WO1996041830A1 - Cascade polymers with iodine-containing aromatic compounds - Google Patents

Abstract

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

Description

 Cascade polymers with aromatic iodine

The invention relates to those characterized in the claims

Articles, ie new iodine-containing dendrimeric polymers, agents containing these compounds, 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 of atheroskierotic vascular processes, tumors, infarcts, diseases of the kidneys and urinary tract, and perfusion disorders, e.g. on the heart (ischemia and inflammation).

The requirements that must be placed on such contrast media relate above all to: 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 center! also desirable, e.g. if the thinning in the body is otherwise too strong (injection into the heart chambers, the aorta or with intravenous digital subtraction angiography) or with unfavorable

Conditions of admission (so the beam path through the body of a heavy patient can become very long); b) chemotoxicity,

 an inherent property of contrast medium solutions, which is linked among other things to the lipophilicity of the molecules, their protein affinity and

Electron density. It manifests itself in clinical use through the occurrence of side effects such as nausea, vomiting, of certain

Circulatory reactions, urticaria, bronchospasm and other symptoms up towards shock and death. Pharmacologically, chemotoxic effects can be measured, for example, as LD ₅₀ after intravenous injection; c) the viscosity.

 a size that is important for the process of applying the contrast agents, e.g. if larger volumes (30 - 100 ml) of highly concentrated and therefore more viscous solutions should be injected quickly. Except for the bad

 Injectables with 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 obstruction of the passage by capillaries, e.g. the lungs; d) osmolality

 of contrast media solutions. In the case of the application of solutions that are very hypertonic to blood and tissue (the physiological value is 310 m osm / kg), water is driven out of the cells, which among other things Cell membranes are destroyed and the overall electrolyte balance is disturbed.

 This makes a large number of sometimes serious

 Side effects such as Drop in blood pressure, bradycardia to

 Cardiac arrest, disorders of the blood-him barrier, vascular pain, etc.

 caused; e) solubility.

 which must be sufficiently high for the practical use of the contrast agents at physiological pH values in water, but without doing so

 at the same time the tolerance and iodine content of the molecule are too high

 impair; f) chemical stability

 the contrast agent solutions, which allow heat sterilization and a shelf life of at least 24 months.

X-ray contrast media that are distributed exclusively in the vascular space would be desirable for the display of vessels, ie the volume of distribution of the contrast medium should correspond to the intravascular space. The contrast media used hitherto for 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

Catheter (e.g. in the cranial area) must be carried out, which is associated with many inconveniences for the patient. It would therefore be desirable to have blood pool agents (perfusion agents) which, after systemic application using X-ray technology, can be used to differentiate between well-perfused and poorly perfused tissue in order to prevent ischemia

diagnose. Infected tissue could also be distinguished from the surrounding healthy or ischemic tissue due to its anemia if a vasal contrast agent was used. This is of particular importance if e.g. is about distinguishing a heart attack from ischemia.

Another application is in the diagnosis of

Vascular areas with reduced or increased permeability, e.g. can be caused by inflammation or tumors, as well as in the

Lymphography and mammography. There is therefore a need for X-ray contrast media that can mark the vasal space (blood pool agent). These compounds are said to be well tolerated and to be highly effective (high increase in signal intensity or lower dose) and by the molecules remaining in the vasal space (no extravasation) and by a longer half-life compared to those used for angiography Mark contrast media.

The approach to solve at least some of these problems by using iodinated macromolecular contrast agents has so far been very unsuccessful.

For example, in International Patent Application WO 88/06162

described dextran derivatives a broad molecular weight distribution and associated with an incomplete excretion and an insufficient tolerance.

The iodine-containing polyamines disclosed in international patent application WO 93/10824 are not very readily soluble in water and, moreover, are relatively poorly tolerated.

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 object is achieved by the present invention.

It has been found that iodine-containing dendrimeric polymers, which have a nitrogen-containing core and triiodoaromatics and have aliphatic carboxy, sulfo or phosphono-containing imaging residues, are surprisingly outstandingly suitable for producing X-ray diagnostics without having the disadvantages mentioned.

Dendrimers are branched polymeric molecules such as those e.g. in Angew. Chem. Vol. 104, 1609 (1992).

The iodine-containing dendrimers (cascade polymers) according to the invention can be described by the general formula I 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 for a cascade reproduction unit of the

 Reproductive multiplicity z or w,

D for a group T-B, wherein

B represents a benzene ring of the general formula II,

or represents a group of the formula - (CO) _q -U-COOH, wherein R ¹ and R ² each independently represent a hydrogen atom, a -CONR ³ R ⁴ - or -NR ⁶ COR ⁵ group, where

R ³ , R ⁴ 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 hydroxyl and / or 1-3 C ₁ -

C ₃ alkoxy and / or 1-3 carboxy, sulfo or phosphono group (s) is substituted or

R ³ and R ⁴ together with the nitrogen atom for a heterocyclic 5- or

6-ring, which optionally contains an oxygen atom, an SO ₂ group or an N-CO-R ⁷ radical,

R ⁷ for a carboxy group or an alkyl group with up to

12 carbon atoms, which optionally contains 1-5 hydroxyl, 1-3 C ₁ -C ₃ alkoxy or 1-3 carboxy, sulfo or phosphono group (s),

R ^{5 represents} a carboxy group or a straight-chain or branched

C ₁ -C ₁₂ alkyl group, which is optionally interrupted by an oxygen atom, which may also be an

Contains carbonyl group and / or optionally by 1-3 carboxy, sulfo or phosphono and / or 1-5 hydroxy and / or 1-3 C ₁ -C ₃ alkoxy group (s) and / or optionally

 carboxymethyl-substituted imino group is substituted,

R ^{6 represents} a hydrogen atom, or a straight-chain or branched one

Alkyl group with 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 C ₁ -C ₃ - Alkoxy group (s) is substituted

T for a group -CO-, -CS-, -CONH-, -CSNH-, COCH ₂ N (R ⁶ ) CO, -

H

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

16≤a · x · y · z - w≤ 128,

U stands for a group (CH ₂ ) _u q for the digits 0 or 1 and u 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,

U ¹ for Q ¹ or E,

U ² for Q ² or E with the meaning of the group

 wherein

 o for the digits 1 to 6,

Q ¹ for a hydrogen atom or Q ² and

Q ² for a direct bond

M is a C ₁ -C ₁₀ alkylene chain which may be 1 to 3

 Oxygen atoms is interrupted and / or optionally with 1 to 2

Oxo groups is substituted,

R ° for a branched or unbranched C ₁ -C ₁₀ alkyl radical, a nitro,

Amino, carboxylic acid group or for the group

stand,

where the number Q ² 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) are occupied by three reproduction units X and Y (if X stands for a direct bond) or Z (if X and Y each stand for a direct bond); in other words:

the three hydrogen atoms of the underlying cascade starter ammonia A (H) _a = NH ₃ have been substituted by three reproduction units X, Y and Z, respectively. The number Q ² contained in the cascade core A gives the

Base multiplicity a again.

The reproduction units X, Y, Z and W contain -NQ ¹ Q ² groups, in which Q ^{1 is} a hydrogen atom or Q ^{2 is} a direct bond. The number Q ² contained in the respective reproduction unit (eg X) corresponds to the multiplicity of reproduction of this unit (eg x in the case of X). The product of all multiplicities (axyzw) gives the number of triiodinated benzene residues B bound in the cascade polymer. The polymers according to the invention contain at least 16 and at most 128 radicals B in the molecule.

The reproduction units can be terminated both via NHQ ² groups (for example by acylation reactions) and via NQ ² Q ² groups (for example through

Alkylation reactions) to the next generation. The last generation, too, can be bound to the connecting members T via NHQ ² or NQ ² Q ² groups, which in turn are connected 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), but preferably 2 to 4 generations, at least two of the reproduction units in the molecule being different.

The preferred cascade cores A are those which fall under the general formulas mentioned above, if

 m for the numbers 1 to 3, particularly preferably for the number 1,

 n for the numbers 1 to 3, particularly preferably for the number 1,

 p for the numbers 0-3, particularly preferably for the number 1,

 o for number 1,

M for a -CH ₂ -, -CO- or -CH ₂ CO group and R ^O for a -CH ₂ NU ¹ U ² -, CH ₃ - or NO ₂ group

stands.

The following are further preferred cascade starters A (H) _a :

(The base multiplicity a is given in brackets for the case of the subsequent mono- or

Disubstitution)

 It should be noted that the definition as cascade core A and thus the separation of the cascade core and the first reproduction unit can be chosen purely formally and therefore independently of the actual synthetic structure of the desired cascade polymer complexes. So you can e.g.

Tris (aminoethyl) amine itself as cascade core A (compare the first general formula given for A with m = n = p = 1, U ¹ = E with o in the Meaning of the number 1 and U ¹ = U ² = Q ² ) but also as a nitrogen atom (= cascade core A), which is the first generation to have three reproductive units

 (compare the definition of E).

