NO312724B1 - Process for the preparation of metal complex carboxylic acid amides - Google Patents

Abstract

The invention relates to a method for producing metal complex carboxylic acid amides characterized in that a metal complex carboxylic acid mixture consisting of metal complex carboxylic acid and at least one solubilizing substance is pretreated in dimethylsulfoxide (DSMO) with a dehydrating reagent, optionally by adding a coupling adjuvant and made to react with a amine of general formula (I): A(NH2)n, wherein A means the radical of a natural or synthetic amine and n stands for the figures 1 to 100.

Description

The present invention relates to the object according to the claims, that is to say a new method for the production of metal complex carboxylic acid amides.

Metal complex carboxylic acid amides find many applications in medical diagnostics and therapy. In the European patent applications No. 0255471, 0331616, 0430863, 0481526, 0130934 and in the international patent applications WO 96/02669 and WO 94/28940, such compounds and their use as contrast agents are thus described, above all in nuclear magnetic resonance imaging (MRI). Their production is carried out by coupling an amine to activated carboxylic acids in a complex former where the carboxylic acids must as a rule be present in a protected form.

Anhydrides and N-hydroxysuccinimides are often used. After cleavage of the acid protecting groups present, the desired metal is introduced.

Disadvantages of this method should above all be mentioned: a) Incomplete coupling and thereby accompanying problems with separation of the reaction products. The unreacted amines

usually have undesirable pharmacological properties.

b) Incomplete metal incorporation (complex formation) in the complexing conjugate. An undesirable result follows from this

antidote effect (damage to the cardiovascular system) as well as a lower effectiveness of the formed product as a diagnosticum (less metal content in the contrast medium) .

c) A protecting group chemistry always leads to further reaction steps where the protecting groups must be removed. Hereby

a deterioration of the pharmacological properties of the desired product can very easily occur. During the removal of protective groups, large quantities of by-products are also formed which must be removed. Therefore, an avoidance of protecting groups is directly desirable for methods to be used on an industrial scale.

d) The obtained yield of metal complex carboxylic acid amides using methods according to known techniques is often

unsatisfactory.

e) The incorporation of metal, above all when macrocyclic complex formers are used, must be carried out at higher

temperatures. Here too, a deterioration in the purity of the reaction products follows.

The present invention thus has the task of providing a method for the production of metal complex carboxylic acid amides which avoids, or at least reduces, the above-mentioned disadvantages.

It was surprisingly found that this task could be solved with the help of the present invention, i.e. by the method for the production of metal complex carboxylic acid amides, which is characterized in that a metal complex carboxylic acid mixture consisting of the metal complex carboxylic acid where the metal is selected from the group of lanthanides, iron, manganese, yttrium and bismuth , and at least one solubilizing compound in dimethylsulfoxide (DMSO) is pretreated with a water-splitting reagent, optionally with the addition of a coupling aid, followed by reaction with an amine of the general formula I

in which

A denotes the residue of a natural or synthetic amine, where the amine is selected from the group of antibiotics,

nucleosides, aminoterpenes, aminoporphyrins, aminosteroids, aminosugars, dendrimers, proteins, polylysines, aminopolysaccharides, polyvinylamines, polyalkylamines, poly[N(2-aminoethyl)] methacrylamides,

polynucleotides and polypeptides, and

n denotes the numbers 1-100,

provided that the reaction takes place in solution with a temperature of 0 to 70 °C.

The mixture used in the coupling reaction of metal complex carboxylic acid and at least one solubilizing compound in an amount of up to 5, for example 0.5-2, molar equivalents with respect to the metal complex carboxylic acid can be prepared both by means of an initial reaction step and isolated (e.g. by evaporation, freeze-drying or spray-drying of an aqueous or water-miscible solution of the components, or by precipitation with an organic solvent from a corresponding solution), followed by reaction in DMSO with a water-splitting reagent and possibly a coupling aid, and can also be formed in in situ by adding a solubilizing compound (solvents) to the DMSO suspension of the metal complex carboxylic acid, a water splitting reagent and optionally a coupling aid.

