a shelf life of at least 24 months.

X-ray contrast media would be desirable for imaging vessels, which are distributed exclusively in the vascular space, d. H. the volume of distribution of the contrast medium should correspond to the intravascular space. So far for the Contrast agents used in angiography have the disadvantage that they leave the vasal space very quickly because they are too small and hydrophilic and can be distributed in the extracellular space. In addition, your  Elimination so quickly that usually a local application by means of Catheters (e.g. in the cranial area) must be carried out with many Inconvenience to the patient. Would be desirable therefore blood pool agents (perfusion agents), which make it possible to systemic application with the help of X-ray technology well perfused by to delimit poorly perfused tissue to cause ischemia diagnose. Because of its anemia, infected tissue can also be removed from the delimit surrounding healthy or ischemic tissue when a vasal Contrast medium is applied. This is of particular importance if e.g. B. is about distinguishing a heart attack from ischemia.

Another application is in the diagnosis of Vascular areas with reduced or increased permeability, the z. B. by Inflammation or tumors can be caused, as well as in the Lymphography and mammography.

There is therefore a need for x-ray contrast media that cover the vasal space can mark (blood pool agent). These connections should be characterized by a good tolerance and high effectiveness (high increase in Signal intensity or lowering the dose) and by the molecules remaining in the vasal space (no extravasation) and a longer half-life in the Stand out compared to the contrast media used for angiography.

The approach to using at least some of these problems Solving iodinated macromolecular contrast agents has so far been very difficult limited success.

For example, in International Patent Application WO 88/06162 described dextran derivatives a broad molecular weight distribution and connected an incomplete excretion and an insufficient tolerance on.

The iodine-containing ones disclosed in the international patent application WO 93/10824 Polyamines are not very soluble in water and are also relatively poor compatible.

The task was therefore to use new X-ray contrast media primarily for Detection and localization of vascular diseases, which have the disadvantages mentioned  do not possess to provide. This task is accomplished by the present invention solved.

It has been found that iodine-containing dendrimeric polymers, which one nitrogen-containing core and triiodoaromatic and aliphatic Imaging residues bearing carboxy, sulfo or phosphono groups exhibit, surprisingly excellent for the production of X-ray Diagnostics are suitable without the disadvantages mentioned.

Dendrimers are ramified polymeric molecules such as those found in e.g. B. in Appl. Chem. Vol. 104, 1609 (1992).

The iodine-containing dendrimers (cascade polymers) according to the invention are described by the general formula I.

A- {X- [Y- (Z- <WD _w < _z ) _y ] _x } _a (I)

wherein
A for a nitrogen-containing cascade core of base multiplicity a,
X, Y independently of one another for a direct bond or a cascade reproduction unit of the reproduction multiplicity x or y,
Z, W independently of one another for a cascade reproduction unit of reproduction multiplicity z or w,
D for a group TB, wherein
B represents a benzene ring of the general formula II,

or represents a group of the formula - (CO) _q -U-COOH,
wherein
R¹ and R² each independently represent a hydrogen atom, a -CONR³R⁴- or -NR⁶COR⁵ group, wherein
R³, R⁴ either independently of one another for a hydrogen atom or a straight-chain, branched or cyclic alkyl group with up to 12 C atoms, which are optionally substituted by 1-5 hydroxy and / or 1-3 C₁- C₃-alkoxy and / or 1- 3 carboxy, sulfo or phosphono group (s) is substituted or
R³ and R⁴ together with the nitrogen atom represent a heterocyclic 5- or 6-ring which optionally contains an oxygen atom, an SO₂ group or an N-CO-R⁷ radical,
R⁷ represents a carboxy group or an alkyl group with up to 12 C atoms, which optionally contains 1-5 hydroxyl, 1-3 C₁-C₃- alkoxy or 1-3 carboxy, sulfo or phosphono group (s),
R⁵ represents a carboxy group or a straight-chain or branched C₁-C₁₂ alkyl group, which is optionally interrupted by an oxygen atom, which may also contain a carbonyl group and / or optionally by 1-3 carboxy, sulfo- or phosphono- and / or 1-5 hydroxy and / or 1-3 C₁-C₃ alkoxy group (s) and / or an optionally carboxymethyl-substituted imino group is substituted,
R⁶ represents a hydrogen atom, or a straight-chain or branched alkyl group having up to 12 carbon atoms, which may be by 1-3 carboxy, sulfo or phosphono group (s) and / or optionally by 1-3 hydroxy group (s) and / or 1-3 C₁-C₃- alkoxy group (s) is substituted
T for a group -CO-, -CS-, -CONH-, -CSNH-, COCH₂N (R⁶) CO, - CHR-CHR-CONH-,

a stands for the digits 2 to 12,
x, y, z stand independently of one another for the digits 1 to 4 and
w represents the digits 1 to 8,
with the proviso that at least two reproductive units are different and that the product of multiplicities applies

16axxyzw128

U for a group (CH₂) _u
q for the digits 0 or 1 and
u stands for the digits 1-4
and their salts with physiologically acceptable organic and / or inorganic bases, amino acids or amino acid amides.

The following are suitable as cascade core A:
Nitrogen atom,

wherein
m, n independently of one another for the digits 1 to 10,
p for the digits 0 to 10,
U¹ for Q¹ or E,
U² for Q² or E with
E in the meaning of the group

wherein
o for the digits 1 to 6,
Q¹ is a hydrogen atom or Q² and
Q² for a direct bond
M is a C₁-C₁₀ alkylene chain which is optionally interrupted by 1 to 3 oxygen atoms and / or is optionally substituted by 1 or 2 oxo groups,
R⁰ for a branched or unbranched C₁-C₁₀ alkyl radical, a nitro, amino, carboxylic acid group or for the group

stand
where the number Q² corresponds to the base multiplicity a.

The simplest case of a cascade nucleus is the nitrogen atom, whose three bonds (base multiplicity a = 3) in a first "inner layer" (generation 1) of three reproduction units X or Y (if X stands for a direct bond) or Z ( when X and Y each represent a direct bond) are occupied; in other words:
the three hydrogen atoms of the underlying cascade starter ammonia A (H) _a = NH₃ have been substituted by three reproduction units X or Y or Z. The number Q² contained in the cascade core A reflects the base multiplicity a.

The reproductive units X, Y, Z and W contain -NQ¹Q² groups, where Q¹ a hydrogen atom or Q² is a direct bond. The one in each Reproduction unit (eg X) contained number Q² corresponds to the reproduction multiplicity of this unit (e.g. x in the case of X). The product of all multiplicities (a · x · y · z · w) gives the number of triiodinated bound in the cascade polymer Benzene residues B. The polymers according to the invention contain at least 16 and at most 128 residues B in the molecule.

The reproduction units can be terminated both via NHQ² groups (e.g. by acylation reactions) as well as via NQ²Q² groups (e.g. by Alkylation reactions) to the next generation. The last one too Generation, can be connected to the connecting links T via NHQ² or NQ²Q² groups be bound, which in turn are linked to the triiodinated aromatics.

The cascade polymer complexes according to the invention have a maximum of 10 Generations (i.e. more than one of the Reproduction units X, Y and Z are present in the molecule), preferably however, 2 to 4 generations, with at least two of the reproductive units are different in the molecule.

The preferred cascade cores A are those which fall under the general formulas mentioned above, if
m for the digits 1-3, particularly preferred for the digit 1
n for the numbers 1-3, particularly preferably for the number 1
p for the digits 0-3, particularly preferably for the digit 1
o for number 1,
M for a -CH₂-, -CO- or -CH₂CO group and
R⁰ represents a -CH₂NU¹U²-, CH₃- or NO₂ group.

As a further preferred cascade starter A (H) _a . B. listed:
(The parent multiplicity a is given in brackets for the case of the subsequent mono or disubstitution used to build the next generation)

Tris (aminoethyl) amine (a = 6 or 3);
Tris (aminopropyl) amine (a = 6 or 3);
Diethylene triamine (a = 5 or 3);
Triethylenetetramine (a = 6 or 4);
Tetraethylene pentamine (a = 7 or 5);
1,3,5-tris (aminomethyl) benzene (a = 6 or 3);
Trimesic acid triamide (a = 6 or 3);
1,4,7-triazacyclononane (a = 3);
1,4,7,10-tetraazacyclododecane (a = 4);
1,4,7,10,13-pentaazacyclopentadecane (a = 5);
1,4,8,11-tetraazacyclotetradecane (a = 4);
1,4,7,10,13,16-hexaazacyclooctadecane (a = 6);
1,4,7,10,13,16,19,22,25,28-decaazacyclotriacontane (a = 10);
Tetrakis (aminomethyl) methane (a = 8 or 4);
1,1,1-tris (aminomethyl) ethane (a = 6 or 3);
Tris (aminopropyl) nitromethane (a = 6 or 3);
2,4,6-triamino-1,3,5-triazine (a = 6 or 3);
1,3,5,7-adamantanetetracarboxamide (a = 8 or 4);
3,3 ', 5,5'-diphenyl ether tetracarboxamide (a = 8 or 4);
1,2-bis [phenoxyethane] -3 ′, 3′′5 ′, 5 ′ ′ - tetracarboxamide (a = 8 or 4);
1,4,7,10,13,16,21, 24-octaazabicyclo [8.8.8.] Hexacosan (a = 6).

It should be noted that the definition as cascade core A and thus the Separation of the cascade core and the first reproduction unit in purely formal and independent of the actual synthetic structure of the desired one Cascade polymer complexes can be chosen. So you can z. B. Tris (aminoethyl) amine both itself as cascade core A (compare the first for A given general formula with m = n = p = 1, U¹ = E with o in the  Meaning of the number 1 and U¹ = U² = Q²) but also as a nitrogen atom (= Cascade core A), the first generation to have three reproductive units

(compare the definition of E).

The cascade reproduction units X, Y, Z and Q become independent from each other

certainly,
wherein
U¹ for Q¹ or E,
U² for Q² or E with
E in the meaning of the group

in which
o for the digits 1 to 6,
Q¹ is a hydrogen atom or Q²
Q² for a direct bond,
U³ for a C₁-C₂₀ alkylene chain which is optionally interrupted by 1 to 10 oxygen atoms and / or 1 to 2-N (CO) _q -R²-, 1 to 2 phenylene and / or 1 to 2 phenyleneoxy radicals and / or optionally is substituted by 1 to 2 oxo, thioxo, carboxy, C₁-C₅-alkylcarboxy, C₁-C₅-alkoxy, hydroxy, C₁-C₅-alkyl groups, wherein
q for the digits 0 or 1 and
R² represents a hydrogen atom, a methyl or an ethyl radical which is optionally substituted by 1-2 hydroxyl or 1 carboxy group (s)
L for a hydrogen atom or the group

stands,
V for the methine group

stands if at the same time U⁴ is a direct bond or the group M and U⁵ has one of the meanings of U³ or
V for the group

stands when U⁴ and U⁵ at the same time
are identical and denote the direct bond or the group M.

Preferred cascade reproduction units X, Y, Z and W are those in the above general formulas
the rest U³ stands for -CO-, -COCH₂OCH₂CO-, -COCH₂-, -CH₂CH₂-, -CONHC₆H₄-, -COCH₂CH₂CO-, -COCH₂-CH₂CH₂CO-or -COCH₂CH₂CH₂CH₂CO-,
the rest U⁴ stands for a direct bond or for -CH₂CO-,
the rest U⁵ stands for a direct bond or for - (CH₂) ₄-, -CH₂CO-, -CH (COOH) -, CH₂OCH₂CH₂-, -CH₂C₆H₄-, CH₂-C₆H₄OCH₂CH₂- or
the rest E for a group

stands.

The cascade reproduction units X, Y, Z and W are given as examples:

-CH₂CH₂NH-; -CH₂CH₂N <;
-COCH (NH -) (CH₂) ₄NH-; -COCH (N <) (CH₂) ₄N <
-COCH₂OCH₂CON (CH₂CH₂NH-) ₂; -COCH₂OCH₂CON (CH₂CH₂N <) ₂;
-COCH₂N (CH₂CH₂NH-) ₂; -COCH₂N (CH₂CH₂N <) ₂;
-COCH₂NH-; -COCH₂N <;
-COCH₂CH₂CON (CH₂CH₂NH-) ₂; -COCH₂CH₂CON (CH₂CH₂N <) ₂;
-COCH₂OCH₂CONH-C₆H₄-CH [CH₂CON (CH₂CH₂NH-) ₂] ₂;
-COCH₂OCH₂CONH-C₆H₄-CH [CH₂CON (CH₂CH₂N <) ₂] ₂;
-COCH₂CH₂CO-NH-C₆H₄-CH [CH₂CON (CH₂CH₂NH-) ₂] ₂;
-COCH₂CH₂CO-NH-C₆H₄-CH [CH₂CON (CH₂CH₂N <) ₂] ₂;
-CONH-C₆H₄-CH [CH₂CON (CH₂CH₂NH-) ₂] ₂;
-CONH-C₆H₄-CH [CH₂CON (CH₂CH₂N <) ₂] ₂;
-COCH (NH-) CH (COOH) NH-;
-COCH (N <) CH (COOH) N <;

As alkyl groups contained in the R¹ or R² substituent of the triiodoaromatic B R³, R⁴ and R⁷ come straight or branched or cyclic Hydrocarbons with up to 12, preferably up to 10, particularly preferred up to 6 carbon atoms into consideration, which are replaced by 1-5, preferably 1-3, hydroxy and / or 1-3 C₁-C₃ alkoxy and / or 1-3, preferably one, carboxy, sulfo- or phosphono group (s) is substituted.  

The methyl, hydroxymethyl, ethyl, 2-hydroxyethyl, 2-hydroxy-1- (hydroxymethyl) ethyl, 1 - (hydroxymethyl) ethyl, Propyl, isopropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 1,2,3-trihydroxypropyl, butyl, isobutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl-, 2-, 3- and 4-hydroxy-2-methylbutyl-, 2- and 3-hydroxyisobutyl-, 2,3,4-trihydroxybutyl, 1,2,4-trihydroxybutyl, pentyl, cyclopentyl, cyclohexyl, 2,3,4,5,6-pentahydroxyhexyl, 2-methoxyethyl, carboxymethyl, 2-sulfoethyl, Phosphonomethyl, 2-carboxyethyl, 10-hydroxydecyl, carboxy, 3-sulfopropyl, 2-phosphonoethyl group.

The by R³ and R⁴ including the amide nitrogen if necessary heterocyclic 5- or 6-ring formed may optionally be a Contain oxygen atom, a SO₂ group or an N-CO-R⁷ radical.

Examples of suitable heterocycles are:
the piperidyl, pyrazolidyl, morpholinyl, N-substituted piperazinyl and the S, S-dioxothio-morpholinyl ring.

The radicals R⁵ and R⁶ contained in the R¹ or R² substituent of the triiodoaromatic B are, in addition to the corresponding radicals listed for R³, R⁴, R⁷, the following:
Carboxymethoxymethyl, 5-carboxy-1,5-dihydroxy-3-oxapentyl, 2-carboxy-1-hydroxyethyl, 3-carboxy-2-oxapropyl group.

The alkyl, aryl or aralkyl radical or alkylene, arylene or aralkylene radical which represents R⁸ and R⁹ or V can be straight-chain or branched and contain up to 20, preferably up to 12, carbon atoms. The R⁸ and R⁹ substituent can be substituted by 1-4, preferably 1-2 hydroxyl group (s), the chain representing V (optionally additionally) can be interrupted by 1-4, preferably 1-2 oxygen atoms. The following groups are mentioned as examples:
Ethylene, butylene, 1-methylpropylene, propylene, 3,6-dioxaoctylene, xylylene, 2-hydroxypropylene, 3-oxapentylene.

The alkylene chain for U can have up to 6, preferably up to 2, carbon atoms and may be interrupted by 1-2 oxygen atoms and / or optionally by 1-4, preferably 1-2 hydroxyl groups and / or 1-2 carboxy group ( n) be substituted. The following are examples of the residues - (CO) _q -U-COOH:
-CO (CH₂) ₂COOH; -COCOOH; -CO (CHOH) ₂COOH; -COCH₂OCH₂COOH;
-COCH₂COOH; -COCH (OCH₃) COOH, -CH₂CH₂COOH, -CH (CH₃) CH₂COOH,
-CH₂CH (CH₃) COOH, -CH (CH₃) CH (CH₃) COOH, the residues
-CO (CH₂) ₂COOH,
-COCH₂OCH₂COOH, -CH₂CH₂COOH are preferred.

The acidic hydrogen atoms of the acid groups contained in the polymer can be wholly or partly by cations of inorganic and / or organic bases, amino acids or amino acid amides can be replaced.

Suitable cations of inorganic bases are, for example, lithium Potassium, calcium, magnesium, zinc and especially that Sodium ion. Suitable cations of organic bases include those of primary, secondary or tertiary amines, such as. B. ethanolamine, Diethanolamine, morpholine, glucamine, N, N-dimethyl-glucamine and in particular N-methylglucamine. Suitable cations of amino acids are, for example of lysine, arginine and ornithine and the amides are otherwise acidic or neutral amino acids.

The compounds according to the invention have those described at the outset desired properties. They contain the for their use as X-ray contrast medium required number of triiodoaromatics. They just spread out in the vascular space and can therefore use X-ray diagnostics to mark.