The cascade reproduction units X, Y, Z and Q are run independently

wherein

U ¹ for Q ¹ or E,

U ² for Q ² or E with

E in the meaning of the group

in which

o for the digits 1 to 6,

Q ¹ for a hydrogen atom or Q ² ,

Q ² for a direct bond,

U ³ for a C ₁ -C ₂₀ alkylene chain which may be 1 to 10

Oxygen atoms and / or 1 to 2 -N (CO) _q -R ² -, 1 to 2 phenylene and / or 1 to 2 phenyleneoxy radicals is interrupted and / or optionally by 1 to 2 oxo, thioxo, carboxy, C ₁ -C ₅ alkylcarboxy, C ₁ -C ₅ alkoxy, hydroxy, C ₁ -C ₅ alkyl groups is substituted, wherein

q for the digits 0 or 1 and

R ^{2 represents} a hydrogen atom, a methyl or an ethyl radical which is optionally substituted by 1-2 hydroxyl or 1 carboxy group (s),

L represents a hydrogen atom or the group,

V stands for the methine group if U ^{4 is} a direct one

Binding or the group M means and U ⁵ one of the meanings of

U ³ owns or

for the group if U ⁴ and U ⁵

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 U ³ for -CO-, -COCH ₂ OCH ₂ CO-, -COCH ₂ -, -CH ₂ CH ₂ -,

-CONHC ₆ H ₄ -, -COCH ₂ CH ₂ CO-, -COCH ₂ -CH ₂ CH ₂ CO-or

-COCH ₂ CH ₂ CH ₂ CH ₂ CO-,

the radical U ^{4 stands} for a direct bond or for -CH ₂ CO-,

the radical U ⁵ for a direct bond or for - (CH ₂ ) ₄ -, -CH ₂ CO-, -CH (COOH) -,

CH ₂ OCH ₂ CH ₂ -, -CH ₂ C ₆ H ₄ -, CH ₂ -C ₆ H ₄ OCH ₂ CH ₂ - is or

the rest E for a group

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

-CH ₂ CH ₂ NH-; -CH ₂ CH ₂ N <;

-COCH (NH -) (CH ₂ ) ₄ NH-; -COCH (N <) (CH ₂ ) ₄ N <;

-COCH ₂ OCH ₂ CON (CH ₂ CH ₂ NH-) ₂ ; -COCH ₂ OCH ₂ CON (CH ₂ CH ₂ N <) ₂ ;

-COCH ₂ N (CH ₂ CH ₂ NH-) ₂ ; -COCH ₂ N (CH ₂ CH ₂ N <) ₂ ;

-COCH ₂ NH-; -COCH ₂ N <;

-COCH ₂ CH ₂ CON (CH ₂ CH ₂ NH-) ₂ ; -COCH ₂ CH ₂ CON (CH ₂ CH ₂ N <) ₂ ;

-COCH ₂ OCH ₂ CONH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ NH-) ₂ ] ₂ ;

-COCH ₂ OCH ₂ CONH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ N <) ₂ ] ₂ ;

-COCH ₂ CH ₂ CO-NH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ NH-) ₂ ] ₂ ;

-COCH ₂ CH ₂ CO-NH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ N <) ₂ ] ₂ ;

-CONH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ NH-) ₂ ] ₂ ;

-CONH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ N <) ₂ ] ₂ ;

 -COCH (NH-) CH (COOH) NH-;

-COCH (N <) CH (COOO) N <;

The alkyl groups R ³ , R ⁴ and R ⁷ contained in the R ¹ or R ² substituent of the triiodoaromatic B are straight-chain or branched-chain or cyclic

Hydrocarbons with up to 12, preferably up to 10, particularly preferably up to 6 C atoms into consideration, which are replaced by 1 to 5, preferably 1 to 3 hydroxyl and / or 1 to 3 C ₁ -C ₃ alkoxy and / or 1-3, preferably one, carboxy, sulfo or phosphono group (s) is substituted. Examples include 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 heterocyclic 5- or 6-ring optionally formed by R ³ and R ⁴ including the amide nitrogen can optionally be a

Contain oxygen atom, a SO ₂ group or an N-CO-R ⁷ radical. Examples of suitable heterocycles are:

the piperidyl, pyrazolidyl, morpholinyl, N-substituted piperazinyl and the S, S-dioxothio-morpholinyl ring.

The radicals R ⁵ and R ⁶ contained in the R ¹ or R ² substituent of the triiodoaromatic B are, in addition to the corresponding radicals listed for R ³ , R ⁴ , R ⁷ , 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 R ⁸ and R ⁹ or V can be straight-chain or branched and contain up to 20, preferably up to 12, carbon atoms. The R ⁸ and R ⁹ substituent can be substituted by 1 to 4, preferably 1 to 2, hydroxyl group (s), the chain for V (optionally additionally) interrupted by 1 to 4, preferably 1 to 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 representing 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 (s) may be substituted. The following are examples of the residues - (CO) _q -U-COOH:

-CO (CH ₂ ) ₂ COOH; -COCOOH; -CO (CHOH) ₂ COOH; -COCH ₂ OCH ₂ COOH;

-COCH ₂ COOH; -COCH (OCH ₃ ) COOH, -CH ₂ CH ₂ COOH, -CH (CH ₃ ) CH ₂ COOH, -CH ₂ CH (CH ₃ ) COOH, -CH (CH ₃ ) CH (CH ₃ ) COOH, where the Leftovers

-CO (CH ₂ ) ₂ COOH,

-COCH ₂ OCH ₂ COOH, -CH ₂ CH ₂ COOH are preferred.

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

Suitable cations of inorganic bases are, for example, lithium, potassium, calcium, magnesium, zinc and in particular that

Sodium ion. Suitable cations of organic bases include those of primary, secondary or tertiary amines, e.g. Ethanolamine,

Diethanolamine, morpholine, glucamine, N, N-dimethyl-glucamine and in particular N-methylglucamine. Suitable cations of amino acids are, for example, those of lysine, arginine and ornithine and the amides of otherwise acidic or neutral amino acids.

The compounds according to the invention have the desired properties described at the outset. They contain the number of triiodoaromatics required for their use as X-ray contrast media. They are only distributed in the vasal space and can therefore be marked using X-ray diagnostics.

The iodine content of the compounds according to the invention exceeds

on average 45% the iodine content of other aromatics containing iodine

Macromolecules - such as the dextran derivatives described in WO 88/06162 (approx. 2 to 35%) - in some cases many times over. The invention

In contrast to the dextran derivatives described in WO 88/06162, compounds can surprisingly be mixed with water in any ratio, which leads to a higher contrast agent concentration in the blood vessels shortly after injection and thus has a favorable effect on the delimitation of the

Blood vessels. The osmolality value responsible for side effects such as pain, damage to blood vessels and cardiovascular disorders is significantly reduced and no longer hyperosmolar as is often observed with X-ray contrast media.

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

The chemotoxicity responsible for the acute tolerance

Compounds according to the invention (example 18: iv-LD ₅₀ mouse> 5 g iodine / kg) are both compared to the macromolecular contrast agents based on carbohydrates (WO 88/06162) and to 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 is also significantly lower, which allows a bolus injection and thus significantly better differentiation of the blood vessels from the surrounding tissue (Example 18: 2.8 mPas at 37 ° C and 100 mg iodine / ml; Example 10 of WO 88/06162: 26 mPas at 37 ° C and 90 mg iodine / ml).

With the compounds according to the invention, it has been possible to produce macromolecules with a precisely defined molecular weight. Such macromolecular contrast agents with iodoaromatics, which are precisely defined in terms of their molecular size, have hitherto had significantly poorer properties than the inventive ones

Connections. For example, the compound mentioned in Example 12 of WO 94/21600 has a significantly lower solubility and at the same time a significantly higher viscosity than the compounds according to the invention.

In the dextran-based macromolecules, e.g. Dextran 40,000

(Rheomacrodex ^® ), it is a mixture of macromolecules of various sizes, whose average molecular weight is, for example, 40,000 Daltons. However, this mixture also contains dextran molecules that are larger than 50,000 or 60,000 daltons. This proportion of high molecular weight

Dextran compounds may be between 5 and 10% of the total. As 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 become no longer filtered glomerularly, and the renal clearance of these molecules is therefore almost zero. Also those in the patents EP 0206551, EP 0436316 and in the Examples 1, 2 and 3 of the compounds described in WO 93/10824 cannot be complete because of their high molecular weight components after iv administration

be eliminated. However, a diagnostic agent is expected to be completely eliminated from the body in a short period of time after intravenous injection. The other compounds described in WO 93/10824, on the other hand, leave the intravascular space too quickly and are therefore not as

Perfusion agents suitable. With the compounds according to the invention, it has surprisingly been possible to provide iodine-containing polymers which only leave the vasal space slowly, but at the same time still pass through the capillaries of the kidney and are therefore completely eliminated.

The invention therefore relates to the compounds described by the formula I.

Due to the molecular structure, the compounds according to the invention show a blood concentration in the first 10 minutes after intravenous administration, which is about four times higher than with the extracellular X-ray contrast agents such as e.g. Ultravist®. The cascade polymers are only in the body

Vasal space, i.e. the volume of distribution is approximately 0.05 l / kg. This makes it possible to produce macromolecular contrast media with triiodoaromatics to suit the body.