The reaction solution prepared according to one of these methods is stored for pretreatment (acid activation) for 1-24, preferably 3-12, hours at temperatures from 0 to 50 oC, preferably at room temperature. An amine of general formula I is then added without solvent, or preferably dissolved in DMSO, in water or in water-miscible solvents. For amide coupling, the reaction solution thus formed is kept at temperatures from 0 to 70 °C, preferably 30 to 60 °C, for 1-48, preferably 8-24, hours.

In some cases, it has proven advantageous to use the amine in the reaction in the form of a salt, e.g. as hydrobromide or hydrochloride. To release the amine, a base is added, such as e.g. triethylamine, diisopropylamine, N-methyl-morpholine, pyridine, tripropylamine, triamine, lithium hydroxide, lithium carbonate, sodium hydroxide or sodium carbonate. Isolation of the reaction product is carried out according to methods known to those skilled in the art, for example by precipitation with organic solvents, for example acetone, 2-butanone, diethyl ether, acetic ester, methyl t-butyl ether, isopropanol or mixtures thereof. The further purification can e.g. carried out by chromatography, crystallization or ultrafiltration.

Suitable solvents are alkali, alkaline earth, trialkylammonium and tetraalkylammonium salts, urea, N-hydroxyimides, hydroxyaryltriazoles, substituted phenols and salts of heterocyclic amines. Examples include: lithium chloride, lithium bromide, lithium iodide, sodium bromide, sodium iodide, lithium methanesulfonate, sodium methanesulfonate, lithium p-toluenesulfonate, sodium p-toluenesulfonate, potassium bromide, potassium iodide, sodium chloride, magnesium bromide, magnesium chloride, magnesium iodide, tetraethylammonium p-toluenesulfonate , tetramethylammonium p-toluenesulfonate, pyridine p-toluenesulfonate, triethylammonium p-toluenesulfonate, 2-morpholinoethylsulfonic acid, 4-nitrophenol, 3,5-dinitrophenol, 2,4-dichlorophenol, N-hydroxysuccinimide, N-hydroxyphthalimide, urea , tetramethylurea, N-methylpyrrolidone, formamide, as well as cyclic urea compounds, alkali, alkaline earth, trialkylammonium and tetraalkylammonium salts, urea, N-hydroxyimides, hydroxyaryltriazoles, substituted phenols and salts of heterocyclic amines are preferred as solvents. Particularly preferred are lithium chloride, lithium bromide, lithium iodide, sodium bromide and sodium iodide.

As water-splitting reagents, all agents known to those skilled in the art can be used (see, for example, Houben-Weyl, Methoden der organischen Chemie, vol. XV/2, Georg Thieme-Verlag, Stuttgart, 1974, and J. Chem. Research (S ), 1996, 302.)

Particularly preferred are carbodiimides and onium reagents, such as e.g. dicyclohexylcarbodiimide (DCCI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydroxychloride (EDC), benzotriazol-l-yloxytris(dimethylamino)phosphonium fluorophosphate (BOP) and 0-(benzotriazol-l-yl)-1,1, 3,3-tetrauronium hexafluorophosphate (HBTU), preferably DCCI.

All such substances known in the art can be used as possible coupling aids (Houben-Weyl, Methoden der organischen Chemie, volume XV/2, Georg Thieme-Verlag, Stuttgart, 1974). Examples include 4-nitrophenol, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, 3,5-dinitrophenol and pentaphenol. 4-nitrophenol is particularly preferred.