The iodine content of the compounds according to the invention exceeds on average 45% contains the iodine content of other iodoaromatics Macromolecules - such as the dextran derivatives described in WO 88/06162 (approx. 2 to 35%) - sometimes many times over. The invention Compounds surprisingly can be in contrast to those in the WO 88/06162 described dextran derivatives in any ratio with water mix, resulting in a higher contrast agent concentration in the blood vessels leads shortly after injection and thus favorably delimits the Blood vessels. The for side effects such as pain, damage to the Blood vessels and cardiovascular disorders are responsible values of osmolality  significantly reduced and no longer hyperosmolar as usual with X-ray contrast often observed.

(Example 18: 190 [mosmol / kg] at 37 ° C, 130 mg iodine / ml). The osmolality of the Compounds according to the invention is also significantly less than that in the WO 88/06162 described dextran compounds (440 mosmol / kg at 90 mg Iodine / ml).

The chemotoxicity responsible for the acute tolerance Compounds according to the invention (Example 18: IV LD mouse <5 g iodine / kg) both compared to the macromolecular contrast agents based on Carbohydrates (WO 88/06162) as well as those in WO 93/10824 described examples based on polyamines significantly improved. Compared to the dextran-based macromolecules, the viscosity of the Compounds according to the invention significantly less, which is a bolus injection and thus significantly better demarcation of the blood vessels from the surrounding Tissue allowed (Example 18: 2.8 mPa · s at 37 ° C and 100 mg iodine / ml; Example 10 WO 88/06162: 26 mPa · s at 37 ° C and 90 mg iodine / ml).

With the compounds according to the invention it has been possible to use macromolecules produce exactly defined molecular weight. Such, in their molecular size exactly defined macromolecular contrast agents with iodoaromatics hitherto significantly worse properties than those according to the invention Connections. For example, that in Example 12 of WO 94/21600 called compound a much lower solubility at the same time much higher viscosity than the compounds of the invention.

In the dextran-based macromolecules, e.g. B. Dextran 40,000 (Rheomacrodex®), it is a mixture of macromolecules different sizes, whose average molecular weight z. B. at 40,000 daltons lies. However, dextran molecules larger than are also present in this mixture 50,000 and 60,000 daltons, respectively. This proportion of high molecular weight Dextran compounds may be between 5 and 10% of the total. How known from the literature (G. Arturson and G. Wallenius, The renal clearance of dextran of different molecular sizes in normal humans, Scandinav. J. Clin. & Lab. Investigation 1: 81-86, 1964), dextran molecules of this size no longer become filtered glomerularly, and the renal clearance of these molecules is therefore near zero. Also those in the patents EP 0206551, EP 0436316 and in the  Examples 1, 2 and 3 of WO 93/10824 compounds can not completely due to their high molecular weight after i.v. be eliminated. However, a diagnostic is expected to follow intravenous injection completely out of the body in a short period of time is eliminated. The other compounds described in WO 93/10824 leave the intravascular space too quickly and are therefore not as Perfusion agents suitable. It is with the compounds of the invention Surprisingly, iodine-containing polymers have been made available leave the vascular space only slowly, but at the same time the capillaries of the Kidneys still pass and are therefore completely eliminated.

The invention therefore relates to those described by the formula I. Links.

Due to the molecular structure, the compounds according to the invention show in blood concentration for the first 10 minutes after intravenous administration is about four times higher than with extracellular X-ray contrast media such as e.g. B. Ultravist®. The cascade polymers are only in the body Vasal space, i.e. H. the volume of distribution is approximately 0.05 l / kg. So that's it possible to use macromolecular contrast media with triiodoaromatics to manufacture.

The cascade polymers according to the invention serve as contrast agents for Representation of the vessels using X-ray diagnostics. It is possible distinguish ischemic tissue from normal tissue. But also other damage to the blood-tissue barrier are associated with these connections to recognize. With inflammation and tumors in the brain, the blood-brain Barrier so damaged that the contrast medium infiltrate the diseased tissue can and thus the diseased tissue with X-ray diagnostics is recognizable. Due to the impermeability of the intact blood-brain barrier even to small, but you could already use hydrophilic molecules to treat inflammation and tumors recognize the low molecular weight Ultravist®. However, one applies in these cases the cascade polymers according to the invention, you can dose around Reduce fourfold; because the macromolecules are divided into four smaller space, namely only in the vasal space, i.e. H. to equal concentrations in Reaching blood is enough for a quarter of the dose.  

At the same time, perfusions can be perfused with the compounds according to the invention measurements z. B. perform on the myocardium, what with the low molecular weight Compounds such as Ultravist® were only possible to a limited extent because these molecules are rapid "leak" into the interstitial space. The "leakage" into the interstitium led in the case of the low-molecular compounds, the image is often blurred which can be avoided by the compounds according to the invention. At the same time, the measurement time compared to the low molecular weight compounds be greatly extended.

Another advantage of the present invention is that now Macromolecules with different lipophilic or hydrophilic triiodaryl residues have become accessible. This creates the possibility of tolerance and pharmacokinetics of these cascade polymers by differently substituted ones Control triiodaryl residues.

The invention therefore also relates to the use of Compounds according to the invention for producing X-ray contrast media.  

The production of the iodine-containing dendrimeric polymers according to the invention is carried out by dendrimeric polymers of the general formula I ′

A- {X- [Y- (Z- <W- _w < _z ) _y ] _x } _a (I ′)
wherein

A for a nitrogen-containing cascade core of base multiplicity a,
X, Y independently of one another for a direct bond or a cascade reproduction unit of the reproduction multiplicity x or y,
Z, W independently of one another for a cascade reproduction unit of reproduction multiplicity z or w, a for the digits 2 to 12 and
x, y, z stand independently for the digits 1 to 4
w stands for the digits 1 to 8 and
stand for the binding site of the terminal amino groups of the last generation of the reproduction unit W with the proviso that at least two reproduction units are different and that the multiplicity applies to the product

16 ax.yzw 128,

with compounds of the general formula II ′

T′-B ′ (II ′)

wherein
T 'represents a radical containing a carbonyl, thiocarbonyl, activated carbonyl or a CHR = CR group, which is converted into T by the reaction, where
R has the meaning of a hydrogen atom or a methyl group and
B 'has the meaning given for B of a triiodoaromatic, but carboxy and hydroxyl groups present in B are present in protected form, and then the positions which may not be occupied by the Z radicals are reacted with a - (CO) _q -U-COOH radical introducing reagent acylated or alkylated, wherein
U represents a group (CH₂) _u
q for the digits 0 or 1 and
u stands for the digits 1-4.

As an example of an activated carbonyl group in the residues T 'of the educts of general formula II are anhydride, p-nitrophenyl ester, lactone and Called acid chloride.

Examples of T ′ are the residues COCI, NCO, NCS, NHCO-CR = CHR,

Lower alkyl, aryl and aralkyl groups come as acid protecting groups, for example the methyl, ethyl, propyl, n-butyl, t-butyl, phenyl, benzyl, Diphenylmethyl, triphenylmethyl, bis (p-nitrophenyl) methyl group, and Trialkylsilyl groups in question.

The protective groups are split off according to those known to the person skilled in the art method [see e.g. B. E. Wünsch, Methods of Org. Chemistry (Houben Weyl), Vol. XV 11, 4. Edition 1974, p. 315 ff], for example by hydrolysis, hydrogenolysis, alkaline saponification of the esters with alkali in aqueous-alcoholic solution at temperatures from 0 to 50 ° C, acid saponification with mineral acids or in the case from Z. B. tert-butyl esters with the help of trifluoroacetic acid.

As hydroxyl protective groups such. B. the benzyl, 4-methoxybenzyl, 4-nitro benzyl, trityl, diphenylmethyl, trimethylsilyl, dimethyl-t-butylsilyl, Diphenyl-t-butylsilyl group in question.

The hydroxy groups can also, for. B. as THP ether, α-alkoxyethyl ether, MEM Ethers or as esters with aromatic or aliphatic carboxylic acids, such as. B. Acetic acid or benzoic acid. In the case of polyols, the Hydroxy groups also in the form of ketals with z. B. acetone, acetaldehyde, Cyclohexanone or benzaldehyde must be protected.  

If carboxyl groups are present at the same time, hydroxyl groups can also protected by intramolecular esterification to the corresponding lactones available.

The hydroxyl protective groups can be according to the literature known to the person skilled in the art methods, e.g. B. by hydrogenolysis, reductive cleavage with lithium / ammonia, Acid treatment of the ethers and ketals or alkali treatment of the esters to be released (see e.g. "Protective Groups in Organic Synthesis", T.W. Greene, John Wiley and Sons 1981).

The various processes for producing the polymers according to the invention and the starting compounds required for this are in principle known to the person skilled in the art known. They are based on the conversion of the terminal amino groups desired generation of the dendrimeric polymers of the general Formula I 'with those bound to generate the triiodoaromatics B. Linking elements T suitable compounds of the general formula II '.

This is how the N, N-bis- (carboxymethyl) amine or amide substituted triiodoaromatics in liquid Reaction media such as water, dipolar aprotic solution agents such as diethyl ether, tetrahydrofuran, dioxane, acetonitrile, N-methylpyrrolidone, Dimethylformamide, dimethylacetamide and the like or mixtures thereof with the addition of amines, such as. B. triethylamine, N-ethyldiisopropylamine, N, N-dimethyl-4-aminopyridine. The reaction temperatures are between approx. -80 ° C and 160 ° C, with temperatures of 20 ° C to 80 ° C are preferred. The Response times are between 0.5 hours and 7 days, preferably between 1 hour and 48 hours.

The acid anhydrides can be prepared by known processes, e.g. B. by the method described in US 3,660,388 or DE 16 95 050 with acetic anhydride in pyridine. In certain cases, however, it is advantageous to Dehydration with carbodiimides in a suitable solvent, such as e.g. B. dimethylformamide or dimethyl acetamide, gently.  

The reactions of the isocyanate- or isothiocyanate-substituted triiodoaromatics takes place according to methods known from the literature (DOS 26 10 500, EP 0431 838), for example in aprotic solvents such as DMSO, DMF, DMA or in water or water-containing solvent mixtures Temperatures of 0-120 ° C, preferably 20-75 ° C. The response times are usually between 1-48 hours, preferably 3-24 hours.

The implementation of triiodoaromatics containing lactone structures corresponding dendrimeric polyamines succeed z. B. analogous to that of T. Sheradsky, Y. Knobler and M. Frankel in J. Org. Chem., 26, 2710 (1961) described process for the aminolysis of 2-acylamino-4-butyrolactones.

Addition reactions of an olefinic substituent CHR = CR-CONH having triiodoaromatic z. B. after in Org. Synth. Coll. Vol. VI, p. 75 (1988) specified by using a triiodinated Acrylamide in polar solvents such as DMF, DMA, pyridine, ethanol with the the desired polyamine.

The acylations of the terminal amino groups of the polymers of the general Formula I ′ with triiodoaromatics which contain an acid chloride substituent, are according to the methods known to those skilled in the art, for. B. analogous to the regulation made in EP 0015867. The implementation is generally in polar aprotic solvents such as B. DMF, DMA, or in mixtures of polar aprotic solvents with water, in the presence of an acid scavenger, such as e.g. B. tertiary amine (e.g. triethylamine, trimethylamine, N, N-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] nonen-5 (DBN), 1,5-diazabicyclo [5.4.0] undecene-5 (DBU), Alkali or alkaline earth carbonate, hydrogen carbonate or hydroxide (e.g. Potassium carbonate, sodium carbonate, lithium hydroxide, potassium hydroxide) Temperatures between 0-120 ° C, preferably 20-80 ° C, and Response times of 1-36 hours carried out.

The subsequent acylation or alkylation may not occur Imaging residues T-B bound terminal amino groups are carried out analogously literature-known regulations, see e.g. B. Org. Syn. Coll. Vol. 4, 5 (1963).

The neutralization of the acid groups can be done with the help of inorganic bases (e.g. Hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium,  Lithium, magnesium or calcium and / or organic bases as below other primary, secondary and tertiary amines, such as ethanolamine, Morpholine, glucamine, N-methyl and N, N-dimethylglucamine, and more basic Amino acids such as lysine, arginine and ornithine or from amides originally neutral or acidic amino acids.

The preparation of the cascade polymers carrying terminal amino groups required for the coupling to the activated triiodoaromatics T'-B 'generally starts from commercially available nitrogen-containing cascade starters A (H) _a which can be prepared by or analogously to literature methods. Generations X, Y, Z and W are introduced using methods known from the literature [e.g. J. March, Advanced Organic Chemistry, ^3rd ed .; John Wiley & Sons, (1985), 364-381] by acylation or alkylation reactions with the desired structures having protected amines, which functional groups capable of binding to the cascade nucleus, such as, for. B. carboxylic acids, isocyanates, isothiocyanates or activated carboxylic acids (such as anhydrides, active esters, acid chlorides) or halides (such as chlorides, bromides, iodides), aziridine, mesylates, tosylates or other escape groups known to those skilled in the art .

However, it should be emphasized here again that the distinction between cascade core A and reproductive units is purely formal. It can be synthetically advantageous that the formal cascade starter A (H) _{a is not} used, but that the nitrogen atoms, which by definition belong to the cascade core, are only introduced together with the first generation. So it is z. B. for the synthesis of the compound described in Example 1b) advantageous, not the formal cascade core trimesic acid triamide with z. B. Benzyloxycarbonylaziridin (six times) to alkylate, but to implement trimesic acid trichloride with bis [2- (benzyloxy carbonylamino) ethyl] amine (triple).

The amine protecting groups are the benzyloxycarbonyl, tertiary-butoxycarbonyl, trifluoroacetyl, fluorenylmethoxycarbonyl, benzyl and formyl group [Th. W. Greene, PGM Wuts, Protective Groups in Organic Syntheses, 2nd ed, John Wiley and Sons (1991), pp. 309-385]. After these protective groups have been split off, which is also carried out using methods known from the literature, the next desired generation can be introduced into the molecule. In addition to this structure of a generation consisting of two reaction stages (alkylation or acylation and deprotection), the simultaneous introduction of two, e.g. B. X- [Y] _x , or several generations, e.g. B. X- [Y- (Z) _y ] _x possible. These multi-generation units are constructed by alkylation or acylation of unprotected amines (“reproductive amine”) having the structures of the desired reproductive units with a second reproductive amine, the amine groups of which are in protected form.

The compounds of the general formula A (H) _a required as cascade starters are commercially available or according to or analogously to methods known from the literature [e.g. B. Houben-Weyl, Methods of Org. Chemistry, Georg-Thieme-Verlag, Stuttgart (1957), Vol. 11/1;
M. Micheloni et al., Inorg. Chem. (1985), 24, 3702; TJ Atkins et al., Org. Synth., 15 Vol. 58 (1978), 86-98; The Chemistry of Heterocyclic Compounds: JS Bradshaw et al., Aza-Crown-Macrocycles, John Wiley & Sons, NY (1993)].

Examples include:
Tris (aminoethyl) amine [e.g. B. Fluka-Chemie AG, Switzerland; Aldrich-Chemie, Germany];
Tris (aminopropyl) amine [e.g. BC Woerner et al., Angew. Chem. Int. Ed. Engl. (1993), 32, 1306];
Diethylenetriamine [e.g. B. Fluka; Aldrich];
Triethylenetetramine [e.g. B. Fluka; Aldrich];
Tetraethylene pentamine [e.g. B. Fluka; Aldrich];
1,3,5-tris (aminomethyl) benzene [e.g. BTM Garrett et al., J. Am. Chem. Soc. (1991) 113, 2965];
Trimesic acid triamide [e.g. BH Kurihara; Jpn. Kokai Tokkyo Koho JP 04077481; CA 117.162453];
1,4,7-triazacyclononane [e.g. B. Fluka; Aldrich];
1,4,7,10,1 3-pentaazacyclopentadecane [e.g. BKW Aston, Eur. Pat. Appl. 0524 161, CA 120, 44580];
1,4,8,11-tetraazacyclotetradecane [e.g. B. Fluka; Aldrich];
1,4,7,10,13,16,1 9,22,25,28-decaazacyclotriacontane [e.g. BA Andres et al., J. Chem. Soc. Dalton Trans. (1993), 3507];
1,1,1-tris (aminomethyl) ethane [e.g. BRJ Geue et al., Aust. J. Chem. (1983), 36, 927];
Tris (aminopropyl) nitromethane (e.g. BGR Newkome et al., Angew. Chem. 103, 1205 (1991) analogous to RC Larock, Comprehensive Organic Transformations, VCH Publishers, NY (1989), 419-420]
1,3,5,7-adamantanetetracarboxamide [e.g. BH Stetter et al., Tetr. Lett. 1967, 1841];
1,2-bis [phenoxyethane] -3 ', 3''5', 5 '' - tetracarboxamide [e.g. BJP Collman et al .; 1 d J. Am. Chem. Soc. (1988), 110, 3477-86 analogous to the instructions for example 1b)];
1,4,7,10,13,16,21, 24-octaazabicyclo [8.8.8.] Hexacosan [e.g. BPH Smith et al., J. Org. Chem. (1993), 58, 7939].

The manufacture of those needed to build up the generations above Reproductive amines containing the functional groups mentioned are carried out after or analogous to the regulations described in the experimental section or according to methods known from the literature.