The cascade polymers according to the invention serve as contrast agents for

Representation of the vessels using X-ray diagnostics. It is possible to distinguish ischemic tissue from normal tissue. However, other damage to the blood-tissue barrier can also be seen with these compounds. With inflammation and tumors in the brain, the blood-brain barrier is so damaged that the contrast medium can infiltrate the diseased tissue and the diseased tissue can thus be identified by X-ray diagnosis. Due to the impermeability of the intact blood-brain barrier even to small but hydrophilic molecules, inflammations and tumors could already be recognized with the low-molecular Ultravist®. However, if the cascade polymers according to the invention are used in these cases, the dose can be reduced fourfold; because the macromolecules are distributed in a fourfold smaller space, namely only in the vasal space, ie a quarter of the dose is sufficient to achieve equal concentrations in the blood. At the same time, the compounds according to the invention can be used to carry out perfusion measurements, for example on the myocardium, which was only possible to a limited extent with the low molecular weight compounds such as Ultravist®, since these molecules rapidly "leak" into the interstitial space. The "leakage" into the interstitium often led to a blurring of the image in the case of the low molecular weight compounds, which can be avoided by the compounds according to the invention.

At the same time, the measurement time can be greatly extended compared to the low molecular weight compounds.

Another advantage of the present invention is that now

Macromolecules with different lipophilic or hydrophilic triiodaryl residues have become accessible. This enables the compatibility and pharmacokinetics of these cascade polymers to be controlled by differently substituted triiodaryl radicals.

The invention therefore also relates to the use of

Compounds according to the invention for producing X-ray contrast media.

The iodine-containing dendrimeric polymers according to the invention are prepared by dendrimeric polymers of the general formula I '

A- {X- [Y- (Z- (w-ß _w ) _z ) _y ] x} _a (I '), where

 A for a nitrogen-containing cascade core of base multiplicity a,

X, Y independently 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 the

 Reproductive 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

 ß for the binding site of the terminal amino groups of the last

 Generation of the reproduction unit W are provided that at least two reproduction units are different and that multiplicities apply to the product

 16≤a · x · y · z · w≤ 128, with compounds of the general formula II '

 T'-B '(II'),

 wherein

 T for a carbonyl, thiocarbonyl, activated carbonyl or a

 CHR = CR group containing residue, which by the reaction in

T is converted to

 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 contained in B are in protected

Form,

and then acylated or alkylated the positions β which may not be occupied by the radicals Z with a reagent introducing the radical - (CO) _q -U-COOH, in which

U stands for a group (CH ₂ ) _u

 q for the digits 0 or 1 and

u stands for the digits 1-4. An example of an activated carbonyl group in the radicals T of the starting materials of the 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, for example the methyl, ethyl, propyl, n-butyl, t-butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis (p-nitrophenyi ) 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. E. Wünsch, Methods of Org. Chemistry (Houben Weyl), Vol. XV / 1, 4.

Auf-Iage 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 of e.g. tert-butyl esters with the help of trifluoroacetic acid.

Examples of hydroxyl protective groups are the benzyl, 4-methoxybenzyl, 4-nitrobenzyl, trityl, diphenylmethyl, trimethylsilyl, dimethyl-t-butylsilyl,

 Diphenyl-t-butylsilyl group in question.

The hydroxyl groups can also be present, for example, as THP ether, α-alkoxyethyl ether, MEM ether or as an ester with aromatic or aliphatic carboxylic acids, such as acetic acid or benzoic acid. In the case of polyols, the hydroxy groups can also be protected in the form of ketals with, for example, acetone, acetaldehyde, cyclohexanone or benzaldehyde. If carboxyl groups are present at the same time, hydroxyl groups can also be protected by intramolecular esterification to give the corresponding lactones.

The hydroxyl protecting groups can be prepared according to the literature methods known to the skilled person, e.g. are released by hydrogenolysis, reductive cleavage with lithium / ammonia, acid treatment of the ethers and ketaie or alkali treatment of the esters

(see e.g. "Protective Groups in Organic Synthesis", T.W. Greene, John Wiley and Sons 1981).

The various processes for the preparation of the polymers according to the invention and the starting compounds required therefor are known in principle to the person skilled in the art. They are based on the reaction of the terminal amino groups of the respectively desired generation of the dendrimeric polymers of the general formula I 'with the compounds of the general formula II' suitable for generating the linking members T bound to the triiodoaromatics B. This is how the N, N-bis-

(Carboxymethyl) amine or amide substituted triiodoaromatics in liquid reaction media such as water, dipolar aprotic solvents such as diethyl ether, tetrahydrofuran, dioxane, acetonitrile, N-methylpyrrolidone, dimethylformamide, dimethylacetamide and the like or mixtures thereof with the addition of amines such as e.g. Triethylamine, N-ethyldiisopropylamine,

 N, N-dimethyl-4-aminopyridine. The reaction temperatures are between about -80 ° C and 160 ° C, with temperatures of 20 ° C to 80 ° C are preferred. The reaction 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, for example by the process described in US Pat. No. 3,660,388 or in DE 16 95 050 with acetic anhydride in pyridine. In certain cases, however, it is advantageous to carry out the elimination of water with carbodiimides in a suitable solvent, such as, for example, dimethylformamide or dimethyl acetamide. The isocyanate- or isothiocyanate-substituted triiodoaromatics are reacted by methods known from the literature (DOS 26 10 500, EP 0 431 838), for example in aprotic solvents such as DMSO, DMF, DMA or in water or water-containing solvent mixtures at temperatures of 0 - 120 ° C, preferably 20 - 75 ° C. The reaction times are generally between 1-48 hours, preferably 3-24 hours.

The implementation of triiodoaromatics containing lactone structures

corresponding dendrimeric polyamines succeed e.g. analogous to that of

T. Sheradsky, Y. Knobler and M. Frankel in J. Org. Chem., 26, 2710 (1961) described methods for the aminolysis of 2-acylamino-4-butyrolactones.

Addition reactions of triiodoaromatics containing an olefinic substituent CHR = CR-CONH are e.g. after the in Org. Synth. Coll. Vol. VI, p. 75 (1988) carried out by reacting a triiodinated acrylamide in polar solvents such as DMF, DMA, pyridine, ethanol with 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 carried out by the processes known to the person skilled in the art, e.g. made analogously to the regulation in EP 0015867. The reaction is generally carried out in polar aprotic solvents such as e.g. DMF, DMA, or in mixtures of polar aprotic solvents with water, in the presence of an acid scavenger, e.g. tertiary amine (e.g. triethylamine, trimethylamine, N, N-dimethylaminopyridine, 1, 5-diazabicyclo [4.3.0] nonen-5 (DBN), 1,5-diazabicyclo [5.4.0] undecen-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

Reaction times from 1 to 36 hours.

The subsequent acylation or alkylation of the terminal amino groups, which may not be bound to imaging residues T-B, is carried out analogously to regulations known from the literature, see e.g. Org. Syn. Coll. Vol. 4, 5 (1963).

The neutralization of the acid groups can be carried out with the aid of inorganic bases (e.g. hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium, Lithium, magnesium or calcium and / or organic bases such as, inter alia, primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N-methyl- and N, N-dimethylglucamine, and basic amino acids, such as, for example, lysine, arginine and ornithine or amides of originally neutral or acidic amino acids.

The preparation of the cascade polymers carrying terminal amino groups required for coupling to the activated triiodoaromatics T-B 'generally starts from commercially available or from or analogously known from the literature

Methods of producing nitrogen-containing cascade starters A (H) _a . The

Introduction of generations X, Y, Z and W is carried out by literature methods [for example, J. March, Advanced Organic Chemistry, 3 ^rd ed .; John Wiley & Sons, (1985), 364 - 381] by acylation or alkylation reactions with protected amines having the desired structures, the functional groups capable of binding to the cascade nucleus, such as, for example, carboxylic acids, isocyanates, isothiocyanates or activated carboxylic acids (such as, for example Contain anhydrides, active esters, acid chlorides) or halides (such as chlorides, bromides, iodides), aziridine, mesylates, tosylates or other escape groups known to the person 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. For example, for the synthesis of the compound described in Example 1b) it is more advantageous than the formal one

Cascade core trimesic acid triamide with e.g. Benzyloxycarbonyl aziridine

to alkylate (sixfold), but to implement trimesic acid trichloride with bis [2- (benzyloxycarbonylamino) ethyl] amine (triple).

The amine protecting groups are the benzyloxycarbonyl, tertiary-butoxycarbonyl, trifluoroacetyl, fluorenylmethoxycarbonyl, benzyl and formyl group [Th. W. Greene, P.G.M Wuts, Protective Groups in Organic

Syntheses, 2nd ed, John Wiley and Sons (1991), pp. 309-385]. After splitting off these protective groups, which are also known from the literature

Methods done, the next desired generation can be in the molecule be introduced. In addition to the structure of a generation consisting of two reaction stages (alkylation or acylation and deprotection), the simultaneous introduction of two, e.g. X- [Y] _x , or several generations, e.g. 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 [for example Houben-Weyl, Methods of Org. Chemistry, Georg-Thieme-Veriag, Stuttgart (1957), Vol. 11 /1 ;

M. Micheloni et al., Inorg. Chem. (1985), 24, 3702; T.J. Atkins et al., Org. Synth., Vol. 58

 (1978), 86-98; The Chemistry of Heterocyclic Compounds: J.S. Bradshaw et al., Aza-Crown-Macrocycles, John Wiley & Sons, N.Y. (1993)].

Examples include: tris (aminoethyl) amine [e.g. Fluka Chemie AG, Switzerland; Aldrich chemistry,

 Germany];

 Tris (aminopropyl) amine [e.g. C. Woerner et al., Angew. Chem. Int. Ed. Engl.

(1993), 32, 1306];

 Diethylene triamine [e.g. Fluka; Aldrich];

Triethylene tetramine [e.g. Fluka; Aldrich];

 Tetraethylene pentamine [e.g. Fluka; Aldrich];

 1,3,5-tris (aminomethyl) benzene [e.g. T.M. Garrett et al., J. Am. Chem. Soc.

 (1991) 113, 2965];

 Trimesic acid triamide [e.g. H. Kurihara; Jpn. Kokai Tokkyo Koho JP 04077481; CA 117, 162453];

 1, 4,7-triazacyclononane [e.g. Fluka; Aldrich];

 1,4,7,10,13-pentaazacyclopentadecane [e.g. K.W. Aston, Eur. Pat. Appl. 0 524

161,

 CA 120, 44580];

 1, 4,8,11-tetraazacyclotetradecane [e.g. Fluka; Aldrich];

 1, 4,7,10,13,16,19,22,25,28-decaazacyclotriacontane [e.g. A. Andres et al., J.

Chem. Soc. Dalton Trans. (1993), 3507]; 1,1,1-tris (aminomethyl) ethane [eg RJ Geue et al., Aust. J. Chem. (1983), 36, 927];

 Tris (aminopropyl) nitromethane [e.g. G.R. Newkome et al., Angew. Chem. 103. 1205 (1991) analogous to R.C. Larock, Comprehensive Organic Transformations, VCH Publishers,

 N.Y. (1989), 419-420]

 1,3,5,7-adamantanetetracarboxamide [e.g. H. Stetter et al., Tetr. Lett. 1967, 1841];

1,2-bis [phenoxyethane] ^-3, 3 ", 5 ', 5" -tetracarbonsäureamid [for example, JP Collman et al .; 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. P.H. Smith et al., J. Org. Chem. (1993), 58, 7939]. The reproduction amines containing the abovementioned functional groups required for the generation of the generations are produced in accordance with or analogously to the instructions described in the experimental section or in accordance with methods known from the literature. Examples include:

N ^α , N ^ε -Di-CO-O-CH ₂ C ₆ H ₅ -lysine-p-nitrophenyl ester [see. Regulation for Example 1c)];

HOOC-CH ₂ OCH ₂ CO-N (CH ₂ CH ₂ NH-CO-O-CH ₂ C ₆ H ₅ ) ₂ [s. Regulation for example

7a)];

HOOC-CH ₂ N (CH ₂ CH ₂ NH-CO-O-CH ₂ C ₆ H ₅ ) ₂ [s. Regulation for Example 9e)];

HOOC-CH ₂ CH ₂ CO-N (CH ₂ CH ₂ NH-COCF ₃ ) ₂ [to be produced according to the instructions for the

Example 7a) by replacing bis (benzyloxycarbonylaminoethyl) amine from

Bis (trifluoroacetylaminoethyl) amine and instead of diglycolic anhydride from

Succinic anhydride runs out];

HOOC-CH ₂ OCH ₂ CONH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ NH-CO-O-CH ₂ C ₆ H ₅ ) ₂ ] ₂

[To be prepared according to the instructions for Example 7a) by instead of

 Bis (benzyloxycarbonylaminoethyl) amine of that described in Example 9b)

Amine runs out];

O = C = NC ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ NH-CO-O-CH ₂ C ₆ H ₅ ) ₂ ] ₂ [s. Regulation for example 9c)]

 to be prepared according to the instructions for Example 15c) by reacting with triphosgene analogously to the instructions for Example 9c) instead of diglycolic anhydride

N-Benzyloxycarbonyl-aziridine see instructions for Example 13a) N-Benzyloxycarbonyl-glycine commercially available from Bachern California, for example

to be produced according to CJ Cavallito et al., J. Amer. Chem. Soc. 1943, 65, 2140, by replacing benzyl chloride with N-CO-O-CH ₂ C ₆ H ₅ - (2-bromoethyl) amine [AR Jacobson et al., J. Med. Chem. (1991), 34, 2816] goes out.

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

For example, in German Offenlegungsschriften DE 2928417 and

DE 29 09439 describes iodinated aromatics which can easily be mixed with e.g. Thionyl chloride can be converted to the corresponding aromatics containing acid chloride groups.

Isocyanate- or isothiocyanate-substituted triiodoaromatics can by

 Implementation of the corresponding aniline derivatives with phosgene or thiophosgene in aprotic solvents such as 1, 2-dichloroethane, dichloromethane, pyridine, dimethyl sulfoxide, tetrahydrofuran, dioxane, diethyl ether, ethyl acetate (literature: DOS 2541 491).

A triiodoaromatic containing lactone residue can be obtained, for example, by reacting a triiodobenzoyl chloride derivative with 2-amino-4-butyrolactone hydrochloride. An implementation of this type is e.g. by J. Brennan and

 P.J. Murphy in Tetrahedron Lett., 29 (17), 2063 (1988).

Triiodoaromatics with an olefinic substituent CHR = CR-CONH 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 process for the preparation of these agents, which is characterized in that the shading substance with the additives and stabilizers customary in galenics in a for enteral or

parenteral application is brought into a suitable form. The pharmaceutical preparation can generally be adapted to the specific needs of the user. The concentration of the new

X-ray contrast medium in an aqueous medium is based 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 applied in a dose of 30 mg iodine / kg to 2000 mg iodine / kg.

The aqueous X-ray contrast medium solution can be applied enterally or parenterally, thus orally, rectally, intravenously, intraarterially, intravascularly, intracutaneously, subcutaneously (lymphography), subarachnoidally (myelography).

Suitable additives are, for example, physiologically harmless buffers (such as tromethamine, bicarbonate, phosphate, citrate), stabilizers (such as DTPA, sodium edetate, calcium disodium edetate) or - if necessary - electrolytes (such as sodium chloride) or - if necessary - Antioxidants (e.g.

Ascorbic acid) or substances to adjust the osmolality (such as mannitol, glucose).

If suspensions or solutions of the agents according to the invention in water or physiological saline are desired for enteral administration or other purposes, they are combined with one or more adjuvants customary in galenics (for example methyl cellulose, lactose, mannitol) and / or surfactants (e.g. lecithins, Tweens®, Myrj® and / or flavoring agents for flavor correction (e.g. essential oils) mixed.

The following examples serve to explain the subject matter of the invention in more detail without wishing to restrict it to them.

Examples

example 1

Tetracosakis {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 diethylene triamine and 139 ml (1 mol) of triethylamine are dissolved in dichloromethane and mixed with 161 g of benzyl cyanoformate (Fluka) in dichloromethane at -20 ° C. and then stirred overnight at room temperature. After the reaction is evaporated in the hood, the

 Residue taken up in diethyl ether, the organic phase with

 Washed 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)

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)

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

3.6 g (20 mmol) of lysine hydrochloride and 6.95 ml (50 mmol) of triethylamine are dissolved in DMF, with 26.8 g (50 mmol) of N ^α , N ^ε -dibenzyloxycarbonyl-lysine-p-nitrophenyl ester (Bachern ) 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- (trilysyl-amino) -ethyl] -trimesinsäuretriamids

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, which is then treated with 5.16 ml (30 mmol) N -Ethyldiisopropylamine and with 0.95 g (1 mmol) of the above

described hexa-amine hydrobromide and added overnight

Room temperature stirred. 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).

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

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)

 Succinic acid monoethyl ester added at room temperature. The. Batch is refluxed for several hours until loud

 Thin layer chromatography no longer shows any educt; 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

f) Tetracosakis {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

4.20 g (0.7 mmol) of the poly-benzyloxycarbonylamine described in Example 1d 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 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 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: 12.5 g (87.2% of theory) of colorless lyophilisate

Example 2

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 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 ^α , N ^ε - dibenzyloxycarbonyl-lysine-p-nitrophenyl ester are dissolved in DMF and over

Stirred at room temperature overnight. After the reaction is over

Evaporated in vacuo, the residue was stirred with diethyl ether, the precipitate was filtered off with suction and recrystallized from ethyl acetate.

 Yield: 12.55 g (94% of theory)

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 one started with diethyl ether

 Precipitation completed, the resulting hexamine hydrobromide 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 ^ε- bis (N, N'-dibenzyloxycarbonyl-lysyl) -lysine (protected "tri-lysine") described in Example 1 c are obtained in a manner analogous to Example 1d 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) N-Ethyldiisopropylamine implemented and worked up in the same manner as described there.

Yield: 4.42 g (73% of theory)

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 NN-dimethylformamide is mixed with 27.6 g (220 mmol) of glycine methyl ester hydrochloride and 61.0 ml (440 mmol) of triethylamine. A suspension is formed which is stirred overnight under argon at room temperature. After evaporating the suspension in vacuo, the residue is recrystallized from methanol.