Examples include:
N ^α , N ^ε -Di-CO-O-CH₂C₆H₅-lysine-p-nitrophenyl ester [s. Regulation for Example 1c)];
HOOC-CH₂OCH₂CO-N (CH₂ CH₂NH-CO-O-CH₂C₆H₅) ₂ [s. Regulation for Example 7a)];
HOOC-CH₂N (CH₂CH₂NH-CO-O-CH₂C₆H₅) ₂ [s. Regulation for Example 9e)];
HOOC-CH₂CH₂CO-N (CH₂CH₂NH-COCF₃) ₂ [to be prepared according to instructions for Example 7a) by starting from bis (trifluoroacetylaminoethyl) amine instead of bis (benzyloxycarbonylaminoethyl) amine and succinic anhydride instead of diglycolic anhydride];
HOOC-CH₂OCH₂CONH-C₆H₄-CH [CH₂CON (CH₂CH₂NH-CO-O-CH₂C₆H₅) ₂] ₂
[to be prepared according to the instructions for Example 7a) by starting from the amine described in Example 9b) instead of bis (benzyloxycarbonylaminoethyl) amine];
O = C = N-C₆H₄-CH [CH₂CON (CH₂CH₂NH-CO-O-CH₂C₆H₅) ₂] ₂ [s. Regulation for example 9c)]

[s. Regulation for example 16b)]

[s. Regulation for example 15c)]

(To be produced according to the instructions for Example 15c) by analogous to triphosgene instead of diglycolic anhydride the rule for example 9c))

N-benzyloxycarbonyl aziridine (see instructions for Example 13a)
N-benzyloxycarbonyl-glycine (commercially available from e.g. Bachem California)

(Manufactured according to C. J. Cavallito et al., J. Amer. Chem. Soc. 1943, 65, 2140, by replacing benzyl chloride from N-CO-O-CH₂C₆H₅- (2-bromoethyl) amine [A.R. Jacobson et al., J. Med. Chem. (1991), 34, 2816])

The iodinated aromatics used in the various processes are known or easily generated from known.

So z. B. in German Offenlegungsschriften DE 29 28 417 and DE 29 09 439 iodinated aromatics described, which are easily with z. B. thionyl chloride the corresponding aromatics containing acid chloride groups are implemented.

Isocyanate- or isothiocyanate-substituted triiodoaromatics can by Implementation of the corresponding aniline derivatives with phosgene or thiophosgene in aprotic solvents such as B. 1,2-dichloroethane, dichloromethane, pyridine, Dimethyl sulfoxide, tetrahydrofuran, dioxane, diethyl ether, ethyl acetate (Literature: DOS 2541 491).

For example, a triiodoaromatic containing lactone residue is obtained by reacting a triiodobenzoyl chloride derivative with 2-amino-4-butyrolactone Hydrochloride. An implementation of this type is e.g. B. by J. Brennan and P.J. Murphy in Tetrahedron Lett., 29 (17), 2063 (1988).

Triiodoaromatics with an olefinic substituent CHR = CR-CONH can can be obtained analogously to the information in WO 85/01727.

Other aromatic residues are as in M. Sovak; Radiocontrast agents, Handbook of Experimental Pharmacology Vol. 73 (1984), Springer-Verlag, Berlin -  Heidelberg - New York - Tokyo or in the European patent EP 0 015 867.

The invention further relates to pharmaceutical compositions which contain at least one of the compounds according to the invention.

The invention further relates to a method for producing these agents, the is characterized in that the shading substance with the in the Galenics usual additives and stabilizers in a for enteral or parenteral application is brought into a suitable form. The pharmaceutical Preparation can generally be tailored to the specific needs of the Be customized. The concentration of the new X-ray contrast medium in the aqueous medium depends entirely on the X-ray diagnostic method. The iodine content of the solutions is usually in the range between 50 to 450 mg / ml, preferably 70 to 200 mg / ml.

The resulting agents are then heat sterilized if desired. They are used depending on the iodine content and the X-ray diagnostic method or question usually in one dose from 30 mg iodine / kg to 2000 mg iodine / kg.

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

Suitable additives are, for example, physiologically acceptable buffers (such as e.g. 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 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 Desired saline solution, they will be with one or more in galenics usual auxiliary substances (e.g. methyl cellulose, lactose, mannitol) and / or surfactants  (e.g. lecithins, Tweens®, Myrj® and / or flavorings for Flavor correction (e.g. essential oils) mixed.

The following examples serve to explain the Objects of the invention without wishing to restrict them to them.

Examples example 1 Tetracosaki (3- (3-sodium carboxylatopropionylamino) -5- (2,3- dihydoxypropylcarbamoyl) -2,4,6-triiodobenzoyl derivative of the N, N, N ′, N ′, N ′ ′, N ′ ′ - Hexakis [2- (trilysylamino) ethyl] trimesic acid triamide a) Bis [2- (benzyloxycarbonylamino) ethyl] amine

51.5 g (500 mmol) of diethylenetriamine and 139 ml (1 mol) of triethylamine are dissolved in 10 dichloromethane and mixed with 161 g of benzylcyanformate (Fluka) in dichloromethane at -20 ° C. and then stirred overnight at room temperature. After the reaction is evaporated in the hood, the residue is taken up in diethyl ether, the organic phase is washed with sodium carbonate solution and dried with sodium sulfate. Hexane is added to the filtrate, the precipitate is filtered off and dried.
Yield: 163.4 g (88% of theory)

Analysis:
calc .: C 64.67; H 6.78; N 11.31;
Found: C 64.58; H 6.83; N 11.28.

b) N, N, N ′, N ′, N ′ ′, N ′ ′ - hexakis [2- (benzyloxycarbonylamino) ethyl] trimesic acid triamide

13.27 g (50 mmol) of trimesic acid trichloride (Aldrich) and 34.7 ml (250 mmol) of triethylamine are dissolved in dimethylformamide (DMF) and at 0 ° C. with 65.0 g (175 mmol) of the one described in Example 1a Amine added and then stirred overnight at room temperature. The solution is evaporated in vacuo and the residue is chromatographed on silica gel using ethyl acetate.
Yield: 39.4 g (62% of theory)

Analysis:
calc .: C 65.24; H 5.95; N 9.92;
Found: C 65.54; H 5.95; N 9.87.

c) N ^α , N ^ε- bis (N, N'-dibenzyloxycarbonyl-lysyl) -lysine, protected 'tri-lysine''

3.6 g (20 mmol) lysine hydrochloride and 6.95 ml (50 mmol) triethylamine are dissolved in DMF, with 26.8 g (50 mmol) N ^α , N ^ε dibenzyloxycarbonyl-lysine p-nitrophenyl ester (Bachem) added and stirred for 2 days at room temperature. After the reaction is evaporated in vacuo, the residue is taken up in ethyl acetate and extracted with dilute hydrochloric acid. The organic phase is dried with sodium sulfate, the solvent is evaporated and the residue is chromatographed with ethyl acetate / ethanol in a step gradient.
Yield: 10.7 g (57% of theory)

Analysis:
calc .: C 63.95; H 6.65; N 8.95;
Found: C 63.63; H 6.69; N 8.93.

d) Fully protected benzyloxycarbonyl-24-polyamine based on the N, N, N ′, N ′, N ′ ′, N ′ ′ - hexakis [2- (trilysylamino) ethyl] trimesic acid triamide

1.27 g (1 mmol) of the hexa-benzyloxycarbonylamine described in Example 1b are dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid are added with stirring. After 60 minutes, the precipitation started is completed with diethyl ether, the hexamine hydrobromide formed is washed with diethyl ether, dried in vacuo and used in the reaction described below without further purification.
Yield: 0.95 g (quantitative).

7.0 g (7.5 mmol) of the protected "tri-lysine" described in Example 1c, 1.2 g (7.5 mmol) of 1-hydroxybenzotriazole and 2.4 g (7.5 mmol) of 2- (1 H-Benzotriazol-1-yl) - 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU; Peboc Limited, UK) are dissolved in DMF and stirred for 15 minutes. This solution is then mixed with 5.16 ml (30 mmol) of N-ethyldiisopropylamine and with 0.95 g (1 mmol) of the hexaamine hydrobromide described above and stirred overnight at room temperature. After the reaction has ended, the mixture is evaporated in vacuo and the residue is chromatographed on silica gel using ethyl acetate / ethanol (2: 1).
Yield: 4.55 g (76% of theory)

Analysis:
calc .: C 64.35; H 6.71; N 10.52;
Found: C 64.08; H 6.57; N 10.29.

e) 5- (3-Ethoxycarbonylpropionylamino) -2,4,6-triiodisophthalic acid-N- (2,3-- diacetoxypropyl) amide chloride

To a suspension of 73.4 g (100 mmol) of 5-amino-2,4,6-triiodisophthalic acid N- (2,3-diacetoxypropyl) amide chloride (EP 0308364) in 500 ml of anhydrous dioxane, stirred with exclusion of moisture 24.7 g (150 mmol) of succinic acid monoethyl ester were added at room temperature. The batch is refluxed for several hours until, according to thin layer chromatography, no educt can be detected; then it is evaporated, the residue is taken up in dichloromethane and extracted with saturated aqueous sodium bicarbonate solution. After drying over anhydrous magnesium sulfate, the organic phase is evaporated and the residue is recrystallized from ethyl acetate / tert-butyl methyl ether.
Yield: 74.8 g (86.7% of theory) of colorless crystals

Analysis (based on solvent-free substance):
calc .: C 29.84; H 2.57; Cl 4.11; I 44.14; N 3.25; O 16.69;
Found: C 30.19; H 2.63; Cl 4.21; I 44.07; N 3.18.

f) Tetracosakis {3- (3-sodium carboxylatopropionylamino) -5- (2,3- dihydoxypropylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of N, N, N ′, N ′, N ′ ′, N ′ ′ - Hexakis [2- (trilysylamino) ethyl] trimesic acid triamide

4.20 g (0.7 mmol) of the poly-benzyloxycarbonylamine described in Example 1d are dissolved in glacial acetic acid and with stirring with 33 percent hydrogen bromide placed in glacial acetic acid. After 3 hours, the precipitation started with diethyl ether completed, the resulting 24-amine hydrobromide with diethyl ether washed and dried in vacuo.  

The residue is then taken up in water and adjusted to pH 9.5 by adding 1N sodium hydroxide solution. This solution is slowly added dropwise to a solution of 21.8 g (25.2 mmol) of the acid chloride prepared in Example 1e and 4.2 ml (30 mmol) of triethylamine in 200 ml of N, N-dimethylformamide, which is stirred mechanically at room temperature. The mixture is stirred for 2 days at room temperature, then mixed with 100 ml of 2N sodium hydroxide solution and stirred at 50 ° C. for two hours. After cooling to room temperature, the mixture is neutralized with 2N hydrochloric acid, then completely evaporated in vacuo, taken up in water, filtered and then subjected to ultrafiltration, with low-molecular constituents being separated off by a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 μm, Sartorius) and freeze-dried.
Yield: 12.5 g (87.2% of theory) of colorless lyophilisate

Analysis (based on anhydrous substance):
calc .: C 28.74; H 2.68; I 44.71; N 6.37; Na 2.70; O 14.80;
Found: C 28.93; H 2.82; I 44.39; N 6.45 Na 2.61

Example 2 Tetracosakis [3,5-di- (sodiumcarboxylatomethylcarbamoyl) -2,4,6-triiodophenylcarbamoyl} derivative of the 24-amine N, N, N-tris- [2- (N ^α , N ^ε -bis- {trilysyl} lysylamino) ethyl] amines a) N, N, N-tris- [2- (N ^α , N ^ε -dibenzyloxycarbonyl-lysylamino) ethyl] amine

1.46 g (10 mmol) of tris (2-aminoethyl) amine and 21.4 g (40 mmol) of N ^a , N ^ε - dibenzyloxycarbonyl-lysine-p-nitrophenyl ester are dissolved in DMF and stirred overnight at room temperature. After the reaction has ended, the mixture is evaporated in vacuo, the residue is stirred with diethyl ether, the precipitate is filtered off with suction and recrystallized from ethyl acetate.
Yield: 12.55 g (94% of theory)

Analysis:
calc .: C 64.75; H 6.79; N 10.49;
Found: C 64.48; H 6.88; N 10.26.

b) Fully protected benzyloxycarbonyl-24-polyamine based on the N, N, N-tris- [2- (N ^α , N ^ε -bis- {trilysyl} -lysylamino) -ethyl] amine

1.33 g (1 mmol) of the hexa-benzyloxycarbonylamine described in Example 2a are dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid are added with stirring. After 60 minutes, the precipitation started is completed with diethyl ether, the hexamine hydrobromide formed is washed with diethyl ether, dried in vacuo and used in the reaction described below without further purification.
Yield: 1.02 g (quantitative).

7.0 g (7.5 mmol) of the N ^α , N ^e bis- (N, N'-dibenzyloxycarbonyl-lysyl) -lysine (protected "tri-lysine") described in Example 1c are treated analogously to Example 1d with TBTU and N-Hydroxybenzotriazole activated and in an analogous manner with 1.02 g (1 mmol) of the above-described N, N, N-tris [2- (lysylamino) ethyl] amine hexahydrobromide and 5.16 ml (30 mmol) of N-ethyldiisopropylamine implemented and processed in the same way as described there.
Yield: 4.42 g (73% of theory)

Analysis:
calc .: C 64.25; H 6.89; N 10.64;
Found: C 64.06; H 7.04; N 10.69.

c) 5-Amino-2,4,6-triiodoisophthalic acid-N, N'-bis (methoxycarbonylmethyl) diamide (EP 0129932)

A solution of 59.6 g (100 mmol) of 5-amino-2,4,6-triiodoisophthalic acid dichloride in 300 ml of N, N-dimethylformamide is mixed with 27.6 g (220 mmol) of glycine methyl ester hydrochloride and 61.0 ml (440 mmol) triethylamine added. A suspension is formed which is stirred under argon overnight at room temperature. After evaporating the suspension in vacuo, the residue is recrystallized from methanol.
Yield: 66.3 g (94.6% of theory)

Analysis (based on solvent-free substance):
calc .: C 23.99; H 2.01; I 54.31; N 5.99; O 13.69;
Found: C 23.95; H 2.14; I 54.28; N 6.09.

d) 5-isocyanato-2,4,6-triiodoisophthalic acid-N, N'-bis- (methoxycarbonylmethyl) - diamid

To a suspension of 20.7 g (29.5 mmol) of the aniline derivative prepared in Example 2c in 200 ml of 1,2-dichloroethane, stirred at 60 ° C in an argon atmosphere, in 147 ml (73.8 mmol) of a two-normal toluene phosgene solution and 2 ml of N, N-dimethylformamide were added. After the aniline derivative has been completely reacted, the mixture is evaporated in vacuo, the residue is extracted with anhydrous ethyl acetate, suction filtered under a nitrogen atmosphere and dried in an oil pump vacuum.
Yield: 21.5 g (100% of theory) of a light beige solid

Analysis (based on solvent-free substance):
calc .: C 24.78; H 1.66; I 52.37; N 5.78; O 15.40;
Found: C 24.82; H 1.73; I 52.35; N 5.70.

e) tetracosakis {3,5-di- (sodium carboxylatomethylcarbamoyl) -2,4,6-triiodophenylcarbamoyl} derivative of the 24-amine N, N, N-tris- [2- (N ^α , N ^ε -bis- { trilysyl} - lysylamino) ethyl] amines

4.00 g (0.66 mmol) of the 24-benzyloxycarbonylamine described in Example 2b are dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid are added with stirring. After 3 hours, the precipitation started is completed with diethyl ether, the resulting 24-amine hydrobromide is washed with diethyl ether and dried in vacuo. The solid is stirred into a solution of 17.3 g (23.8 mmol) of the isocyanate prepared in Example 2d, stirred at room temperature under an argon atmosphere, in 200 ml of anhydrous dimethyl sulfoxide and 3.3 ml (24 mmol) of triethylamine. The mixture is stirred at room temperature for 2 days, then mixed with 25 ml of 2N sodium hydroxide solution and stirred at 50 ° C. for 2 hours. After cooling to room temperature, the solution is neutralized with 2N hydrochloric acid and largely evaporated in vacuo; the residue is taken up in water, filtered and then subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried.
Yield: 10.9 g (80.0% of theory) of yellowish lyophilisate

Analysis (based on anhydrous substance):
calc .: C 25.80; H 2.02; I 44.21; N 8.00; Na 5.34; O 14.63;
Found: C 26.01; H 2.11; I 43.96; N 8.14; Na 5.19.

Example 3 Tetracosakis {3,5-bis- [N, N-bis- (sodium carboxylatomethyl) carbamoyl] -2,4,6- triiiodphenylcarbamoyl} derivative of N, N, N ′, N ′, N ′ ′, N ′ ′ - hexakis [2- (trilysylamino) - ethyl] trimesic acid triamide a) 5-Amino-2,4,6-triiodoisophthalic acid-N, N, N ′, N′-tetrakis (methoxycarbonylmethyl) diamide

A solution of 47.2 g (79.2 mmol) of 5-amino-2,4,6-triiodoisophthalic acid dichloride in 250 ml of N, N-dimethylformamide is mixed with 34.4 g (174 mmol) of dimethyl iminodiacetate hydrochloride (synthesis according to Dubsky, Graenacher, Chem. Ber. 50 1693 (1917)) and 48.2 ml (348 mmol) of triethylamine. A suspension is formed which is stirred under argon overnight at room temperature. After evaporating the suspension in vacuo, the residue is taken up in dichloromethane and shaken out with aqueous sodium bicarbonate solution. The organic phase is dried with anhydrous magnesium sulfate, filtered and, after concentration, chromatographed on silica gel 60 (Merck, Darmstadt) (eluent: dichloromethane / methanol). The product fractions are evaporated to dryness in vacuo.
Yield: 57.1 g (85.3% of theory) of a colorless solid

Analysis (based on solvent-free substance):
calc .: C 28.42; H 2.62; I 45.05; N 4.97; O 18.93;
Found: C 28.61; H 2.77; I 44.83; N 4.72.

b) 5-isocyanato-2,4,6-triiodoisophthalic acid-N, N, N ′, N′-tetrakis (methoxycarbonylmethyl) diamide

45.3 ml (90.5 mmol) of a two-normal solution are added to a solution of 30.6 g (36.2 mmol) of the aniline derivative prepared in Example 3a) which is stirred at 60 ° C. in an oil bath temperature under an argon atmosphere added toluene phosgene solution and 3 ml of N, N-dimethylformamide. After the aniline derivative has been completely reacted, the mixture is evaporated in vacuo, the residue is stirred with tert-butyl methyl ether, suction filtered under a nitrogen atmosphere and dried in an oil pump vacuum.
Yield: 30.3 g (96.2% of theory) of reddish solid

Analysis (based on solvent-free substance):
calc .: C 28.95; H 2.31; I 43.70; N 4.82; O 20.20;
Found: C 29.14; H 2.46; I 43.56; N 4.73.

c) tetracosakis {3, 5-bis- [N, N-bis- (sodium carboxylatomethyl) carbamoyl] -2,4,6- triiodophenylcarbamoyl} derivative of N, N, N ′, N ′, N ′ ′, N ′ ′ - hexakis- [2- (trilysyl-amino) - ethyl] trimesic acid triamide

5.50 g (0.92 mmol) of the poly-benzyloxycarbonylamine prepared according to Example 1d are converted into the corresponding polyamine hydrobromide as described in Example 1f. This is added to a solution of 28.8 g (33.1 mmol) of the isocyanate prepared in Example 3b and 6.93 ml (50 mmol) of triethylamine in 250 ml of anhydrous dimethyl sulfoxide, which is stirred at room temperature under an argon atmosphere. The mixture is stirred for 2 days at room temperature, then mixed with 70 ml of 2N sodium hydroxide solution and stirred at 50 ° C. for two hours. After cooling to room temperature, the solution is neutralized with 2N hydrochloric acid and then subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried.
Yield: 19.2 g (85.7% of theory) of yellowish lyophilisate

Analysis (based on anhydrous substance):
calc .: C 26.39; H 1.84; I 37.38; N 6.70; Na 9.03; O 18.65
Found: C 26.45; H 1.98; I 37.17; N 7.80; Na 8.76.

Example 4 Tetracosakis {3-sodium carboxylatoformylamino-5- (2, 3- dihydroxypropylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of N, N, N ′, N ′, N ′ ′, N ′ ′ - Hexakis (2- (trilysylamino) ethyl) trimesic acid triamide a) 5- (Ethoxycarbonylformylamino) -2,4,6-triiodisophthalic acid N- (2, 3- diacetoxypropyl) amide chloride

To a suspension of 73.4 g (100 mmol) of 5-amino-2,4,6-triiodisophthalic acid N- (2,3-diacetoxypropyl) amide chloride (EP 0308364) in 300 ml of anhydrous dioxane, stirred with exclusion of moisture 20.5 g (150 mmol) of monoethyl oxalate are added at room temperature. The mixture is boiled under reflux for several hours until, according to thin layer chromatography, no more educt can be detected, then the mixture is evaporated, the residue is taken up in dichloromethane and extracted with saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulfate, the organic phase is evaporated and the residue is recrystallized from ethyl acetate / tert-butyl methyl ether.
Yield: 73.9 g (88.6% of theory) of colorless crystals

Analysis (based on solvent-free substance):
calc .: C 27.35; H 2.17; Cl 4.25; I 45.62; N 3.36; O 17.25;
Found: C 27.33; H 2.28; Cl 4.17; I 45.49; N 3.42.

b) Tetracosakis {3-sodium carboxylatoformylamino-5- (2,3- dihydroxypropylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of N, N, N ′, N ′, N ′ ′, N ′ ′ - Hexakis [2- (trilysylamino) ethyl] trimesic acid triamide

5.99 g (1.00 mmol) of the polybenzyloxycarbonylamine prepared according to Example 1d are converted into the corresponding polyamine hydrobromide as described in Example 1f. This is added in 40 ml of water to a solution of 30.0 g (36.0 mmol) of the acid chloride prepared in Example 4a and 10.4 ml (75 mmol) of triethylamine in 200 ml of N, N-dimethylformamide, which is mechanically stirred at room temperature . The mixture is stirred for 2 days at room temperature, then mixed with 70 ml of 2N sodium hydroxide solution and stirred at 50 ° C. for two hours. After cooling to room temperature, the solution is neutralized with 2N hydrochloric acid and evaporated in vacuo; the residue is taken up in water, filtered and subjected to ultrafiltration, low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried.
Yield: 17.5 g (88.4% of theory) of colorless lyophilisate

Analysis (based on anhydrous substance):
calc .: C 26.80; H 2.28; I 46.23; N 6.59; Na 2.79; O 15.30;
Found: C 26.94; H 2.30; I 45.97; N 6.67; Na 2.60.

Example 5 Tetracosakis {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3- dihydroxy-propylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the N, N, N ′, N ′, N ′ ′, N ′ ′ - hexakis [2- (trilysylamino) ethyl] trimesic acid triamide a) Diglycolic acid chloride monoisopropyl ester

46.4 g (400 mmol) of diglycolic anhydride are added to 24.0 g (400 mmol) of anhydrous isopropanol with exclusion of moisture. The temperature of the exothermic reaction is moderated to 90-100 ° C with a water bath. After 1 hour, the reaction mixture is allowed to cool and 32.0 ml (440 mmol) of thionyl chloride and 0.1 ml of N, N-dimethylformamide are added and the mixture is stirred for 15 hours at room temperature and for 1 hour at 50 ° C. The title compound is obtained by distillation at 0.01 torr and a boiling point of 100-101 ° C.
Yield: 67.6 g (86.8% of theory) of colorless liquid
Gas chromatography (100% method): content 96.4%

Analysis (based on solvent-free substance):
calc .: C 43.20; H 5.70; Cl 18.22; O 32.88;
Found: C 43.34; H 5.83; Cl 18.01.

b) 5- [4- (2-methylethyloxycarbonyl) -3-oxabutyrylamino] -2,4,6-triiodoisophthalic acid- N- (2,3-diacetoxypropyl) amide chloride

To a suspension of 73.4 g (100 mmol) of 5-amino-2,4,6-triiodisophthalic acid N- (2,3-diacetoxypropyl) amide chloride (EP 0308364) in 500 ml of anhydrous dioxane, stirred with exclusion of moisture 29.2 g (150 mmol) of the acid chloride prepared according to Example 5a) were added at room temperature. The mixture is boiled under reflux for several hours until starting material is no longer detectable by thin layer chromatography, then the mixture is evaporated, the residue is taken up in dichloromethane and extracted with saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulfate, the organic phase is evaporated and the residue is recrystallized from ethyl acetate / tert-butyl methyl ether.
Yield: 68.2 g (76.4% of theory) of colorless crystals

Analysis (based on solvent-free substance):
calc .: C 29.60; H 2.71; Cl 3.97; I 42.65; N 3.14; O 32.88;
Found: C 29.77; H 2.83; Cl 3.92; I 42.41; N 3.38.

c) Tetracosakis {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2, 3- dihydroxy-propylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the N, N, N ′, N ′, N ′ ′, N ′ ′ - Hexakis [2- (trilysylamino) ethyl] trimesic acid triamide

8.32 g (1.39 mmol) of the polybenzyloxycarbonylamine prepared according to Example 1d are converted into the corresponding polyamine hydrobromide as described in Example 1f. This is added in 50 ml of water to a solution of 44.6 g (50.0 mmol) of the acid chloride prepared in Example 5b and 13.9 ml (100 mmol) of triethylamine in 200 ml of N, N-dimethylformamide, which is mechanically stirred at room temperature . The mixture is stirred for 2 days at room temperature, then mixed with 100 ml of 2N sodium hydroxide solution and stirred at 50 ° C. for two hours. After cooling to room temperature, the solution is neutralized with 2N hydrochloric acid and evaporated in vacuo. The residue is taken up in water, filtered and subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried.
Yield: 25.3 g (87.5% of theory) of colorless lyophilisate

Analysis (based on anhydrous substance):
calc .: C 28.21; H 2.63; I 43.89; N 6.26; Na 2.65; O 16.37;
Found: C 28.41; H 2.65; I 43.52, N 6.38; Na 2.47.

Example 6 Tetracosakis- {3- [N, N-bis- (sodium carboxylatomethyl) carbamoyl)] - 5- methoxyacetylamino-2,4,6-triiodobenzoyl} derivative of N, N, N ′, N ′, N ′ ′, N ′ ′ - hexakis [2- (trilysylamino) ethyl] trimesic acid triamide a) 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid-N, N-bis- (methoxycarbonylmethyl) amide chloride

A solution of 66.8 g (100 mmol) of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride (EP 0015867) in 300 ml of anhydrous N, N-dimethylformamide is mixed with 21.75 g (110 mmol) of dimethyl iminodiacetate hydrochloride (synthesis according to Dubsky, Graenacher, Chem. Ber. 50 1693 (1917)) and 30.5 ml (220 mmol) of triethylamine. A suspension is formed which is stirred under argon at room temperature for 14 hours. The mixture is taken up in dichloromethane, shaken once with water, twice with two normal aqueous citric acids and once with aqueous sodium hydrogen carbonate solution. The organic phase is dried over anhydrous magnesium sulfate and concentrated in vacuo. By dropwise addition of tert-butyl ether to the concentrated solution, the title compound can be precipitated as a crystalline solid, which is filtered off with suction and dried in vacuo.
Yield: 57.4 g (72.4% of theory)

Analysis (based on solvent-free substance):
calc .: C 25.76; H 2.04; Cl 4.47; I 48.04; N 3.54; O 16.15;
Found: C 25.82; H 2.11; Cl 4.48; I 48.01; N 3.38.

b) Tetracosakis- {3- [N, N-bis- (sodium carboxylatomethyl) carbamoyl)] - 5- methoxyacetylamino-2,4,6-triiodobenzoyl} derivative of N, N, N ′, N ′, N ′ ′, N ′ ′ - hexakis [2- (trilysylamino) ethyl] trimesic acid triamide

3.00 g (0.50 mmol) of the poly- Benzyloxycarbonylamines are described in Example 1f corresponding polyamine hydrobromide transferred. This is given in 20 ml Water to a solution of 15.0 g stirred mechanically at room temperature (18.0 mmol) of the acid chloride prepared in Example 6a and 6.9 ml (50 mmol) of triethylamine in 100 ml ml of N, N-dimethylformamide. The approach becomes 2  Stirred for days at room temperature, then mixed with 20 ml of 2N sodium hydroxide solution stirred at 50 ° C for two hours. The solution is opened after cooling Neutralized room temperature with 2N hydrochloric acid and evaporated in vacuo. Of the Residue is taken up in water and subjected to ultrafiltration, where low molecular weight components through a hollow fiber membrane (H1 P3-20, Amicon) can be separated.

The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried.
Yield: 9.12 g (85.6% of theory) of colorless lyophilisate

Analysis (based on anhydrous substance):
calc .: C 27.85; H 2.23; I 42.90; N 6.12; Na 5.18; O 16.00;
Found: C 27.97; H 2.25; I 42.68; N 6.23; Na 4.93.

Example 7 Dotriakontacontakis- {N- [3,5-di- (acetylamino) -2,4,6-triiodobenzoyl] -N- (sodium carboxylato-methyl) -glycyl} derivative of the deblocked 32-amine Example 7c a) N, N′-bis (benzyloxycarbonyl) -3- [carboxymethoxyacetyl] -3-azapentane-1,5-- diamine

37.14 g (100 mmol) of the bis (benzyloxycarbonylaminoethyl) amine described in Example 1a are dissolved in DMF, and 17.4 g (150 mmol) of diglycolic anhydride (Janssen Chimica) and 21 ml (150 mmol) of triethylamine are added in an ice bath and then stirred overnight at room temperature. The solution is evaporated in vacuo, the residue is taken up in ethyl acetate and extracted with dilute hydrochloric acid. The organic phase is dried with sodium sulfate and, after filtration from the drying agent, is crystallized by adding hexane.
Yield: 41.4 g (85% of theory)

Analysis:
calc .: C 59.13; H 6.00; N 8.62;
Found: C 58.99; H 5.93; N 8.70.

b) N, N ′, N ′ ′, N ′ ′ ′ - tetrakis {8- (benzyloxycarbonylamino) -6- [2- (benzyloxycarbonylamino) ethyl] -5-oxo-3-oxaoctanoyl} cycles

345 mg (2 mmol) 1,4,7,10-tetraazacyclododecane (Cyclen; Fluka) are with Toluene dewatered azeotropically. The cooled solution of cycles in toluene is a solution of 4.88 g (10 mmol) of N, N′-bis- at room temperature (benzyloxycarbonyl) -3- [carboxymethoxyacetyl] -3-azapentane-1,5-diamine (example 7a) in tetrahydrofuran (THF) and 2.47 g (10 mmol) of 2-ethoxy-1-ethoxycarbonyl 1,2-dihydroquinoline (EEDQ; Fluka) added and stirred overnight. To When the reaction is complete, the product is precipitated by adding hexane, decanted from the solvent and again from THF / hexane and  then reprecipitated from THF / toluene. After drying in a vacuum 2.78 g (68% of theory) of a pale yellow solid.

Analysis:
calc .: C 60.93; H 6.29; N 10.93;
Found: C 60.68; H 6.40; N 10.97.

c) Fully protected benzyloxycarbonyl-32-polyamine based on the from N, N ', N'',N''' - tetrakis [8-benzyloxycarbonylamino) -6- [2- (benzyloxycarbonylamino) -ethyl] -5-oxo -3-oxaoctanoyl] -cycles with N ^α , N ^ε -Bis- (lysyl) -lysine - ("tri-lysine") condensed 32-amine

2.05 g (1 mmol) of the octa-benzyloxycarbonylamine described in Example 7b are dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid are added with stirring. After 90 minutes, the beginning precipitation is completed with diethyl ether, the octaamine hydrobromide formed is washed with diethyl ether, dried in vacuo and used in the reaction described below without further purification.
Yield: 1.6 g (quantitative).

9.4 g (10 mmol) of the protected "tri-lysine" described in Example 1c, 1.5 g (10 mmol) of 1-hydroxybenzotriazole and 3.2 g (10 mmol) of 2- (1 H-benzotriazole-1 - yl) - 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU; Peboc Limited, UK) are dissolved in DMF and stirred for 15 minutes. This solution is then mixed with 5.16 ml (30 mmol) of N-ethyldiisopropylamine and with 1.6 g (1 mmol) of the octaamine hydrobromide described above and stirred overnight at room temperature. After the reaction has ended, the mixture is evaporated in vacuo and the residue is chromatographed on silica gel using dichloromethane / methanol (10: 1).
Yield: 6.0 g (72% of theory)

Analysis:
calc .: C 63.32; H 6.76; N 10.74;
Found: C 62.98; H 6.91; N 10.43.

d) 3,5-dinitrobenzoyl-N, N-bis (carboxymethyl) amide

133.1 g (1.00 mol) of iminodiacetic acid are dissolved in 1.50 1 of two normal sodium hydroxide solution and 230.6 g (1.00 mol) of 3,5-dinitrobenzoyl chloride are added with mechanical stirring. A dark red solution is formed, from which the title compound is precipitated by acidification with half-concentrated hydrochloric acid. The precipitate is filtered off, washed with water and dried in vacuo.
Yield: 260.5 g (79.6% of theory) of colorless crystals

Analysis (based on anhydrous substance):
calc .: C 40.38; H 2.77; N 12.84; O 44.01;
Found: C 40.42; H 2.85; N 12.63.

e) 3,5-diaminobenzoyl-N, N-bis (carboxymethyl) amide

32.7 g (100 mmol) of the dinitro compound described in Example 7d are placed in 500 ml of methanol, 1.6 g of palladium catalyst (10% palladium on activated carbon) are added and the mixture is hydrogenated with shaking with hydrogen. After the theoretical amount of hydrogen has been taken up, the catalyst is filtered off and evaporated to dryness. The residue is reacted further without purification.
Yield: 26.7 g (100% of theory) of a colorless solid

Analysis (based on solvent-free substance):
calc .: C 49.44; H 4.90; N 15.72; O 29.93;
Found: C 49.40; H 4.98; N 15.68.

f) 3,5-diamino-2,4,6-triiodobenzoyl-N, N-bis (carboxymethyl) amide

24.7 g (92.4 mmol) of the compound prepared in Example 7e are added in 200 ml of water and 150 ml of a two-normal iodine monochloride solution within 30 minutes. The mixture is stirred for 12 hours at room temperature and the precipitate formed is suction filtered. The solid is slurried in water, treated with 10 g sodium bisulfite and isolated again. The material is dissolved in 300 ml of water by adding 30% sodium hydroxide solution at pH 8, mixed with 2 g of activated carbon, stirred for 5 hours and filtered. Acidification of the filtrate with concentrated hydrochloric acid formed a precipitate, which was filtered off with suction and dried in vacuo.
Yield: 40.1 g (67.3% of theory) of a colorless solid

Analysis (based on anhydrous substance):
calc .: C 20.49; H 1.59; I 59.03; N 6.52; O 12.40;
Found: C 20.61; H 1.63; I 58.86; N 6.68.

g) 3,5-bis (acetylamino) -2,4,6-triiodobenzoyl-N, N-bis (carboxymethyl) amide

38.6 g (59.9 mmol) of the compound prepared in Example 7f are introduced into a mixture of 180 ml of acetic anhydride and 0.5 ml of concentrated sulfuric acid. After stirring overnight at room temperature, diethyl ether is added and the solid formed is filtered off. The solid is dissolved in 300 ml of water by adding 30% sodium hydroxide solution at pH 9 and then precipitated again by acidification with concentrated hydrochloric acid at pH 1. The precipitate is filtered off and dried in vacuo.
Yield: 29.9 g (68.6% of theory) of a colorless solid.