 Yield: 66.3 g (94.6% of theory)

d) 5-isocyanato-2,4,6-triiodoisophthalic acid-N, N ^, -bis- (methoxycarbonylmethyl) - diamide

To a stirred at 60 ° C oil bath temperature under an argon atmosphere

 Suspension of 20.7 g (29.5 mmol) of that prepared in Example 2c

 Aniline derivatives in 200 ml of 1,2-dichloroethane are added to 147 ml (73.8 mmol) of a two-normal toluene phosgene solution and 2 ml of N, N-dimethylformamide. 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

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 with diethyl ether

washed and dried in vacuo. The solid becomes a

 Room temperature solution under an argon atmosphere of 17.3 g (23.8 mmol) of the isocyanate prepared in Example 2d in 200 ml of anhydrous

 Dimethyl sulfoxide and 3.3 ml (24 mmol) triethylamine stirred. The mixture is stirred at room temperature for 2 days, then 25 ml of 2N sodium hydroxide solution are added and the mixture is 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

Example 3

Tetracosakis- {3,5-bis [N, N-bis- (natriumcarboxylatomethyl) carbamoyl] -2,4,6 triiodphenylcarbamoyl} 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)

 Iminodiacetic acid dimethyl ester 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 with aqueous

 Sodium bicarbonate solution shaken out. The organic phase is dried with anhydrous magnesium sulfate, filtered and concentrated after

 Kieselgel 60 (Merck, Darmstadt) chromatographed (eluent:

 Dichloromethane / methanol). The product fractions are evaporated to dryness in vacuo.

 Yield: 57.1 g (85.3% of theory) of a colorless solid

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) in 300 ml of 1,2-dichloroethane, which is stirred at 60 ° C. in an oil bath 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 Residue was stirred out 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

c) Tetracosakis- {3,5-bis [N, N-bis- (natriumcarboxylatomethyl) carbamoyl] -2,4,6 triiodphenylcarbamoyl} derivative of N, N, ^N, N ', N ", N "-Hexakis [2- (trilysylamino) ethyl] trimesic acid triamide

5.50 g (0.92 mmol) of the poly-benzyloxycarbonylamine prepared according to Example 1d are, as described in Example 1f, into the

 corresponding polyamine hydrobromide transferred. 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

Example 4

Tetracosakis {3-sodium carboxylatoformylamino-5- (2,3-dihydroxypropylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the N, N, N ', N', N ", N" - hexakis [2- ( trilysyl-amino) -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 (stirred under exclusion of moisture) ( 100 mmol) 5-amino-2,4,6-triiodoisophthalic acid N- (2,3-diacetoxypropyl) amide chloride (EP 0308364) in 300 ml anhydrous dioxane, 20.5 g (150 mmol)

 Monoethyl oxalic acid chloride added at room temperature. The mixture is boiled under reflux for several hours until no starting material can be detected according to thin layer chromatography, then the mixture is evaporated, the residue is taken up in dichloromethane and saturated with aqueous

 Sodium bicarbonate solution shaken out. 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

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

5.99 g (1.00 mmol) of the poly-benzyloxycarbonylamine prepared according to Example 1d are, as described in Example 1f, in the

corresponding polyamine hydrobromide transferred. 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 two Stirred at 50 ° C for 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

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- (trilysyl-amino) -ethyl] -trimesic acid triamide a) Diglycolic acid chloride monoisopropyl ester

To 24.0 g (400 mmol) of anhydrous isopropanol are added

 Exclusion of moisture given 46.4 g (400 mmol) of diglycolic anhydride. 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%

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

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 batch is refluxed for several hours until loud

 Thin layer chromatography is no longer detectable educt, 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: 68.2 g (76.4% of theory) of colorless crystals

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 poly-benzyloxycarbonylamine prepared according to Example 1d are, as described in Example 1f, in the

 corresponding polyamine hydrobromide transferred. 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

Example 6

 Tetracosakis {3- [N, N-bis (sodium carboxylatomethyl) carbamoyl)] - 5-methoxyacetylamino-2,4,6-triiodobenzoyl} derivative of the N, N, N ', N', N ", N" -Hexakis- [2- (trilysyl-amino) -ethyl] -trimesinsäuretriamids a) 5-methoxyacetylamino-2,4,6-triiodisophthalic 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)

b) tetracosakis {3- [N, N-bis (sodium carboxylatomethyl) carbamoyl)] - 5-methoxyacetylamino-2,4,6-triiodobenzoyl} derivative of the N, N, N ', N', N ", N "-Hexakis- [2- (trilysyl-amino) -ethyl] -trimesic acid triamide

3.00 g (0.50 mmol) of the poly-benzyloxycarbonylamine prepared according to Example 1d are described in Example 1f

corresponding polyamine hydrobromide transferred. This is added in 20 ml of water to a solution of 15.0 g (18.0 mmol) of the acid chloride prepared in Example 6a and 6.9 ml (50 mmol) of triethylamine in 100 ml of N, N-dimethylformamide, which is mechanically stirred at room temperature to. The approach becomes 2 Stirred for days at room temperature, then mixed with 20 ml of 2N sodium hydroxide solution and stirred at 50 ° C for two hours. The solution is opened after cooling

Neutralized room temperature 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: 9.12 g (85.6% of theory) of colorless lyophilisate

Example 7

Dotriakontacontakis- {N- [3,5-di-facetylamino) -2,4,6-triiodobenzoyl] -N- (sodium carboxylato-methyl) -glycyl} derivative of the deblocked 32-amine from 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, in an ice bath with 17.4 g (150 mmol) of diglycolic anhydride (Janssen Chimica) and 21 ml (150 mmol) of triethylamine added 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 with

 Dried sodium sulfate and crystallized from the drying agent after filtration by adding hexane.

 Yield: 41.4 g (85% of theory)

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 dewatered azeotropically with toluene. A solution of 4.88 g (10 mmol) of N, N'-bis (benzyioxycarbonyl) -3- [carboxymethoxyacetyl] -3-azapentane-1, 5-diamine (example) is added to the cooled solution of cycles in toluene at room temperature 7a) in tetrahydrofuran (THF) and 2.47 g (10 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ; Fluka) were added and the mixture was stirred overnight. After the reaction has ended, 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 vacuo, 2.78 g (68% of theory) of a pale yellow solid are obtained.

c) Fully protected benzyloxycarbonyl-32-polyamine based on the

N, ^N, N ", N '" - tetrakis {8-benzyloxycarbonylamino) -6- [2-

(Benzyloxycarbonylamino) -ethyl] -5-oxo-3-oxaoctanoyl} -cycles with 32-amine condensed with N ^α , N ^ε- bis (lysyl) -lysine - ('tri-lysine ")

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 with 5.16 ml (30 mmol) of N-ethyldiisopropylamine and with 1.6 g (1 mmol) of the above

 described Octa-amine hydrobromids and added overnight

 Room temperature stirred. 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)

d) 3,5-dinitrobenzoyl-N, N-bis (carboxymethyl) amide 133.1 g (1.00 mol) of iminodiacetic acid are dissolved in 1.50 l 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

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, with 1.6 g of palladium catalyst (10 % Palladium on activated carbon) and hydrogenated while 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

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 dissolved in 200 ml of water and with 150 ml of a two normal iodine monochloride solution were added 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. By Acidification of the filtrate with concentrated hydrochloric acid formed a precipitate, which is filtered off and dried in vacuo.

 Yield: 40.1 g (67.3% of theory) of a colorless solid

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 in 300 ml. Water dissolved 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.

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

i) Dotriakontacontakis- {N- [3,5-di- (acetylamino) -2,4,6-triiodobenzoyl] -N- (sodium carboxylato-methyl) -glycyl} 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 33% hydrogen bromide in glacial acetic acid are added with stirring. After 3 hours, the precipitation started is completed with diethyl ether, the 32-amine hydrobromide formed is washed with diethyl ether 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)

Example 8

Dotriakontacontakis- {3 - [(N-sodium carboxylatomethyl) methoxyacetylamino-5- (2,3-dihydroxypropylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the deblocked 32-amine 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) 5-amino-2,4,6-triiodoisophthalic acid N- (2nd , 3-diacetoxypropyl) amide chloride (EP 0308364) in 500 ml of anhydrous dioxane, 24.7 g (150 mmol)

Methoxyacetyl chloride added at room temperature. The mixture is boiled under reflux for several hours until thin layer chromatography no longer detects any starting material, 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

b) 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid N- (2,3-dihydroxypropyl) monoamide 60.6 g (75.1 mmol) of the acid chloride prepared in Example 8a are introduced into 376 ml in a normal sodium hydroxide solution and about 45 min under nitrogen atmosphere. stirred vigorously. The completeness of sales is about

Thin layer chromatography checked and the product solution used for the next step without processing. 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 in a nitrogen atmosphere

 Chloroacetic acid was added and the mixture was 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 on silica gel 60 (Merck) (eluent

 Chromatograph dichloromethane / methanol / acetic acid (2: 2: 1). The

 Product fractions are evaporated to dryness in vacuo and the

 Crystallized residue from methanol / isopropanol.

 Yield: 47.7 g (83.3% of theory) of colorless crystals

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

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

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 in dichloromethane

 recorded and shaken with saturated aqueous sodium bicarbonate solution. The organic phase is dried over anhydrous magnesium sulfate and filtered. By dropwise addition of tert-butyl methyl ether to

 concentrated filtrate gives a colorless precipitate which is filtered off and dried in vacuo.

 Yield: 30.6 g (84.1% of theory) of a colorless solid

g) Dotriakontacontakis- {3 - [(N-sodium carboxylatomethyl) methoxyacetylamino- 5- (2,3-dihydroxypropylcarbamoyl) -2,4,6-triiodobenzoyl} 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 33% hydrogen bromide in glacial acetic acid are added with stirring. After 3 hours, the precipitation started is completed with diethyl ether, the 32-amine hydrobromide formed is washed with diethyl ether 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- is 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

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)

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) FeSO ₄ x 7 H ₂ O 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)

c) N, N ', N ", N ^, " -Cyclen-tetra-ureido conjugate from 1,4,7,10-tetraazacyclododecane 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. To this

 0.17 g (1 mmol) of anhydrous 1, 4,7,10-tetraazacyclododecane (Cyclen) (Aldrich) in toluene / pyridine (10: 1) are added and the suspension is added overnight

 Room temperature stirred. 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)

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)

 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)

f) Fully protected benzyloxycarbonyl-32-polyamine from the N, N-bis- [2- (benzyloxycarbonylamino) -ethyl] -glycine condensed with 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 hexadecaamine hydrobromide formed 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 treated with 13.76 ml (80 mmol) of N

Ethyldiisopropylamine and mixed with 3.2 g (1 mmol) of the hexadecaamine hydrobromide described above and stirred overnight at room temperature. To The reaction is evaporated in vacuo and the residue is chromatographed on silica gel using dichloromethane / methanol (9: 1).

Yield: 7.3 g (87% of theory)

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

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 polyvinylpyndine (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

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, 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 solid becomes a solution of 17.8 g (24.0 mmol) of the isothiocyanate and 2.0 described in Example 9g, which is mechanically stirred at room temperature (14 mmol) triethylamine in 120 ml of dimethyl sulfoxide was added dropwise. 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. The solution is opened after cooling

 Neutralized room temperature 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

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-triiodoisophthalic acid-N'-ethoxycarbonylmethyl 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 14.0 g (100 mmol) glycine ethyl ester hydrochloride (presentation according to DA

 Hoogwater, M. Peereboom, Tetrahedron, 46, 5325-5332 (1990)) and 10.1 g (100 mmol) of triethylamine. A suspension is formed which is stirred overnight under argon at room temperature. It is then evaporated and the residue on silica gel 60 (Merck)

 Chromatographed 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)

b) Dotriacontakis- {3-sodium carboxylatomethylcarbamoyl-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, 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 solid is dissolved in 30 ml of water to give a solution of 18.0 g (24.0 mmol) of mechanically stirred at room temperature under an argon atmosphere acid chloride prepared in Example 10a and 6.9 ml (50.0 mmol)

 Triethylamine in 120 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. The solution is left on after cooling

 Neutralized room temperature with 2 N hydrochloric acid and evaporated in vacuo in a vacuum. The residue is taken up in water and one

 Subjected to ultrafiltration, with low-molecular components separated by a hollow fiber membrane (H1 P3-20, Amicon). The watery

 The 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

Example 11

Dotriacontakis {N-methoxyacetyl-3-methylamino-5- (2-sodium sulfonatoethylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the deblocked 32-amine 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 with

Toluene dewatered azeotropically. A solution of 4.29 g (10 mmol) of the N, N-bis [2- (benzyloxycarbonylamino) ethyl] glycine described in Example 9e is added to the cooled solution of cycles in toluene at room temperature

Tetrahydrofuran (THF) and 2.47 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)

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 with

Diethyl ether completes the precipitation that begins, 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 1 c, 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 with 5.16 ml (30 mmol) of N-ethyldiisopropylamine and with 1.39 g (1 mmol) of the above

described Octa-amine hydrobromids and added overnight

Room temperature stirred. 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)

c) N-methoxyacetyl-5-methylamino-2,4,6-triiodoisophthalic acid N '- (2-bromethyl) 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-bromoethylamine hydrobromide and 20.2 g (200 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: 55.3 g (71.88% of theory)

 d) Dotriacontakis {N-methoxyacetyl-3-methylamino-5- (2-sodium sulfonatoethylcarbamoyl) -2,4,6-triiodobenzoyl} 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 while stirring with 33 percent hydrogen bromide added to glacial acetic acid. 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 taken up in water and added to a solution of 18.5 g (24.0 mmol) of the acid chloride prepared in Example 11c and 8.3 ml (60 mmol) of triethylamine in 100 ml of N, N, which is mechanically stirred at room temperature under an argon atmosphere -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

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)

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

To a stirred at 65 ° C oil bath temperature under an argon atmosphere

 Suspension of 25.7 g (30 mmol) of that prepared in Example 12a

 Aniline derivatives in 200 ml of 1,2-dichloroethane are added to 147 ml (73.8 mmol) of a two-normal toluene phosgene solution and 2 ml of N, N-dimethylformamide. 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

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 reduced to a at room temperature

 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, stirred in an argon atmosphere, was added. The approach will take 3 days

 Stirred at room temperature, then evaporated in a high vacuum, mixed with 13.8 ml (108 mmol) of bromotrimethylsilane and 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.

Example 13

Octatetracontakis {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3-dihydroxy-propylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the deblocked 48-amine from Example 13d a) N, N, N ', ^, N ", N" -Hexakis- {2- [N, N-bis- (2-benzyloxycarbonylamino-ethyl) -amino] - ethyl} N -trimesinsäuretriamid 1.27 g (1 mmol) of the hexa described in example 1b -Benzyloxycarbonylamines are dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid is added with stirring. After 60 minutes, the one started with diethyl ether

 Precipitation completed, the resulting hexamine hydrobromide 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

b) N, N, N ', ^N', N ", N" -Hexakis- {2- [N, N-bis- (2-aminoethyl) amino] ethyl} - trimesinsäuretriamid

2.2 g (0.85 mmol) of the title compound from Example 13a are dissolved in 100 ml

 Dissolved methanol and 3 g of peariman catalyst (palladium hydroxide on activated carbon; Fluka) 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)

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 triamids

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-benzyloxycarbonylaziridine

 (manufactured according to J. Chem. Soc, Perkin Trans., 1, 21-26, 1993) and heated under reflux 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 / triethyiamine 20: 1: 0, 1).

 Yield: 3.62 g (85% of theory) of a glassy solid

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 pearimane catalyst (palladium hydroxide on activated carbon) is added. The mixture is hydrogenated for 10 hours at 5 bar (room temperature). It is from The catalyst was filtered off, the filtrate was 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 (Bachern, Switzerland), 1.2 g (7.5 mmol) 1 -hydroxybenzotriazole and 2.4 g (7, 5 mmol) of 2- (1H-benzotriazol-1-yl) -1,3,3,3-tetramethyluronium tetrafluoroborate (TBTU; Peboc Limited, UK) are dissolved in DMF and stirred for 15 minutes. This solution is then with 5.16 ml (30 mmol) of N-ethyldiisopropylamine and with 0.40 g (0.2 mmol) of the above

 24-polyamine described added 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)

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

1.15 g (0.10 mmol) of the title compound from Example 13d 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 48-amine hydrobromide is washed with ether and dried in vacuo.

 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), which is stirred at room temperature under an argon atmosphere.

Triethylamine in 25 ml of anhydrous N, N-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 an ultrafiltration, whereby low molecular weight components through a hollow fiber membrane (H1 P3-20, Amicon) be separated. 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.

Example 14

Tetracosakis {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3-dihydroxy-propylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the 1, 4,7,10,13,16-hexakis [2 - (trilysylamino) -ethyl] -hexacyclens a) 1, 4,7,10,13,16-hexakis [2- (benzyloxycarbonylamino) -ethyl] -1, 4,7,10,13,16-hexaazacyclooctadecane 1, 29 g (5 mmol) 1, 4,7,10,13,16-hexaazacyclooctadecane (Hexacyden; 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 hexacyden in toluene, cooled to room temperature, and the mixture is stirred for 3 days Heated nitrogen under reflux. It 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

b) Fully protected benzyloxycarbonyl-24-polyamine based on the

 1, 4.7, 10, 13, 16-hexakis [2- (triysylamino) ethyl] hexacyciens

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 1 c, 1.2 g (7.5 mmol) of 1-hydroxybenzotriazole and 2.4 g (7.5 mmol) 2- (1 H-benzotriazol-1-yl) - 1, 1, 3,3-tetramethyluronium tetrafluoroborate (TBTU; Peboc Limited, UK) are described in DMF dissolved and stirred for 15 minutes. This solution is then with 5.16 ml (30 mmol) of N-ethyldiisopropylamine and with 1.48 g (1 mmol) of the above

 described hexa-amine hydrobromide and added overnight

 Room temperature stirred. 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)

c) Tetracosakis {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3-dihydroxy-propylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the 1, 4,7,10,13,16-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 16.1 g solution is stirred at room temperature under an argon atmosphere

 (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 were added. The mixture is stirred for 3 days at room temperature, then with 36 ml of 2N

 Sodium hydroxide solution was added and the mixture was 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.