Analysis (based on anhydrous substance):
calc .: C 24.71; H 1.94; I 52.22; N 5.76; O 15.36;
Found: C 24.65; H 2.03; I 52.31; N 5.65.

h) N- [3,5-bis (acetylamino) -2,4,6-triiodobenzoyl] -2,6-dioxomorpholine

28.1 g (38.5 mmol) of the compound shown in Example 7g are dissolved in 56 ml of anhydrous pyridine, 7.3 ml (77 mmol) of acetic anhydride are added and the mixture is stirred at room temperature for 10 hours with the exclusion of moisture. The anhydride formed is precipitated by dropwise addition of anhydrous diethyl ether, filtered off and dried in vacuo.
Yield: 27.4 g (100% of theory) of a light beige solid

Analysis (based on solvent-free substance):
calc .: C 25.34; H 1.70; I 53.55; N 5.91; O 13.50;
Found: C 25.21; H 1.83; I 53.58; N 5.86; O 13.73.

i) Dotriakontacontakis- {N- [3,5-di- (acetylamino) -2,4,6-triiodobenzoyl] -N- (sodium carboxylato-methyl) -glycyl} derivative of the deblocked 32-amine Example 7c

4.17 g (0.5 mmol) of the poly-benzyloxycarbonylamine described in Example 7c are dissolved in glacial acetic acid and with stirring with 33 percent hydrogen bromide placed in glacial acetic acid. After 3 hours, the precipitation started with diethyl ether completed the resulting 32-amine hydrobromide with diethyl ether washed and dried in vacuo.

The solid is added to a solution of 17.1 g (24 mmol) of the anhydride prepared under Example 7h and 5.5 ml (40 mmol) of triethylamine in 100 ml of N, N-dimethylformamide, which is mechanically stirred at room temperature. The mixture is stirred for 2 days at room temperature and evaporated in vacuo. The residue is neutralized with 2N sodium hydroxide solution, filtered and subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried.
Yield: 11.3 g (82.3% of theory)

Analysis (based on anhydrous substance):
calc .: C 28.99; H 2.64; I 44.29; N 8.15; Na 2.67; O 13.26
Found: C 29.19; H 2.67; I 43.96; N 8.21; Na 2.53.

Example 8 Dotriakontacontakis- {3 - [(N-sodium carboxylatomethyl) methoxyacetylamino-5- (2,3-dihydroxypropylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the deblocked 32- Amines from Example 7c a) 5-Methoxyacetylamino-2,4,6-triiodoisophthalic acid-N- (2,3-diacetoxypropyl) -amide chloride

To a suspension of 73.4 g (100 mmol) of 5-amino-2,4,6-triiodisophthalic acid-N- (2,3-diacetoxypropyl) amide chloride (EP 0308364) in 500 ml of anhydrous dioxane, stirred with the addition of moisture 24.7 g (150 mmol) of methoxyacetyl chloride were added at room temperature. The mixture is boiled under reflux for several hours until, according to thin layer chromatography, no more educt can be detected, then the mixture is evaporated, the residue is taken up in dichloromethane and extracted with saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulfate, the organic phase is evaporated and the residue is recrystallized from ethyl acetate / tert-butyl methyl ether.
Yield: 73.2 g (90.7% of theory) of colorless crystals

Analysis (based on solvent-free substance):
calc .: C 26.81; H 2.25; Cl 4.40; I 47.21; N 3.47; O 15.87;
Found: C 26.79; H 2.32; Cl 4.48; I 47.13; N 3.44.

b) 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid N- (2,3-dihydroxyprop-yl) - monoamide

60.6 g (75.1 mmol) of the acid chloride prepared in Example 8a are dissolved in 3 53484 00070 552 001000280000000200012000285915337300040 0002019521945 00004 5336576 ml entered in a normal sodium hydroxide solution and under a nitrogen atmosphere about 45 min. stirred vigorously. The completeness of sales is about Thin layer chromatography checked and the product solution without working up used for the next stage.  

c) N-carboxymethyl-5-methoxyacetylamino-2,4,6-triiodisophthalic acid-N ′ - (- 2,3- dihydroxypropyl) monoamide

The solution of the starting material (75.1 mmol) prepared according to Example 8b is mixed with 17.5 g (150.2 mmol) of the sodium salt of chloroacetic acid under a nitrogen atmosphere and stirred at 90 ° C. for about 18 hours. The solution is adjusted to pH 1 with 2 normal hydrochloric acid and evaporated completely. The residue is chromatographed on silica gel 60 (Merck) (eluent dichloromethane / methanol / acetic acid (2: 2: 1). The product fractions are evaporated to dryness in vacuo and the residue is recrystallized from methanol / isopropanol.
Yield: 47.7 g (83.3% of theory) of colorless crystals

Analysis (based on solvent-free substance):
calc .: C 25.22; H 2.25; I 49.96; N 3.68; O 18.90;
Found: C 25.31; H 2.51; I 49.82; N 3.72.

d) N-methoxycarbonylmethyl-5-methoxyacetylamino-2,4,6-triiodisophthalic acid N ′ - (2, 3-dihydroxypropyl) monoamide

45.8 g (60.1 mmol) of the compound shown in Example 8c is introduced into 150 ml of anhydrous methanol and stirred under a nitrogen atmosphere. 5.6 ml (6.6 mmol) of dimethyl sulfite are added dropwise with stirring. The mixture is stirred for 4 hours at room temperature and boiled under reflux for 1 hour. It is then evaporated, the residue is stirred with isopropanol, filtered off and dried in vacuo.
Yield: 41.2 g (88.4% of theory) of colorless crystals

Analysis (based on solvent-free substance):
calc .: C 26.31; H 2.47; I 49.06; N 3.61; O 18.55;
Found: C 26.21; H 2.35; I 49.13; N 3.53.

e) N-methoxycarbonylmethyl-5-methoxyacetylamino-2,4,6-triiodisophthalic acid N ′ - (2, 3-diacetoxypropyl) monoamide

38.2 g (49.2 mmol) of the compound shown in Example 8d are stirred into a mixture of 16.3 ml (172 mmol) of acetic anhydride and 150 ml of dioxane with the exclusion of moisture. 0.60 g (4.9 mmol) of 4-N, N-dimethylaminopyridine are added and the mixture is stirred at 50 ° C. for 2 hours. The mixture is then evaporated, the residue is stirred with ethyl acetate / tert-butyl methyl ether, filtered off and dried in vacuo.
Yield: 37.0 g (87.4% of theory) of a colorless solid

Analysis (based on solvent-free substance):
calc .: C 29.32; H 2.70; I 44.26; N 3.26; O 20.46;
Found: C 29.38; H 2.77; I 44.17; N 3.30.

f) N-methoxycarbonylmethyl-5-methoxyacetylamino-2,4,6-triiodisophthalic acid N ′ - (2,3-diacetoxypropyl) amide chloride

35.6 g (41.4 mmol) of the compound described in Example 8e are introduced into 150 ml of 1,2-dichloroethane. 0.1 ml of N, N-dimethylformamide and 4.50 ml (62.1 mmol) of thionyl chloride are added to the suspension which is stirred at room temperature with the exclusion of moisture. The mixture is boiled under reflux until gas evolution can no longer be observed. The solution now present is evaporated in vacuo, the residue is taken up in dichloromethane and extracted with saturated, aqueous sodium hydrogen carbonate solution. The organic phase is dried over anhydrous magnesium sulfate and filtered. Dropwise addition of tert-butyl methyl ether to the concentrated filtrate gives a colorless precipitate which is filtered off with suction and dried in vacuo.
Yield: 30.6 g (84.1% of theory) of a colorless solid.

Analysis (based on solvent-free substance):
calc .: C 28.71; H 2.52; Cl 4.04; I 43.33; N 3.19; O 18.21;
Found: C 28.81; H 2.80; Cl 4.28; I 43.17; N 3.21.

g) Dotriakontacontakis- {3 - [(N-sodium carboxylatomethyl) methoxyacetylamino- 5- (2,3-dihydroxypropylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the deblocked 32-amines from Example 7c

4.17 g (0.5 mmol) of the poly-benzyloxycarbonylamine described in Example 7c are dissolved in glacial acetic acid and with stirring with 33 percent hydrogen bromide placed in glacial acetic acid. After 3 hours, the precipitation started with diethyl ether completed the resulting 32-amine hydrobromide with diethyl ether washed and dried in vacuo.

The solid is dissolved in 30 ml of water and a solution of 21.1 g (24.0 mmol) of the acid chloride prepared in Example 8f and 5.5 ml (40 mmol) of triethylamine in 100 ml of N, N- mechanically stirred at room temperature. Dimethylformamide added dropwise. The mixture is stirred for 2 days at room temperature, then mixed with 60 ml of 2N sodium hydroxide solution and stirred at 50 ° C. for two hours. After cooling to room temperature, the solution is neutralized with 2N hydrochloric acid and evaporated in vacuo. The residue is taken up in water and subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried.
Yield: 12.9 g (90.0% of theory) of colorless lyophilisate

Analysis (based on anhydrous substance):
calc .: C 29.26; H 2.88; I 42.65; N 6.28; Na 2.58; O 16.35;
Found: C 29.51; H 3.01; I 42.34; N 6.40; Na 2.49.

Example 9 Dotriacontakis- {3,5- [N, N-bis (sodium carboxylatomethyl) carbamoyl)] - 2,4,6- triiodophenylthiocarbamoyl} derivative of the deblocked 32-amine from Example 9f a) 1.11 -Bis- (benzyloxycarbonylamino) -3,9-bis [-2- (benzyloxycarbonylamino) -ethyl] - 4,8-dioxo-6- (4-nitrophenyl) -3,9-diazaundecane

6.33 g (25 mmol) of 3- (4-nitrophenyl) glutaric acid (J. Org. Chem., 26 3856 (1961)), 6.33 g (55 mmol) of N-hydroxysuccinimide and 20.43 g (55 mmol) of the bis (benzyloxycarbonylaminoethyl) amine described in Example 1a are dissolved in DMF and, after adding 11.35 g (55 mmol) of dicyclohexylcarbodiimide, stirred for 3 days at room temperature. The precipitated dicyclohexylurea is then filtered off, the filtrate is evaporated to dryness in vacuo and purified by chromatography on silica gel with ethyl acetate as the eluent.
Yield: 17.3 g (72% of theory)

Analysis:
calc .: C 63.81; H 5.98; N 10.21;
Found: C 63.94; H 5.77; N 10.26.

b) 1,11-bis- (benzyloxycarbonylamino) -3,9-bis- [2- (benzyloxycarbonylamino) ethyl] - 4,8-dioxo-6- (4-aminophenyl) -3,9-diazaundecane

15.57 g (56 mmol) FeSO₄ × 7 H₂O are dissolved in water and combined with 7.68 g (8 mmol) of the nitro compound described in Example 9a in the same volume of ethanol and heated to boiling. At this temperature, 24 ml of conc. Ammonia added dropwise, whereby a black precipitate forms. The suspension is allowed to cool slowly with stirring, then the mixture is filtered, the precipitate is washed with ethyl acetate and the combined filtrates are evaporated to dryness in vacuo. The residue is chromatographed on silica gel using ethyl acetate / ethanol (98: 2).
Yield: 4.84 g (65% of theory)

Elemental analysis:
calc .: C 65.86; H 6.39; N 10.54.
Found: C 65.68; H 6.31; N 10.62.

c) N, N ′, N ′ ′, N ′ ′ ′ - cyclen-tetra-ureido conjugate from 1,4,7,10-tetraazacyclododecane 5 with 1,11-bis (benzyloxycarbonylamino) -3,9-bis [2- (benzyloxycarbonylamino) - ethyl] -4,8-dioxo-6- (4-isocyanatophenyl) -3,9-diazaundecane

4.65 g (5 mmol) of the phenylamine described in Example 9b are dissolved in toluene, evaporated to dryness twice for dehydration and taken up again with fresh toluene. The solution of the amine in toluene dried in this way is mixed with 0.54 g (1.8 mmol) of triphosgene at 10 ° C., stirred for one hour at 10 ° C. and overnight at room temperature. 0.17 g (1 mmol) of anhydrous 1,4,7,10-tetraazacyclododecane (Cyclen) (Aldrich) in toluene / pyridine (10: 1) are added to this suspension and the mixture is stirred overnight at room temperature. The mixture is then evaporated to dryness in vacuo and the residue is chromatographed on silica gel in ethyl acetate.
Yield: 3.55 g (89% of theory)

Analysis:
calc .: C 64.98; H 6.16; N 11.23;
Found: C 64.70; H 6.29; N 11.04.

d) N, N-bis- [2- (benzyloxycarbonylamino) ethyl] glycine tert-butyl ester

18.6 g (50 mmol) of the bis [2- (benzyloxycarbonylamino) ethyl] amine described in Example 1a in tetrahydrofuran / water (25: 1) are mixed with 4.2 g (30 mmol) of potassium carbonate. 11.7 g (60 mmol) of tert-butyl bromoacetate are added dropwise to this suspension at room temperature and the mixture is then stirred at this temperature overnight. The undissolved material is filtered off, the filtrate is evaporated to dryness and chromatographed on silica gel (diethyl ether / diisopropyl ether 1: 1).
Yield: 20.4 g (84% of theory)

Analysis:
calc .: C 64.31; H 7.26; N 8.65;
Found: C 64.35; H 7.00; N 8.58.

e) N, N-bis [2- (benzyloxycarbonylamino) ethyl] glycine

19.4 g (40 mmol) of the t-butyl ester described in Example 9d are mixed with 150 ml of trifluoroacetic acid and stirred for 20 minutes at room temperature. The product is then precipitated by adding diethyl ether and stirred once more with ether and finally with water. The precipitate is filtered off and dried.
Yield: 13.4 g (78% of theory)

Analysis:
calc .: C 61.52; H 6.34; N 9.79;
Found: C 61.64; H 6.20; N 9.94.

f) Fully protected benzyloxycarbonyl-32-polyamine from the with N, N-bis- [2- (benzyloxycarbonylamino) ethyl] glycine condensed N, N ′, N ′ ′, N ′ ′ ′ - cyclen- Tetra-ureido conjugate from Example 9c

3.99 g (1 mmol) of the hexadeca- benzyloxycarbonylamine described in Example 9c are dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid are added with stirring. After 90 minutes, the precipitation started is completed with diethyl ether, the resulting hexadeca amine hydrobromide is washed with ether, dried in vacuo and used in the reaction described below without further purification.
Yield: 3.2 g (quantitative).

8.6 g (20 mmol) of the N, N-bis [2- (benzyloxycarbonylamino) ethyl] glycine described in Example 9e, 3.2 g (20 mmol) of 1-hydroxybenzotriazole and 6.4 g (20 mmol) 2- (1 H-Benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU; Peboc Limited, UK) are dissolved in DMF and stirred for 15 minutes. This solution is then mixed with 13.76 ml (80 mmol) of N-ethyldiisopropylamine and with 3.2 g (1 mmol) of the hexadeca amine hydrobromide described above and stirred overnight at room temperature. After the reaction has ended, the mixture is evaporated in vacuo and the residue is chromatographed on silica gel using dichloromethane / methanol (9: 1).
Yield: 7.3 g (87% of theory)

Analysis:
calc .: C 62.69; H 6.55; N 13.29;
Found: C 62.37; H 6.72; N 13.38.

g) 5-isothiocyanato-2,4,6-triiodoisophthalic acid-N, N'-bis- (methoxycarbonylmethyl) - diamid

To a suspension of 17.3 g (24.7 mmol) of the aniline derivative described in Example 2c in 170 ml of 1,2-dichloroethane, stirred at room temperature, 20 ml of polyvinylpyridine (Reillex), 50 ml of water and 3.66 ml (49, 4 mmol) of thiophosgene in 30 ml of 1,2-dichloroethane were added. After stirring for three hours at 50 ° C., the mixture is taken up in dichloromethane, the organic phase is separated off, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated in vacuo, the residue is extracted with ethyl acetate, suction filtered and dried in vacuo.
Yield: 16.6 g (90.7% of theory) of a light beige solid

Analysis (based on solvent-free substance):
calc .: C 24.25; H 1.63; I 51.24; N 5.66; O 12.92, S 4.32;
Found: C 24.33; H 1.74; I 51.12; N 5.65; S 4.53.

h) Dotriacontakis- {3,5- [N, N-bis (sodium carboxylatomethyl) carbamoyl)] - 2,4,6- triiodophenylthiocarbamoyl} derivative of the deblocked 32-amine from Example 9f

4.23 g (0.5 mmol) of the poly-benzyloxycarbonylamine described in Example 9f are dissolved in glacial acetic acid while stirring with 33 percent hydrogen bromide Glacial acetic acid. After 3 hours, the precipitation started with diethyl ether completed, the resulting 32-amine hydrobromide washed with ether and dried in vacuo.

The solid is added dropwise to a solution of 17.8 g (24.0 mmol) of the isothiocyanate described in Example 9g and 2.0 (14 mmol) of triethylamine in 120 ml of dimethyl sulfoxide, which is stirred mechanically at room temperature. The mixture is stirred for 2 days at room temperature, then mixed with 30 ml of 2N sodium hydroxide solution and stirred at 50 ° C. for two hours. After cooling to room temperature, the solution is neutralized with 2N hydrochloric acid and evaporated in vacuo. The residue is taken up in water and subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried.
Yield: 11.9 g (83.6% of theory) of colorless lyophilisate.

Analysis (based on anhydrous substance):
calc .: C 25.35; H 1.94; I 42.86; N 8.67; Na 5.18; O 12.38; S 3.61;
Found: C 25.63; H 2.02; I 42.55; N 7.73; Na 5.28; S 3.52.

Example 10 Dotriacontakis- {3-sodium carboxylatomethylcarbamoyl-5 - [(N-methoxyacetyl) methylamino] -2,4,6-triiodobenzoyl derivative of the deblocked 32-amine from Example 9f a) N-methoxyacetyl-5-methylamino-2,4,6-triiodisophthalic acid-N'- ethoxycarbonylmethyl amide chloride

A solution of 68.2 g (100 mmol) of N-methoxyacetyl-5-methylamino-2,4,6-triiodisophthalic acid dichloride (EP 0015867) in 500 ml of N, N-dimethylformamide is mixed with 14.0 g (100 mmol) of glycine ethyl ester. Hydrochloride (preparation according to DA Hoogwater, M. Peereboom, Tetrahedron, 46, 5325-5332 (1990)) and 10.1 g 100 mmol) triethylamine added. A suspension is formed which is stirred overnight under argon at room temperature. The mixture is then evaporated and the residue is chromatographed on silica gel 60 (Merck) with dichloromethane / ethyl acetate. After evaporation of the product fractions, a colorless solid is obtained, which is dried in vacuo.
Yield: 53.4 g (71.49% of theory)

Analysis (based on solvent-free substance):
calc .: C 25.68; H 2.15; Cl 4.74; I 50.87; N 3.74; O 12.83:
Found: C 25.84; H 2.31; Cl 4.62; I 50.59; N 3.69.

b) Dotriacontakis- {3-sodiumcarboxylatomethylcarbamoyl-5 - [(N-methoxyacetyl) methylamino] - 2,4,6-triiodobenzoyl- Derivative of the deblocked 32-amine from example 9f

4.23 g (0.5 mmol) of the poly-benzyloxycarbonylamine described in Example 9f are dissolved in glacial acetic acid while stirring with 33 percent hydrogen bromide Glacial acetic acid. After 3 hours, the precipitation started with diethyl ether completed, the resulting 32-amine hydrobromide washed with ether and dried in vacuo.

The solid is dissolved in 30 ml of water to give a solution of 18.0 g (24.0 mmol) of the acid chloride prepared in Example 10a and 6.9 ml (50.0 mmol) of triethylamine in 120, which is mechanically stirred under an argon atmosphere at room temperature ml of N, N-dimethylformamide added. The mixture is stirred for 2 days at room temperature, then mixed with 50 ml of 2N sodium hydroxide solution and stirred at 50 ° C. for 1.5 hours. After cooling to room temperature, the solution is neutralized with 2 N hydrochloric acid and evaporated in vacuo. The residue is taken up in water and subjected to ultrafiltration, with low-molecular constituents being separated off by a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 μm, Sartorius) and freeze-dried.
Yield: 11.9 g (88.8% of theory) of colorless lyophilisate

Analysis (based on anhydrous substance):
calc .: C 28.40; H 2.55; I 45.58; N 7.55; Na 2.75; O 13.17;
Found: C 28.61; H 2.62; I 45.37; N 7.64; Na 2.63.

Example 11 Dotriaconiakis- {N-methoxyacetyl-3-methylamino-5- (2- sodium sulfonatoethylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the deblocked 32-amines from Example 11b a) N, N ′, N ′ ′, N ′ ′ ′ - tetrakis {N, N-bis- [2- (benzyloxycarbonylamino) ethyl] glycyl} - cyclen

345 mg (2 mmol) 1,4,7,10-tetraazacyclododecane (Cyclen; Fluka) are dewatered azeotropically with toluene. A solution of 4.29 g (10 mmol) of the N, N-bis [2- (benzyloxycarbonylamino) -ethyl] -glycine in tetrahydrofuran (THF) and 2. Is added to the cooled solution of cycles in toluene at room temperature , 47 g (10 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ; Fluka) were added and the mixture was stirred overnight. The solution is evaporated to dryness in vacuo and chromatographed on silica gel in ethyl acetate / methanol (10: 1).
Yield: 2.69 g (74% of theory)

Analysis:
calc .: C 63.42; H 6.65; N 12.33;
Found: C 63.17; H 6.80; N 12.28.

b) Fully protected benzyloxycarbonyl-32-polyamine based on the N, N ′, N ′ ′, N ′ ′ ′ - Tetrakis {N, N-bis- [2- (trilysylamino) ethyl] glycyl} cyclene

1.82 g (1 mmol) of the octa-benzyloxycarbonylamine described in Example 11a are dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid are added with stirring. After 90 minutes, the beginning precipitation is completed with diethyl ether, the octaamine hydrobromide formed is washed with ether, dried in vacuo and used in the reaction described below without further purification.
Yield: 1.39 g (quantitative).

9.4 g (10 mmol) of the protected "tri-lysine" described in Example 1c, 1.5 g (10 mmol) of 1-hydroxybenzotriazole and 3.2 g (10 mmol) of 2- (1H-benzotriazol-1-yl ) - 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU; Peboc Limited, UK) are dissolved in DMF and stirred for 15 minutes. This solution is then mixed with 5.16 ml (30 mmol) of N-ethyldiisopropylamine and with 1.39 g (1 mmol) of the octaamine hydrobromide described above and stirred overnight at room temperature. After the reaction has ended, the mixture is evaporated in vacuo and the residue is chromatographed on silica gel using dichloromethane / methanol (10: 1).
Yield: 6.0 g (74% of theory)

Analysis:
calc .: C 63.95; H 6.86; N 11.05;
Found: C 64.23; H 7.01; N 10.92.

c) N-methoxyacetyl-5-methylamino-2,4,6-triiodisophthalic acid-N ′ - (2-bromomethyl) amide chloride

A solution of 68.2 g (100 mmol) of N-methoxyacetyl-5-methylamino-2,4,6-triiodoisophthalic acid dichloride (EP 0015867) in 500 ml of N, N-dimethylformamide is mixed with 20.5 g (100 mmol) 2 -Bromethylamine hydrobromide and 20.2 g (200 mmol) of triethylamine were added. A suspension is formed which is stirred overnight under argon at room temperature. The mixture is then evaporated and the residue is chromatographed on silica gel 60 (Merck) with dichloromethane / ethyl acetate. After evaporation of the product fractions, a colorless solid is obtained, which is dried in vacuo.
Yield: 55.3 g (71.88% of theory)

Analysis (based on solvent-free substance):
calc .: C 21.86; H 1.70; Br 10.39; Cl 4.61; I 49.49; N 3.64; O 8.32;
Found: C 21.84; H 1.81; Br 10.48; Cl 4.62; I 49.59; N 3.69.

d) Dotriacontakis- {N-methoxyacetyl-3-methylamino-5- (2- sodium sulfonatoethylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the deblocked 32-amines from Example 11b

4.06 g (0.5 mmol) of the poly- described in Example 11b Benzyloxycarbonylamines are dissolved in glacial acetic acid while stirring with 33  percent hydrogen bromide added to glacial acetic acid. After 3 hours with Diethyl ether completed the precipitation started, the resulting 32-amine hydrobromide washed with ether and dried in vacuo.

The residue is then taken up in water and added to a solution of 18.5 g (24.0 mmol) of the acid chloride prepared under Example 11c and 8.3 ml (60 mmol) of triethylamine in 100 ml of N, which is mechanically stirred at room temperature under an argon atmosphere. N-Dimethylformamide added dropwise. The mixture is stirred for 2 days at room temperature and, after adding 30.2 g (0.24 mmol) of sodium sulfite in 100 ml of water, stirring is continued for 72 h. The mixture is then filtered and the filtrate is subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 μm, Sartorius) and freeze-dried.
Yield: 8.9 g (63.7% of theory) of colorless lyophilisate

Analysis (based on anhydrous substance):
calc .: C 26.75; H 2.68; I 43.49; N 6.40; Na 2.63; O 14.39; S 3.66;
Found: C 27.04; H 2.77; I 43.19; N 6.56; Na 2.38; S 3.48.

Example 12 Dotriacontakis- {3,5-bis- (disodium phosphonatomethylcarbamoyl) -2,4,6- triiodarylcarbamoyl} derivative of the deblocked 32-amine from Example 11b a) 5-Amino-2,4,6-triiodoisophthalic acid-N, N'-bis- (diethylphosphonomethyl) - diamide

A solution of 59.6 g (100 mmol) of 5-amino-2,4,6-triiodoisophthalic acid dichloride (DOS 2926428) in 300 ml of N, N-dimethylformamide is mixed with 36.8 g (220 mmol) of aminomethanephosphonic acid diethyl ester and 61.0 ml (440 mmol) triethylamine added. A suspension is formed which is stirred under argon overnight at room temperature. After evaporating the suspension in vacuo, the residue is recrystallized from methanol.
Yield: 59.8 g (69.8% of theory)

Analysis (based on solvent-free substance):
calc .: C 25.22; H 3.29; I 44.42; N 4.90; P 7.23; O 14.93;
Found: C 25.16; H 3.41; I 44.26; N 4.78; P 7.17.

b) 5-isocyanato-2,4,6-triiodoisophthalic acid-N, N'-bis- (diethylphosphonomethyl) - diamid

147 ml (73.8 mmol) of a two-normal toluene phosgene solution and 2 ml are added to a suspension of 25.7 g (30 mmol) of the aniline derivative prepared in Example 12a in 200 ml of 1,2-dichloroethane and stirred at 65 ° C. in an argon atmosphere under an argon atmosphere N, N-dimethylformamide added. After the aniline derivative has been completely reacted, the mixture is evaporated in vacuo, the residue is stirred with anhydrous ethyl acetate, suction filtered under a nitrogen atmosphere and dried in an oil pump vacuum.
Yield: 25.6 g (96.7% of theory) of a light beige solid

Analysis (based on solvent-free substance):
calc .: C 25.84; H 2.97; I 43.11; N 4.76; P 7.02; O 16.31;
Found: C 25.72; H 3.08; I 42.98; N 4.59; P 6.91.

c) Dotriacontakis- {3,5-bis- (disodium phosphonatomethylcarbamoyl) -2,4,6- triiodarylcarbamoyl} derivative of the deblocked 32-amine from Example 11b

4.06 g (0.5 mmol) of the polybenzyloxycarbonylamine described in Example 11b are dissolved in glacial acetic acid, with 33 percent hydrogen bromide in glacial acetic acid being added with stirring. After 3 hours, the precipitation started is completed with diethyl ether, the 32-amine hydrobromide formed is washed with ether and dried in vacuo. The residue is then added to a solution of 21.2 g (24.0 mmol) of the isocyanate prepared in Example 12b and 2.35 ml (17.0 mmol) of triethylamine in 200 ml of anhydrous dimethyl sulfoxide, which is stirred at room temperature under an argon atmosphere. The mixture is stirred for 3 days at room temperature, then evaporated in a high vacuum, 13.8 ml (108 mmol) of bromotrimethylsilane are added and the mixture is stirred at 50 ° C. for 24 hours. 150 ml of water are added dropwise to the crude product and the mixture is stirred at room temperature for four hours. After neutralization with sodium hydroxide solution, the mixture is filtered and the filtrate is subjected to ultrafiltration, low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried.
Yield: 11.1 g (71.1% of theory) of yellowish lyophilisate.

Analysis (based on anhydrous substance):
calc .: C 20.26; H 1.78; I 38.92; N 7.16; Na 9.40; O 16.15; P 6.33;
Found: C 20.62; H 2.86; I 38.60; N 7.31; Na 9.03; P 6.30.

Example 13 Octatetracontakis- {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3-dihydroxy propylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the deblocked 48-amine Example 13d a) N, N, N ′, N ′, N ′ ′, N ′ ′ - hexakis- [2- [N, N-bis- {2-benzyloxycarbonylamino-ethyl) -amino] - ethyl} trimesic acid triamide

1.27 g (1 mmol) of the hexa-benzyloxycarbonylamine described in Example 1b are dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid are added with stirring. After 60 minutes, the precipitation started is completed with diethyl ether, the hexamine hydrobromide formed is washed with ether, dried in vacuo and used in the reaction described below without further purification.
Yield: 0.95 g (quantitative).

0.95 g (1 mmol) of the hydrobromide thus produced are suspended in 50 ml of acetonitrile and 3 ml of triethylamine are added. Then 3.54 g (20 mmol) of N-benzyloxycarbonyl aziridine (produced according to J. Chem. Soc. Perkin Trans. 1, 21-26, 1993) are added and the mixture is heated under reflux under nitrogen for 5 days. It is evaporated to dryness, taken up in 100 ml of methylene chloride and washed twice with 100 ml of 5 percent potassium carbonate solution. The methylene chloride phase is dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / methanol / triethylamine 20: 1: 0.1).
Yield: 2.31 g (89% of theory) of a pale yellow viscous oil

Analysis:
calc .: C 65.34; H 6.65; N 11.35;
Found: C 65.12; H 6.80; N 11.19.

b) N, N, N ′, N ′, N ′ ′, N ′ ′ - hexakis- {2- [N, N-bis- (2-aminoethyl) amino] ethyl} - trimesic acid triamide

2.2 g (0.85 mmol) of the title compound from Example 13a are dissolved in 100 ml of methanol and 3 g of Pearlman catalyst (palladium hydroxide on activated carbon; Fluka) are added. The mixture is hydrogenated for 10 hours at 5 bar (room temperature). The catalyst is filtered off and the filtrate is evaporated to dryness.
Yield: 825 mg (99% of theory)

Analysis:
calc .: C 55.02; H 10.16; N 26.94;
Found: C 54.87; H 10.25; N 29.85.

c) Fully protected benzyloxycarbonyl-24-polyamine based on the N, N, N ′, N ′, N ′ ′, N ′ ′ - hexakis- {2- [N, N-bis- (2- (N, N-bis-aminoethyl) amino) ethyl] - aminoethyl} trimesic acid triamide

800 mg (0.814 mmol) of the title compound from Example 13b are dissolved in 150 ml of acetonitrile and 5.77 g (32.56 mmol) of N-benzyloxycarbonyl aziridine (produced according to J. Chem. Soc., Perkin Trans., 1, 21-26 , 1993) and refluxed for 5 days (under nitrogen). It is evaporated to the dry state in a vacuum and chromatographed on silica gel (mobile solvent: methylene chloride / methanol / triethylamine 20: 1: 0.1).
Yield: 3.62 g (85% of theory) of a glassy solid

Analysis:
calc .: C 65.39; H 6.99; N 12.04;
Found: C 65.21; H 7.10; N 11.90.

d) Fully protected benzyloxycarbonyl-48-polyamine based on the 24-lysyl Derivative of Example 13c

1.05 g (0.2 mmol) of the title compound from Example 13c are dissolved in 30 ml of methanol and 1 g of Pearlman catalyst (palladium hydroxide on activated carbon) is added. The mixture is hydrogenated for 10 hours at 5 bar (room temperature). The catalyst is filtered off, the filtrate is evaporated to dryness and used in the reaction described below.
Yield: 0.40 g (quantitative).

3.11 g (7.5 mmol) N _a , N _e -Bis- (benzyloxycarbonyl) lysine (Bachem, Switzerland), 1.2 g (7.5 mmol) 1-hydroxybenzotriazole and 2.4 g (7, 5 mmol) of 2- (1 H-benzotriazol-1-yl) 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU; Peboc Limited, UK) are dissolved in DMF and stirred for 15 minutes. This solution is then mixed with 5.16 ml (30 mmol) of N-ethyldiisopropylamine and with 0.40 g (0.2 mmol) of the 24-polyamine described above and stirred overnight at room temperature. After the reaction has ended, the mixture is evaporated in vacuo and the residue is chromatographed on silica gel using ethyl acetate / ethanol / triethylamine (2: 1: 0.2).
Yield: 1.36 g (59% of theory)

Analysis:
calc .: C 64.69; H 6.95; N 11.30;
Found: C 64.42; H 7.11; N 11.19.

e) Octatetrocontakis- {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3- dihydroxypropylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the deblocked 48- Amines from Example 13d

1.15 g (0.10 mmol) of the title compound from Example 13d are in glacial acetic acid dissolved and mixed with 33 percent hydrogen bromide in glacial acetic acid while stirring. After 3 hours, the precipitation started is completed with diethyl ether Resulting 48-amine hydrobromide washed with ether and in vacuo dried.