Example 15

Tetrahexacontakis- {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3-dihydroxypropylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the deblocked 64-polyamine 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

b) N, N, N ', N'-tetrakis [2- (benzyloxycarbonylamino) ethyl] -5-aminoisophthalic acid diamide

9.18 g (10 mmol) of the nitro compound described in the previous example in 200 ml of ethanol are added to a solution of 27.8 g (100 mmol) of FeSO ₄ x 7 H ₂ O in 200 ml of water and heated to boiling. After adding 50 ml of conc. Ammonia is stirred under reflux for a further 90 minutes. You leave them

Cool the suspension, then the ethanol is concentrated in vacuo and the aqueous phase is shaken out with ethyl acetate. After drying over sodium sulfate, 8.61 g (97% of theory) of an almost colorless viscous oil are obtained.

c) N, N, N ', N'-tetrakis [2- (benzyloxycarbonylamino) ethyl] -5- (carboxymethoxyacetylamino) 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) diglycolic anhydride (Fluka) was added and the mixture was stirred at 0 ° C. for 2 hours.

It is evaporated to dryness in vacuo, the residue is between

Distributed ethyl acetate and 1 M citric acid, washed neutral with water and dried the organic phase.

Yield: 4.62 g (92% of theory) of a viscous oil

d) Fully protected benzyloxycarbonyl-hexadeca-amine based on the

 N, N ', N ", N'" - tetrakis (triiysylaminomethylj-methanes

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 2 days at room temperature. 300 ml of ethyl acetate are added, the precipitated urea is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is chromatographed on silica gel (mobile solvent: methylene chloride / isopropanol 20: 1). Yield: 58.02 g (67% of theory) of a colorless viscous oil

e) Fully protected benzyloxycarbonyl-64-amine from the 16-amine condensed with the tetraamine monocarboxylic acid 17f 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- (1H-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 is evaporated in vacuo and the residue with ethyl acetate / ethanol (2: 1)

 Chromatographed silica gel.

 Yield: 4.54 g (52% of theory) of a light yellow oil

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-benzyloxycarbonylamine described in Example 17e 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 64-amine hydrobromide formed is washed with ether and dried in vacuo. The residue is then taken up in water and added to a solution of 21.4 g which is stirred at room temperature under an argon atmosphere

(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 were added. The mixture is stirred for 3 days at room temperature, then with 48 ml of 2N

Sodium hydroxide solution was added and the mixture was 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.

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 2N sodium hydroxide solution. 42.65 g (250 mmol) are added dropwise at 0 ° C. with vigorous stirring

 Benzyl chloroformate, dissolved in 50 ml of tetrahydrofuran, and maintaining the pH at 9 with the simultaneous addition of 2 N sodium hydroxide solution. The mixture is then stirred for 5 hours at pH 9 and 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

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

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 the dry state in a vacuum, the residue is taken up in 300 ml

 Methylene chloride and washes 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

 (Eluent: methylene chloride / methanol 20: 1)

 Yield: 17.07 g (81% of theory) of a colorless solid

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

4.02 g (0.5 mmol) of the 32-benzyloxycarbonylamine described in Example 21c 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 32-amine hydrobromide formed is washed with ether and dried in vacuo.

 The residue is then taken up in water and added to a solution of 21.4 g stirred at room temperature under an argon atmosphere

(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 were added. The mixture is stirred for 3 days at room temperature, then with 48 ml of 2N

 Sodium hydroxide solution was added and the mixture was 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.

Example 17 a) 1,4,7,10,13,16-Hexakis [benzyloxycarbonylglycyl] -1,4,7,10,13,16-hexaazacyclooctadecane

516 mg (2 mmol) 1, 4,7,10,13,16-hexaazacyclooctadecane (Hexacyden; Fluka) are dewatered azeotropically with toluene. To the cooled solution from

 Hexacyden in toluene is 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-1, 2-dihydroquinoline at room temperature (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%)

b) 1, 4,7,10,13,16-Hexakis [N, N-bis- (benzyloxycarbonylaminoethyI) -glycyI] - 1, 4,7,10,13,16-hexaazacyclooctadecane

1.41 g (1 mmol) of the hexa- benzyloxycarbonylamine described in the example above 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 washes 2 times with 100 ml of 5 percent potassium carbonate solution is dried over magnesium sulfate and evaporated. The backlog is on

Chromatographed silica gel (eluent: methylene chloride / methanol / triethylamine

20: 1: 0.1).

Yield: 2.29 g (84% of theory) of a pale yellow viscous oil

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, 4,7,10,13,16-hexaazacyclooctadecane

1.36 g (0.5 mmol) of the title compound from Example 17b are dissolved in 100 ml

 Dissolved methanol and 3 g of peariman catalyst (palladium hydroxide on activated carbon;

Fluka) 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 without further

Purification used in the following reaction.

 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 (prepared according to J. Chem.

Soc, Perkin Trans. 1, 21-26, 1993) and added under nitrogen for 5 days

Reflux heated. 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

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

d) Tetracosakis {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3-dihydroxy-propylcarbamoyl) -2,4,6-triiodobenzoyl} derivative of the deblocked 24-amine from Example 17c 2.69 g (0. 50 mmol) of the title compound from Example 17c 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 in vacuo

 dried.

 The residue is then taken up in water and a 16.1 g solution is stirred at room temperature under an argon atmosphere

 (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 were added. The mixture is stirred for 3 days at room temperature, then with 36 ml of 2N

 Sodium hydroxide solution was added and the mixture was 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.

Example 18

Tetracosakis {3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3-dihydroxy-propylcarbamoyl) -2,4,6-triiodobenzoyl} -octakis (4-sodium carboxylatomethoxyacetylamino) 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 33% hydrogen bromide in glacial acetic acid are added with stirring. After 3 hours, the precipitation started is completed with diethyl ether, the 32-amine hydrobromide formed is washed with diethyl ether and dried in vacuo.

 The residue is then taken up in water and a 16.1 g solution is stirred at room temperature under an argon atmosphere

 (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 were added. The mixture is stirred at room temperature for 2 days, then 1.16 g (10.0 mmol) of diglycolic anhydride are added and the mixture is stirred for a further 24 hours. Then 50 ml of 2 N sodium hydroxide solution are 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

Blood levels in rats (Figure 1)

Concentration-time course (blood level) in the blood of the rat after a single intravenous administration of 400 mg iodine / kg of the macromolecular substance according to Example No. 18 in comparison to the monomeric nonionic lopromide. The data were collected from three animals each and represent the mean.

Despite the same dose, the macromolecular blood level is clearly higher in the first ten minutes after application

Contrast medium according to Example No. 18 in comparison to lopromide. The higher concentration in the blood is due to the fact that the distribution of the substance according to Example No. 18 is predominantly restricted to the vascular space, whereas lopromide is distributed throughout the extracellular space, which leads to a smaller one

Concentration in the blood space.

Vascular space is restricted, whereas lopromide is distributed throughout the extracellular space, which leads to a lower concentration in the blood space.

Claims

claims

1.) Iodine-containing dendrimeric polymers of the general formula I

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

 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 reproduction multiplicity x or y,

Z, W independently of one another for a cascade reproduction unit of reproduction multiplicity z or w,

D is a group T-B, in which B is a benzene ring of the general formula II,

or represents a group of the formula - (CO) _q -U-COOH, wherein

R ¹ and R ² each independently represent a hydrogen atom,

is a -CONR ³ R ⁴ - or -NR ⁶ COR ⁵ group, where

R ³ , R ⁴ 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 C ₁ - C ₃ alkoxy and / or 1-3 carboxy, sulfo or phosphono group (s) is substituted or R ³ and R ⁴ together with the nitrogen atom represent a heterocyclic 5- or 6-ring which optionally contains an oxygen atom, an SO ₂ group or an N-CO-R ⁷ radical,

R ⁷ for a carboxy group or an alkyl group with up to

12 C atoms, which are optionally 1-5 hydroxy, 1-3 C ₁ -C ₃ -

Contains alkoxy or 1-3 carboxy, sulfo or phosphono group (s),

R ^{5 represents} a carboxy group or a straight-chain or branched

C ₁ -C ₁₂ alkyl group, which is optionally interrupted by an oxygen atom, which may also be an

 Contains carbonyl group and / or optionally by 1-3 carboxy,

Sulfo or phosphono and / or 1-5 hydroxy and / or 1-3 C ₁ -C ₃ alkoxy group (s) and / or one optionally

 carboxymethyl-substituted imino group is substituted,

R ^{6 represents} a hydrogen atom, or a straight-chain or branched one

 Alkyl group with up to 12 carbon atoms, which is optionally

1 -3 carboxy, sulfo or phosphono group (s) and / or optionally substituted by 1-3 hydroxy group (s) and / or 1-3 C ₁ -C ₃ alkoxy group (s)

T for a group -CO-, -CS-, -CONH-, -CSNH-, COCH ₂ N (R ⁶ ) CO, - CHR-CHR-CONH-,

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

16≤ax.yzw≤ 128,

U stands for a group (CH ₂ ) _u q for the digits 0 or 1 and u for the digits 1-4 and their salts with physiologically harmless organic and / or inorganic! Bases, amino acids or amino acid amides. 2.) Cascade polymer complexes according to claim 1, characterized in that A

a nitrogen atom,

U ¹ for Q ¹ or E,

U ² for Q ² or E with

E in the meaning of the group

 wherein

 o for the digits 1 to 6,

Q ¹ for a hydrogen atom or Q ² and

Q ² for a direct bond

M is a C ₁ -C ₁₀ alkylene chain which may be 1 to 3

 Oxygen atoms is interrupted and / or optionally substituted with 1 to 2 oxo groups,

R ° for a branched or unbranched C ₁ -C ₁₀ alkyl radical, a nitro,

Amino, carboxylic acid group or for the group

stand,

where the number Q ² 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 for

certainly,

 wherein

U ¹ for Q ¹ or E,

U ² for Q ² or E with

E in the meaning of the group

 in which

 o for the digits 1 to 6,

Q ¹ for a hydrogen atom or Q ² ,

Q ² for a direct bond,

U ³ for a C ₁ -C ₂₀ alkylene chain which may be 1 to 10

Oxygen atoms and / or 1 to 2 -N (CO) _q -R ² -, 1 to 2 phenylene and / or 1 to 2 phenyleneoxy radicals is interrupted and / or optionally by 1 to 2 oxo, thioxo, carboxy, C ₁ -C ₅ alkylcarboxy, C ₁ -C ₅ alkoxy, hydroxy, C ₁ -C ₅ alkyl groups is substituted, wherein q for the digits 0 or 1 and

R ^{2 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

V stands for the methine group if U ^{4 is} a direct one

Binding or the group M means and U ⁵ one of the meanings of

U ³ owns or

V for the group stent 'if U ⁴ and U ⁵ at the same time

are identical and denote the direct bond or the group M.

4.) iodine-containing dendrimeric polymers according to claim 1, characterized

characterized in that the triiodinated benzene radical B bound to the terminal nitrogen atoms of the last generation of the reproduction unit W represents a radical of the general formula II

stands in what

R ¹ and R ² independently of one another for a radical of the formula

-CONHCH ₂ CH (OH) CH ₂ (OH),

-NHCOCH ₂ CH ₂ COOH, -NHCOCH ₂ CH ₂ COONa,

-CONHCH ₂ CO ₂ H,

-CONHCH ₂ CO ₂ Na,

-CON (CH ₂ CO ₂ Na) ₂ ,

-CON (CH ₂ CO ₂ H) ₂ ,

 -NHCOCOOH,

 -NHCOCOONa,

-NHCOCH ₂ OCH ₂ COOH,

-NHCOCH ₂ OCH ₂ COONa,

-NHCOCH ₂ OCH ₃ ,

-NHCOCH ₃ ,

-N (CH ₂ COOH) -COCH ₂ OCH ₃ ,

-N (CH ₃ ) COCH ₂ OCH ₃ ,

-CONHCH ₂ CH ₂ SO ₂ Na,

-CONHCH ₂ PO ₃ Na ₂ or

-NHCH ₂ OCH ₂ COONa stands.

5.) iodine-containing dendrimeric polymers according to claim 4, characterized

characterized that the

the groups representing U ⁶ C ₁ -C ₂₀ alkylene chain

-CH ₂ -, -CH ₂ NHCO-, -NHCOCH ₂ O-, -NHCOCH ₂ OC ₆ H ₄ -, -N (CH ₂ CO ₂ H) -, -NHCOCH ₂ C ₆ H ₄ -, -NHCSNHC ₆ H ₄ -, -CH ₂ OC ₆ H ₄ -, -CH ₂ CH ₂ O-, and / or by the groups -COOH, -CH ₂ COOH

 is substituted.

6.) Iodine-containing dendrimeric polymers according to claim 4, characterized

characterized in that

U ⁶ for one

-CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -C ₆ H ₄ -, -C ₆ H ₁₀ -, -CH ₂ C ₆ H ₅ -, -CH ₂ NHCOCH ₂ CH (CH ₂ CO ₂ H) -C ₆ H ₄ -,

-CH ₂ NHCOCH ₂ OCH ₂ -,

-CH ₂ NHCOCH ₂ C ₆ H ₄ -,

-CH ₂ NHCSNH-C ₆ H ₄ -CH (CH ₂ COOH) CH ₂ -,

-CH ₂ OC ₆ H ₄ -N (CH ₂ COOH) CH ₂ -,

-CH ₂ NHCOCH ₂ O (CH ₂ CH ₂ O) 4-C ₆ H ₄ -,

-CH ₂ OC ₆ H ₄ -,

-CH ₂ CH ₂ -O-CH ₂ CH ₂ -, -CH ₂ CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ CH ₂ -,

7.) iodine-containing dendrimeric polymers according to claim 3, characterized

characterized in that the radical U ³ contained in the cascade reproduction units X, Y, Z and W for -CO-, -COCH ₂ OCH ₂ CO-, -COCH ₂ -, -CH ₂ CH ₂ -, -CONHC ₆ H ₄ -, -COCH ₂ CH ₂ CO-, -COCH ₂ -CH ₂ CH ₂ CO-or

-COCH ₂ CH ₂ CH ₂ CH ₂ CO-,

the radical U ^{4 stands} for a direct bond or for -CH ₂ CO-,

the radical U ⁵ for a direct bond or for - (CH ₂ ) ₄ -, -CH ₂ CO-, -CH (COOH) -,

CH ₂ OCH ₂ CH ₂ -, -CH ₂ C ₆ H ₄ -, CH ₂ -C ₆ H ₄ OCH ₂ CH ₂ - is or

the rest E for a group

 8.) Iodine-containing dendrimeric polymers according to claim 3, characterized

characterized in that the cascade reproduction units X, Y, Z and W are independent of each other for

-CH ₂ CH ₂ NH-; -CH ₂ CH ₂ N <;

-COCH (NH -) (CH ₂ ) ₄ NH-; -COCH (N <) (CH ₂ ) ₄ N <;

-COCH ₂ OCH ₂ CON (CH ₂ CH ₂ NH-) ₂ ; -COCH ₂ OCH ₂ CON (CH ₂ CH ₂ N <) ₂ ;

-COCH ₂ N (CH ₂ CH ₂ NH-) ₂ ; -COCH ₂ N (CH ₂ CH ₂ N <) ₂ ;

-COCH ₂ NH-; -COCH ₂ N <; -COCH ₂ CH ₂ CON (CH ₂ CH ₂ NH-) ₂ ; -COCH ₂ CH ₂ CON (CH ₂ CH ₂ N <) ₂ ;

-COCH ₂ OCH ₂ CONH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ NH-) ₂ ] ₂ ;

-COCH ₂ OCH ₂ CONH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ N <) ₂ ] ₂ ;

-COCH ₂ CH ₂ CO-NH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ NH-) ₂ ] ₂ ;

-COCH ₂ CH ₂ CO-NH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ N <) ₂ ] ₂ ;

-CONH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ NH-) ₂ ] ₂ ;

-CONH-C ₆ H ₄ -CH [CH ₂ CON (CH ₂ CH ₂ N <) 2] ₂ ;

 -COCH (NH-) CH (COOH) NH-; -COCH (N <) CH (COOH) N <;

9.) iodine-containing dendrimeric polymers according to claim 2, characterized in that

stand.

10.) Pharmaceutical compositions containing at least one iodine-containing

dendrimeric polymer according to claim 1, optionally with the additives customary in galenics.

11.) Use of at least one iodine-containing dendrimeric polymer according to claim 1 for the production 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 the X-ray diagnosis of vascular diseases.

13) Process for the preparation of the iodine-containing dendrimeric polymers according to claim 1, characterized in that dendrimeric polymers of the general formula I '

A- {X- [Y- (Z- (W-ß _w ) ₂ ) _y ] _x } _a (I '), wherein

 A for a nitrogen-containing cascade core of base multiplicity a,

X, Y independently for a direct bond or a

 Cascade reproduction unit of reproduction multiplicity x or y,

Z, W independently for a cascade reproduction unit of the

 Reproductive 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

 ß for the binding site of the terminal amino groups of the last

 Generation of the reproduction unit W are provided that at least two reproduction units are different and that multiplicities apply to the product

 16≤ax yzw≤ 128, with compounds of the general formula II '

 T-B '(II),

 wherein

 T for a carbonyl, thiocarbonyl, activated carbonyl or a

 CHR = CR-containing group, which is converted into T by the reaction, wherein

 R has the meaning of a hydrogen atom or a methyl group and

 B 'has the meaning of a triiodoaromatic indicated for B, wherein in

B contained carboxy and hydroxy groups, however, are in protected form,

 implemented and then acylated or alkylated the positions β which may not be occupied by the radicals Z with a reagent introducing the radical - (CO) q-U-COOH, in which

U stands for a group (CH ₂ ) _u

 q for the digits 0 or 1 and

 u stands for the digits 1 -4.

14.) Process for the preparation of the pharmaceutical composition according to claim 1, characterized in that the iodine-containing dendrimeric polymer dissolved or suspended in water or physiological saline solution,

if necessary with the additives customary in galenics, in a form suitable for enteral or parenteral administration.