The residue is then taken up in water and added to a solution of 6.4 g (7.2 mmol) of the acid chloride prepared in Example 5b and 2.1 ml (15 mmol) of triethylamine in 25 ml of anhydrous N, N, which is stirred at room temperature under an argon atmosphere -Dimethylformamide added. The mixture is stirred for 3 days at room temperature, then mixed with 14 ml of 2N sodium hydroxide solution and stirred at 50 ° C. for 2 hours. After evaporation in vacuo, a yellowish oil is obtained which is dissolved in water. The aqueous solution is adjusted to pH 7.3, filtered and the filtrate is subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried.
Yield: 3.79 g (92.2% of theory) of yellowish lyophilisate.

Analysis (based on anhydrous substance):
calc .: C 27.91; H 2.65; I 44.37; N 6.43; Na 2.68; O 15.97;
Found: C 28.20; H 2.77; I 43.94; N 6.54; Na 2.45.

Example 14 Tetracosakis {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3-dihydroxy propylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of 1,4,7,10,13,1 6-hexakis [2- (trilysylamino) ethyl] hexacyclene a) 1,4,7,10,13,1 6-hexakis [2- (benzyloxycarbonylamino) ethyl] -1,4,7,10,13,16- Hexaazacyclooctadecane

1.29 g (5 mmol) 1,4,7,10,13,16-hexaazacyclooctadecane (Hexacyclen; Fluka) are dewatered azeotropically with toluene. A solution of 10.63 g (60 mmol) of N-benzyloxycarbonylaziridine (J. Chem. Soc., Perkin Trans. 1, 21-26, 1993) in acetonitrile is added to the solution of hexacycles in toluene, cooled to room temperature, and 3 days heated under reflux under nitrogen. The mixture is evaporated to dryness and the residue is chromatographed in ethyl acetate / methanol / triethylamine (8: 2: 0.5) on silica gel.
Yield: 5.68 g (86% of theory) of a pale yellow, viscous oil

Analysis:
calc .: C 65.43; H 7.32; N 12.72;
Found: C 65.20; H 7.51; N 12.49.

b) Fully protected benzyloxycarbonyl-24-polyamine based on the 1,4,7,10,13,16-hexakis [2- (trilysylamino) ethyl] hexacyclene

1.32 g (1 mmol) of the hexa- benzyloxycarbonylamine described in Example 14a are dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid are added with stirring. After 60 minutes, the precipitation started is completed with diethyl ether, the hexaamine hydrobromide formed is washed with ether, dried in vacuo and used in the reaction described below without further purification.
Yield: 1.48 g (quantitative).

7.0 g (7.5 mmol) of the protected "tri-lysine" described in Example 1c, 1.2 g (7.5 mmol) of 1-hydroxybenzotriazole and 2.4 g (7.5 mmol) of 2- (1 H-Benzotriazol-1-yl) - 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU; Peboc Limited, UK) are dissolved in DMF and stirred for 15 minutes. This solution is then mixed with 5.16 ml (30 mmol) of N-ethyldiisopropylamine and with 1.48 g (1 mmol) of the hexa-amine hydrobromide described above and stirred overnight at room temperature. After the reaction has ended, the mixture is evaporated in vacuo and the residue is chromatographed on silica gel using dichloromethane / methanol (10: 1).
Yield: 5.02 g (83% of theory)

Analysis:
calc .: C 64.40; H 7.00; N 11.13;
Found: C 64.16; H 6.82; N 10.88.

c) Tetracosakis {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3-dihydroxy propylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of 1,4,7,10,13,1 6-hexakis [2- (trilysylamino) ethyl] hexacyclene

3.02 g (0.5 mmol) of the polybenzyloxycarbonylamine described in Example 14b are dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid are added with stirring. After 3 hours, the precipitation started is completed with diethyl ether, the resulting 24-amine hydrobromide is washed with ether and dried in vacuo. The residue is then taken up in water and a solution of 16.1 g (18.0 mmol) of the acid chloride prepared in Example 5b and 5.5 ml (40 mmol) of triethylamine in 100 ml of anhydrous N, N, stirred at room temperature under an argon atmosphere -Dimethylformamide added. The mixture is stirred for 3 days at room temperature, then mixed with 36 ml of 2N sodium hydroxide solution and stirred at 50 ° C. for 2 hours. After evaporation in vacuo, a yellowish oil is obtained which is dissolved in water. The aqueous solution is adjusted to pH 7.3, filtered and the filtrate is subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried.
Yield: 8.80 g (84.4% of theory) of yellowish lyophilisate.

Analysis (based on anhydrous substance):
calc .: C 28.31; H 2.72; I 43.78; N 6.44; Na 2.64; O 16.10;
Found: C 28.30; H 2.75; I 43.36; N 6.59; Na 2.53.

Example 15 Tetrahexacontakis- {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3- dihydroxypropylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the deblocked 64- Polyamines from Example 15e a) N, N, N ′, N′-tetrakis [2- (benzyloxycarbonylamino) ethyl] -5-nitro- isophthalic acid diamide

14.86 g (40 mmol) of the bis [2- (benzyloxycarbonylamino) ethyl] amine described in Example 1a and 20.24 g (200 mmol) of triethylamine are dissolved in dimethylformamide and 4.96 g (20 mmol) 5 Nitro isophthalic acid dichloride (J. Chem. Soc. 1957, 1172-1175) was added and the mixture was stirred overnight at room temperature. The solution is evaporated in vacuo and the residue is chromatographed on silica gel using ethyl acetate.
Yield: 11.5 g (62.6%) of a viscous oil

Analysis:
calc .: C 62.80; H 5.60; N 10.68;
Found: C 62.62; H 5.77; N 10.41.

b) N, N, N ′, N′-tetrakis [2- (benzyloxycarbonylamino) ethyl] -5-amino- isophthalic acid diamide

9.18 g (10 mmol) of the nitro compound described in the previous example in 200 ml of ethanol become a solution of 27.8 g (100 mmol) FeSO₄ × 7 H₂O in 200 ml of water added and heated to boiling. After adding 50 ml of conc. Ammonia is stirred under reflux for a further 90 minutes. You leave them Cool suspension, then the ethanol is concentrated in vacuo and the aqueous phase shaken with ethyl acetate. After drying, is obtained Sodium sulfate 8.61 g (97% of theory) of an almost colorless viscous oil.  

Analysis:
calc .: C 64.93; H 6.02; N 11.04;
Found: C 65.10; H 5.96; N 10.89.

c) N, N, N ', N'-tetrakis [2- (benzyloxycarbonylamino) ethyl] -5- (carboxymethoxy acetylamino) isophthalic acid diamide

4.44 g (5 mmol) of the amino compound in dimethylformamide described in the previous example are mixed in an ice bath with 5.05 g (50 mmol) of triethylamine and 2.9 g (25 mmol) of diglycolic anhydride (Fluka) and 2 hours at 0 ° C. touched. It is evaporated to dryness in vacuo, the residue is partitioned between ethyl acetate and 1 M citric acid, washed neutral with water and the organic phase is dried.
Yield: 4.62 g (92% of theory) of a viscous oil

Analysis:
calc .: C 62.20; H 5.72; N 9.77;
Found: C 62.03; H 5.60; N 9.89.

d) Fully protected benzyloxycarbonyl-hexadeca-amine based on the N, N ′, N ′ ′, N ′ ′ ′ - tetrakis (trilysylaminomethyl] methane

3.0 g (22.69 mmol) of tetrakis (aminomethyl) methane (manufactured according to US 4,485,237 A, 1984), 127.85 g (136.15 mmol) of the title compound from Example 1c and 15.67 g (136.15 mmol) of N-hydroxysuccinimide in 300 ml Dimethylformamide dissolved. 28.09 g (136.15 mmol) are added at 0 ° C. Add dicyclohexylcarbodiimide and stir for 1 hour at 0 ° C, then for 2 days Room temperature. 300 ml of ethyl acetate are added, and the precipitated product is filtered off Urea and the filtrate is evaporated to dryness in vacuo. The backlog will chromatographed on silica gel (eluent: methylene chloride / isopropanol 20: 1) Yield: 58.02 g (67% of theory) of a colorless viscous oil

Analysis:
calc .: C 64.52; H 6.76; N 10.28;
Found: C 64.41; H 6.91; N 10.05.

e) Fully protected benzyloxycarbonyl-64-amine from the with the tetraamine monocarboxylic acid 17f condensed 16-amine N, N ′, N ′ ′, N ′ ′ ′ - tetrakis (trilysylaminomethyl) methane

1.91 g (0.5 mmol) of the 16-benzyloxycarbonylamine described in Example 17d are dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid are added with stirring. After 3 hours, the precipitation started is completed with diethyl ether, the 16-amine hydrobromide formed is washed with ether, dried in vacuo and used in the following reaction without further purification.
Yield: 1.48 g (quantitative)

12.05 g (12 mmol) of the tetraamine monocarboxylic acid described in Example 17f, 1.92 g (12 mmol) of 1-hydroxybenzotriazole (HOBt) and 3.84 g (12 mmol) of 2- (1 H-benzotriazol-1-yl ) -1,1,3,3-tetramethyl-uronium tetrafluoroborate (TBTU; Peboc Limited, UK) are dissolved in DMF and stirred for 15 minutes. This solution is then mixed with 6.20 ml (36 mmol) of N-ethyldiisopropylamine and with 1.48 g (0.5 mmol) of the 16-amine hydrobromide described above and stirred overnight at room temperature. After the reaction has ended, the mixture is evaporated in vacuo and the residue is chromatographed on silica gel using ethyl acetate / ethanol (2: 1).
Yield: 4.54 g (52% of theory) of a light yellow oil

Analysis:
calc .: C 62.58; H 6.01; N 11.24;
Found: C 62.39; H 6.22; N 11.00.

f) Tetrahexacontakis- {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3- dihydroxypropylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the deblocked 64- Polyamines from Example 15e

4.36 g (0.25 mmol) of the 64- described in Example 17e Benzyloxycarbonylamines are dissolved in glacial acetic acid and 33 percent hydrogen bromide added to glacial acetic acid. After 3 hours with Diethyl ether completed the precipitation started, the 64-amine formed hydrobromide washed with ether and dried in vacuo.  

The residue is then taken up in water and a solution of 21.4 g (24.0 mmol) of the acid chloride prepared in Example 5b and 6.9 ml (50 mmol) of triethylamine in 180 ml of anhydrous N, N, stirred at room temperature under an argon atmosphere -Dimethylformamide added. The mixture is stirred for 3 days at room temperature, then mixed with 48 ml of 2N sodium hydroxide solution and stirred at 50 ° C. for 2 hours. After evaporation in vacuo, a yellowish oil is obtained which is dissolved in water. The aqueous solution is adjusted to pH 7.3, filtered and the filtrate is subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried.
Yield: 12.4 g (87.3% of theory) of yellowish lyophilisate.

Analysis (based on anhydrous substance):
calc .: C 28.60; H 2.52; I 42.76; N 6.59; Na 2.58; O 16.96;
Found: C 28.92; H 2.53; I 42.48; N 6.67; Na 2.36.

Example 16 a) meso-2,3-bis (benzyloxycarbonylamino) succinic acid

14.81 g (100 mmol) diaminosuccinic acid (meso form) are suspended in 300 ml tetrahydrofuran and adjusted to pH 9 with 2 N sodium hydroxide solution. 42.65 g (250 mmol) of benzyl chloroformate, dissolved in 50 ml of tetrahydrofuran, are added dropwise at 0 ° C. with vigorous stirring, and the pH is kept at 9 with the simultaneous addition of 2N sodium hydroxide solution. The mixture is then left at pH 9 and for 5 hours Stir in room temperature. The pH is adjusted to 2 with 10% hydrochloric acid and 300 ml of saturated sodium chloride solution are added. The organic phase is separated off, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile solvent: methylene chloride / methanol 10: 1 (2% acetic acid).
Yield: 27.07 g (65% of theory) of a colorless solid

Analysis:
calc .: C 57.69; H 4.84; N 6.73;
Found: C 57.59; H 4.93; N 6.66.

b) 2,3 bis (benzyloxycarbonylamino) succinic anhydride

25 g (60.04 mmol) of the title compound from Example 16a are stirred in 200 ml of acetic anhydride at 50 ° C. for 12 hours. The mixture is cooled to 0 ° C. in an ice bath and 600 ml of diethyl ether are slowly added dropwise. The crystals are filtered off, washed twice with 100 ml of ether each time and dried overnight in vacuo (50 ° C.).
Yield: 23.44 g (98% of theory) of colorless leaflets

Analysis:
calc .: C 60.30; H 4.55; N 7.03;
Found: C 60.15; H 4.65; N 6.94.

c) Fully protected benzyloxycarbonyl-32-amine based on the (diamino) - succinylated N, N ′, N ′ ′, N ′ ′ ′ - tetrakis [trilysylaminoethyl] methane

10 g (2.62 mmol) of the title compound from Example 15a are dissolved in 100 ml of glacial acetic acid and 33% hydrogen bromide in glacial acetic acid are added (100 ml) with stirring. After 2 hours, the precipitation started is completed with diethyl ether, the hexadeca-bromide formed is filtered off and washed with diethyl ether and used in the further reaction without further purification (quantitative yield). The hydrobromide thus obtained is dissolved in 200 ml of pyridine and 20 ml of triethylamine and 1 g (8.18 mmol) of 4-dimethylaminopyridine is added. 33.4 g (83.84 mmol) of the title compound 16b dissolved in 100 ml of dimethylformamide are added dropwise at 0 ° C. and the mixture is then stirred overnight at room temperature. It is evaporated to dryness in vacuo, the residue is taken up in 300 ml of methylene chloride and washed 3 times with 100 ml of 5% potassium carbonate solution. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / methanol 20: 1)
Yield: 17.07 g (81% of theory) of a colorless solid

Analysis:
calc .: C 59.28; H 5.61; N 10.45;
Found: C 59.13; H 5.79; N 10.29.

d) Dotriacontakis- {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3-dihydroxy propylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the deblocked 32-amine Example 21c

4.02 g (0.5 mmol) of the 32-benzyloxycarbonylamine described in Example 21c are dissolved in glacial acetic acid and with stirring with 33 percent hydrogen bromide placed in glacial acetic acid. After 3 hours, the precipitation started with diethyl ether completed, the resulting 32-amine hydrobromide washed with ether and dried in vacuo.

The residue is then taken up in water and a Room temperature solution under an argon atmosphere of 21.4 g (24.0 mmol) of the acid chloride prepared in Example 5b and 6.9 ml (50 mmol) of triethylamine in 180 ml of anhydrous N, N-dimethylformamide.  

The mixture is stirred for 3 days at room temperature, then mixed with 48 ml of 2N sodium hydroxide solution and stirred at 50 ° C. for 2 hours. After evaporation in vacuo, a yellowish oil is obtained which is dissolved in water. The aqueous solution is adjusted to pH 7.3, filtered and the filtrate is subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried.
Yield: 12.5 g (90.2% of theory) of yellowish lyophilisate.

Analysis (based on anhydrous substance):
calc .: C 26.82; H 2.32; I 43.80; N 6.24; Na 2.65; O 18.18,
Found: C 27.00; H 2.48; I 43.42; N 6.41; Na 2.48.

Example 17 a) 1,4,7,10,13,16-hexakis [benzyloxycarbonylglycyl] -1,4,7,10,13,16- hexaazacyclooctadecan

516 mg (2 mmol) 1,4,7,10,13,1 6-hexaazacyclooctadecane (Hexacyclen; Fluka) are dewatered azeotropically with toluene. A solution of 3.14 g (15 mmol) of benzyloxycarbonylglycine (Fluka) in tetrahydrofuran (THF) and 3.71 g (15 mmol) of 2-ethoxy-1-ethoxycarbonyl- is added to the cooled solution of hexacycles in toluene at room temperature. 1,2-dihydroquinoline (EEDQ; Fluka) added and stirred overnight. After the reaction has ended, the product is precipitated by adding hexane and the precipitate is chromatographed on silica gel using dichloromethane / hexane / isopropanol (20: 10: 1).
Yield: 1.83 g (65%)

Analysis:
calc .: C 61.53; H 6.02; N 11.96;
Found: C 61.40; H 5.96; N 12.08.

b) 1,4,7,10,13,1 6-hexakis [N, N-bis (benzyloxycarbonylaminoethyl) glycyl] - 1,4,7,10,13,1 6-hexaazacyclooctadecane

1.41 g (1 mmol) of the hexa- benzyloxycarbonylamine described in the previous example are dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid are added with stirring. After 60 minutes, the precipitation started is completed with diethyl ether, the hexamine hydrobromide formed is washed with ether, dried in vacuo and used in the reaction described below without further purification.
Yield: 1.09 g (quantitative)

1.09 g (1 mmol) of the hydrobromide thus prepared are suspended in 50 ml of acetonitrile and 3 ml of triethylamine are added. Then 3.54 g (20 mmol) of N-benzyloxycarbonyl aziridine ((prepared according to J. Chem. Soc. Perkin Trans. 1, 21-26, 1993) are added and the mixture is heated under reflux under nitrogen for 5 days. takes up with 100 ml of methylene chloride and washed twice with 100 ml of 5 percent potassium carbonate solution, the methylene chloride phase is dried over magnesium sulfate and evaporated, the residue is chromatographed on silica gel (mobile phase: methylene chloride / methanol / triethylamine 20: 1: 0.1).
Yield: 2.29 g (84% of theory) of a pale yellow viscous oil

Analysis:
calc .: C 63.42; H 6.65; N 12.33;
Found: C 63.29; H 6.60; N 12.47.

c) Fully protected benzyloxycarbonyl-24-polyamine from the Benzyloxycarbonyl aziridine alkylated 12-amine 1,4,7,10,13,16-hexakis [N, N- bis- (aminoethyl) glycyl] -1,4,7,10,13,1 6-hexaazacyclooctadecane

1.36 g (0.5 mmol) of the title compound from Example 17b are dissolved in 100 ml of methanol and 3 g of Pearlman catalyst (palladium hydroxide on activated carbon Fluka) are added. The mixture is hydrogenated for 10 hours at 5 bar (room temperature). The catalyst is filtered off, the filtrate is evaporated to dryness and used in the following reaction without further purification.
Yield: 0.56 g (quantitative)

To 0.56 g (0.5 mmol) of the free 12-amine thus produced in 50 ml of acetonitrile, 3.54 g (20 mmol) of N-benzyloxycarbonyl aziridine (produced according to J. Chem. Soc., Perkin Trans. 1, 21 -26.1993) was added and the mixture was heated under reflux for 5 days under nitrogen. It is evaporated to dryness, taken up in 100 ml of methylene chloride and washed twice with 100 ml of 5 percent potassium carbonate solution. The methylene chloride phase is dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / methanol / triethylamine 20: 1: 0.1).
Yield: 2.23 g (83% of theory) of a pale yellow viscous oil

Analysis:
calc .: C 64.41; H 6.98; N 12.52;
Found: C 64.20; H 7.15; N 12.44.

d) Tetracosakis {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3-dihydroxy propylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the deblocked 24-amine Example 17c

2.69 g (0.50 mmol) of the title compound from Example 17c are in glacial acetic acid dissolved and mixed with 33 percent hydrogen bromide in glacial acetic acid while stirring. After 3 hours, the precipitation started is completed with diethyl ether Resulting 24-amine hydrobromide washed with ether and in vacuo dried.

The residue is then taken up in water and a solution of 16.1 g (18.0 mmol) of the acid chloride prepared in Example 5b and 5.5 ml (40 mmol) of triethylamine in 100 ml of anhydrous N, N, stirred at room temperature under an argon atmosphere -Dimethylformamide added. The mixture is stirred for 3 days at room temperature, then mixed with 36 ml of 2N sodium hydroxide solution and stirred at 50 ° C. for 2 hours. After evaporation in vacuo, a yellowish oil is obtained which is dissolved in water. The aqueous solution is adjusted to pH 7.3, filtered and the filtrate is subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried.
Yield: 8.85 g (87.6% of theory) of yellowish lyophilisate.

Analysis (based on anhydrous substance):
calc .: C 27.12; H 2.58; I 45.24; N 6.66; Na 2.73; O 15.68;
Found: C 27.21; H 2.67; I 45.36; N 6.68; Na 2.61.

Example 18 Tetracosakis {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3-dihydroxy propylcarbamoyl) -2,4,6-triiodobenzoyl} -octakis- (4-sodium carboxylatomethoxy- acetylamino) derivative of the deblocked 32-amine from Example 7c

4.17 g (0.5 mmol) of the poly-benzyloxycarbonylamine described in Example 7c are dissolved in glacial acetic acid and with stirring with 33 percent hydrogen bromide placed in glacial acetic acid. After 3 hours, the precipitation started with diethyl ether completed the resulting 32-amine hydrobromide with diethyl ether washed and dried in vacuo.

The residue is then taken up in water and a Room temperature solution under an argon atmosphere of 16.1 g (18.0 mmol) of the acid chloride prepared in Example 5b and 5.5 ml (40 mmol) of triethylamine in 100 ml of anhydrous N, N-dimethylformamide.

The mixture is stirred for 2 days at room temperature, then 1.16 g (10.0 mmol) of diglycolic anhydride are added and the mixture is stirred for a further 24 hours. 50 ml of 2N sodium hydroxide solution are then added and the mixture is stirred at 50 ° C. for 1.5 hours. After cooling to room temperature, the solution is neutralized with 2 N hydrochloric acid and filtered. The residue is taken up in water and subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon). The aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 μm, Sartorius) and freeze-dried.
Yield: 41.1 g (87.3% of theory) of colorless lyophilisate

Analysis (based on anhydrous substance):
calc .: C 29.81; H 2.95; I 39.38; N 6.76; Na 3.17; O 17.39;
Found: C 29.76; H 2.91; I 39.47; N 6.65; Na 3.04.

Blood levels in rats

Concentration-time course (blood level) in the blood of the rat after Single intravenous administration of 400 mg iodine / kg of the macro molecular substance according to Example No. 18 compared to the monomeric nonionic iopromide. The dates are on three each Animals were collected and represent the mean.

In the first ten minutes after application it shows - despite the same Dose - a significantly higher blood level for the macromolecular Contrast agent according to example no. 18 in comparison to iopromide. The higher concentration in the blood is due to the fact that the Distribution of the substance according to Example No. 18 predominantly on the  Vascular space is restricted, whereas iopromide in all extracellular space is distributed, resulting in less Concentration in the blood space.

Claims (14)

1. Iodine-containing dendrimeric polymers of the general formula A- {X- [Y- (Z- <WD _w < _z ) _y ] _x } _a (I) in which
A for a nitrogen-containing cascade core of base multiplicity a,
X, Y independently of one another for a direct bond or a cascade reproduction unit of the reproduction multiplicity x or y,
Z, W independently of one another for a cascade reproduction unit of reproduction multiplicity z or w,
D for a group TB, wherein
B represents a benzene ring of the general formula II, or represents a group of the formula - (CO) _q -U-COOH,
wherein
R¹ and R² each independently represent a hydrogen atom, a -CONR³R⁴- or -NR⁶COR⁵ group, wherein
R³, R⁴ either independently of one another for a hydrogen atom or a straight-chain, branched or cyclic alkyl group with up to 12 C atoms, which are optionally substituted by 1-5 hydroxy and / or 1-3 C₁- C₃-alkoxy and / or 1- 3 carboxy, sulfo or phosphono group (s) is substituted or
R³ and R⁴ together with the nitrogen atom represent a heterocyclic 5- or 6-ring which optionally contains an oxygen atom, an SO₂ group or an N-CO-R⁷ radical,
R⁷ represents a carboxy group or an alkyl group with up to 12 C atoms, which optionally contains 1-5 hydroxyl, 1-3 C₁-C₃- alkoxy or 1-3 carboxy, sulfo or phosphono group (s),
R⁵ represents a carboxy group or a straight-chain or branched C₁-C₁₂ alkyl group, which is optionally interrupted by an oxygen atom, which may also contain a carbonyl group and / or optionally by 1-3 carboxy, sulfo- or phosphono- and / or 1-5 hydroxy and / or 1-3 C₁-C₃ alkoxy group (s) and / or an optionally carboxymethyl-substituted imino group is substituted,
R⁶ represents a hydrogen atom, or a straight-chain or branched alkyl group having up to 12 carbon atoms, which may be by 1-3 carboxy, sulfo or phosphono group (s) and / or optionally by 1-3 hydroxy group (s) and / or 1-3 C₁-C₃- alkoxy group (s) is substituted
T for a group -CO-, -CS-, -CONH-, -CSNH-, COCH₂N (R⁶) CO, - CHR-CHR-CONH-, a stands for the digits 2 to 12,
x, y, z stand independently of one another for the digits 1 to 4 and
w represents the digits 1 to 8,
with the proviso that at least two reproduction units are different and that the product of multiplicities applies16 a · x · y · z · w 128, U for a group (CH₂) _u
q for the digits 0 or 1 and
u stands for the digits 1-4
and their salts with physiologically acceptable organic and / or inorganic bases, amino acids or amino acid amides. 2. cascade polymer complexes according to claim 1, characterized in that A is a nitrogen atom, wherein
m, n independently of one another for the digits 1 to 10,
p for the digits 0 to 10,
U¹ for Q¹ or E,
U² for Q² or E with
E in the meaning of the group wherein
o for the digits 1 to 6,
Q¹ is a hydrogen atom or Q² and
Q² for a direct bond
M is a C₁-C₁₀ alkylene chain which is optionally interrupted by 1 to 3 oxygen atoms and / or is optionally substituted by 1 or 2 oxo groups,
R ° for a branched or unbranched C₁-C₁₀ alkyl radical, a nitro, amino, carboxylic acid group or for the group stand,
where the number Q² corresponds to the base multiplicity a. 3. cascade polymer complexes according to claim 1, characterized in that the cascade reproduction units X, Y, Z and W independently of one another for certainly,
wherein
U¹ for Q¹ or E,
U² for Q² or E with
E in the meaning of the group in which
o for the digits 1 to 6,
Q¹ is a hydrogen atom or Q²
Q² for a direct bond,
U³ for a C₁-C₂₀ alkylene chain which is optionally interrupted by 1 to 10 oxygen atoms and / or 1 to 2 -N (CO) _q -R²-, 1 to 2 phenylene and / or 1 to 2 phenyleneoxy radicals and / or optionally by 1 to 2 oxo, thioxo, carboxy, C₁-C₅ alkyl carboxy, C₁-C₅ alkoxy, hydroxy, C₁-C₅ alkyl groups is substituted, wherein
q for the digits 0 or 1 and
R² represents a hydrogen atom, a methyl or an ethyl radical which is optionally substituted by 1-2 hydroxyl or 1 carboxy group (s),
L for a hydrogen atom or the group stands,
V for the methine group stands if at the same time U⁴ is a direct bond or the group M and U⁵ has one of the meanings of U³ or
V for the group stands when at the same time U⁴ and U⁵ are identical and denote the direct bond or the group M. 4. iodine-containing dendrimeric polymers according to claim 1, characterized in that the triiodinated benzene radical B bound to the terminal nitrogen atoms of the last generation of the reproduction unit W for a radical of the general formula II stands in what
R¹ and R² independently of one another for a radical of the formula-CONHCH₂CH (OH) CH₂ (OH),
-NHCOCH₂CH₂COOH,
-NHCOCH₂CH₂COONa,
-CONHCH₂CO₂H,
-CONHCH₂CO₂Na,
-CON (CH₂CO₂Na) ₂,
-CON (CH₂CO₂H) ₂,
-NHCOCOOH,
-NHCOCOONa,
-NHCOCH₂OCH₂COOH,
-NHCOCH₂OCH₂COONa,
-NHCOCH₂OCH₃,
-NHCOCH₃,
-N (CH₂COOH) -COCH₂OCH₃,
-N (CH₃) COCH₂OCH₃,
-CONHCH₂CH₂SO₂Na,
-CONHCH ₂PO₃Na₂ or
-NHCH₂OCH₂COONa stands. 5. iodine-containing dendrimeric polymers according to claim 4, characterized characterized that the the groups representing U⁶ C₁-C₂₀ alkylene chain -CH₂-, -CH₂NHCO-, -NHCOCH₂O-, -NHCOCH₂OC₆H₄-, -N (CH₂CO₂H) -, -NHCOCH₂C₆H₄-, -NHCSNHC₆H₄-, -CH₂OC₆H₄-, -CH₂CH₂O-, contains and / or by the groups -COOH, -CH₂COOH is substituted. 6. iodine-containing dendrimeric polymers according to claim 4, characterized in that
U⁶ for a -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, -C₆H₄-, -C₆H₁₀-, -CH₂C₆H₅-,
-CH₂NHCOCH₂CH (CH₂CO₂H) -C₆H₄-,
-CH₂NHCOCH₂OCH₂-,
-CH₂NHCOCH₂C₆H₄-, -CH₂NHCSNH-C₆H₄-CH (CH₂COOH) CH₂-,
-CH₂OC₆H₄-N (CH₂COOH) CH₂-,
-CH₂NHCOCH₂O (CH₂CH₂O) ₄-C₆H₄-,
-CH₂O-C₆H₄-,
-CH₂CH₂-O-CH₂CH₂-, -CH₂CH₂-O-CH₂CH₂-O-CH₂CH₂-, SO₃H CO2H group stands. 7. iodine-containing dendrimeric polymers according to claim 3, characterized in that the radical U³ contained in the cascade reproduction units X, Y, Z and W represents -CO-, -COCH₂OCH₂CO-, -COCH₂-, -CH₂CH₂-, -CONHC₆H₄-, -COCH₂CH₂CO -, -COCH₂-CH₂CH₂CO- or -COCH₂CH₂CH₂CH₂CO- stands,
the rest U⁴ stands for a direct bond or for -CH₂CO-,
the rest U⁵ stands for a direct bond or for - (CH₂) ₄-, -CH₂CO-, -CH (COOH) -, CH₂OCH₂CH₂-, -CH₂C₆H₄-, CH₂-C₆H₄OCH₂CH₂- or
the rest E for a group stands. 8. iodine-containing dendrimeric polymers according to claim 3, characterized in that the cascade reproduction units X, Y, Z and W independently of one another for -CH₂CH₂NH-; -CH₂CH₂N <;
-COCH (NH -) (CH₂) ₄NH-; -COCH (N <) (CH₂) ₄N <;
-COCH₂OCH₂CON (CH₂CH₂NH-) ₂; -COCH₂OCH₂CON (CH₂CH₂N <) ₂;
-COCH₂N (CH₂CH₂NH-) ₂; -COCH₂N (CH₂CH₂N <) ₂;
-COCH₂NH-; -COCH₂N <;
-COCH₂CH₂CON (CH₂CH₂NH-) ₂; -COCH₂CH₂CON (CH₂CH₂N <) ₂;
-COCH₂OCH₂CONH-C₆H₄-CH [CH₂CON (CH₂CH₂NH-) ₂] ₂;
-COCH₂OCH₂CONH-C₆H₄-CH [CH₂CON (CH₂CH₂N <) ₂] ₂;
-COCH₂CH₂CO-NH-C₆H₄-CH [CH₂CON (CH₂CH₂NH-) ₂] ₂;
-COCH₂CH₂CO-NH-C₆H₄-CH [CH₂CON (CH₂CH₂N <) ₂] ₂;
-CONH-C₆H₄-CH [CH₂CON (CH₂CH₂NH-) ₂] ₂;
-CONH-C₆H₄-CH [CH₂CON (CH₂CH₂N <) ₂] ₂;
-COCH (NH-) CH (COOH) NH-; -COCH (NCH (COOH) N <; stand. 9. iodine-containing dendrimeric polymers according to claim 2, characterized in that
m for the digits 1-3,
n for the digits 1-3,
o for number 1,
p for the digits 0-3,
M for a -CH₂-, -CO- or -CH₂CO group and
R ° for a -CH₂NU¹U², CH₃- or NO₂ group
stand. 10. Pharmaceutical compositions containing at least one iodine-containing dendrimeric polymer according to claim 1, optionally with those in galenics usual additives. 11. Use of at least one iodine-containing dendrimeric polymer according to claim 1 for the preparation of agents for X-ray diagnosis. 12. Use of at least one iodine-containing dendrimeric polymer according to claim 1 for the preparation of agents for X-ray diagnostics of vascular diseases. 13. A process for producing the iodine-containing dendrimeric polymers according to claim 1, characterized in that dendrimeric polymers of the general formula I 'A- {X- [Y- (Z- <W-β _w < _z ) _y ] _x } _a ( I ′) in which
A for a nitrogen-containing cascade core of base multiplicity a,
X, Y independently of one another for a direct bond or a cascade reproduction unit of the reproduction multiplicity x or y,
Z, W independently of one another for a cascade reproduction unit of reproduction multiplicity z or w,
a for the digits 2 to 12 and
x, y, z independently of one another represent the digits 1 to 4,
w stands for the digits 1 to 8 and
for the binding site of the terminal amino groups of the last generation of the reproduction unit W, with the proviso that at least two reproduction units are different and that the product of multiplicities applies16 a · x · y · z · w 128 with compounds of the general formula II′T ′ -B ′ (II) wherein
T 'represents a radical containing a carbonyl, thiocarbonyl, activated carbonyl or a CHR = CR group, which is converted into T by the reaction, where
R has the meaning of a hydrogen atom or a methyl group
and
B 'has the meaning given for B of a triiodoaromatic, but carboxy and hydroxyl groups present in B are present in protected form, and then the positions which may not be occupied by the Z radicals are reacted with a - (CO) _q -U-COOH radical introducing reagent acylated or alkylated, wherein
U represents a group (CH₂) _u
q for the digits 0 or 1 and
u stands for the digits 1-4. 14. Process for the preparation of the pharmaceutical compositions according to An saying 1, characterized in that one in water or physiological Saline dissolved or suspended iodine-containing dendrimeric polymer, optionally with the additives common in galenics, in one for enteral ones or parenteral application brings appropriate form.