Suitable as amines of general formula I are monoamines (n = 1) and polyamines (n = 2-100). Preferred as polyamines are those with n = 1 and n = 2 to 50, particularly preferred those with n = 12 to 36. As examples can be mentioned dendrimers (such as mentioned in Polymer Journal, 17, 117 (1985), US -4 587 329, EP 0430863, WO 96/01655), proteins, polylysines (e.g. mentioned in EP 0481526 and EP 0331616), aminopolysaccharides (such as e.g. mentioned in WO 94/28940), polyvinylamines, polyalkylamines , poly-[N(2-aminoethyl)] methacrylamides, polynucleotides (see e.g. WO 96/02669), antisense polynucleotides, polypeptides, antibiotics, nucleosides, aminoterpenes, aminoporphyrins (see e.g. WO 94/07894) , aminosteroids and aminosugars. Above all, those which do not contain any protonatable amino groups in the residue A in general formula I are preferred. Particularly preferred is the 24-mer polyamine mentioned in WO 96/01655, based on N,N,N',N',N'<1>,N''-hexakis[2-(triamino)ethyl]trimesic acid triamide (see example 12).

Suitable as metal complex carboxylic acids are linear (e.g. those mentioned in DE 19507822 and EP 0450742) and macrocyclic (e.g. those mentioned in EP 0485045) compounds. Suitable are macrocyclic compounds based on the 1, 4,7,10-tetraazacyclododokanskelet. Particularly preferred are compounds of general formula II

in which

Z° denotes a metal ion equivalent with ordinal numbers 25, 26,

39, 57-71, 83, and

R denotes a CHX1-CO-NH-CHY1-(CH2)f-COOH group, where X<1>

and Y<1> independently of each other represents a hydrogen atom, a straight-chain or branched d-C7 alkyl radical, a phenyl or benzyl group, and f represents the numbers 0 to 9.

As residues Xi and Yi can e.g. are mentioned: methyl, ethyl, propyl, butyl respectively hydrogen, methyl, isopropyl, phenyl and benzyl. Preference is given to methyl or hydrogen. Particularly preferred are metal complex carboxylic acids with a cyclic structure.

The index f denotes, for example, the number 0, 1 or 2.

Of the above-mentioned lanthanides, gadolinium and dysprosium are preferred. As a complexing agent with general formula II (Z0 = hydrogen) is 10-[4-carboxy-1-methyl-2-oxo-3-aza-butyl]-1,4,7,10-tetraazacyclododecane-1, 4 , 7 - triacetic acid particularly preferred.

It is further preferred that the metal complex carboxylic acid mixture contains up to 5 molar equivalents of the solvents relative to the metal complex carboxylic acid, and more preferably that the metal complex carboxylic acid mixture contains 0.5 to 2 molar equivalents of dissolution mediating compounds relative to the metal complex carboxylic acid.

The synthesis of these compounds is carried out by compounds of general formula III

in which

R' has the same meaning as R, and where the contained carboxyl group is possibly present in protected form,

and

Z<1> denotes a hydrogen atom or a

carboxyl protecting group,

after cleavage of any carboxyl protecting groups present, is reacted in a known manner with a metal oxide or a metal salt of an element with ordinal numbers 25, 26, 39, 57-71, 83.

The introduction of the desired metal ions is carried out as e.g. described in the patent documents EP 71564, EP 130934 and DE-3401052, in that the metal oxide or a metal salt (e.g. nitrate, acetate, carbonate, chloride and sulfate) of the element with the desired order number is dissolved or suspended in water and/or a lower alcohol (such as methanol, ethanol or isopropanol) and reacted with a solution or suspension of the equivalent amount of a complexing agent of general formula

III.

When Z<1> denotes an acid protecting group, e.g. straight-chain or branched Ci-C6 alkyl, aryl and aralkyl groups in question, e.g. the groups methyl, ethyl, propyl, butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis(p-nitrophenyl)methyl, as well as trialkylsilyl groups. The t-butyl group is also suitable.

Removal of protecting groups is carried out according to methods known to those skilled in the art, e.g. by hydrolysis, hydrogenolysis, alkaline saponification of the ester 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, using trifluoroacetic acid [Protective Groups in Organic Synthesis, 2nd ed., T.W. Greene and P.G.M. Wuts, John Wiley and Sons, Inc., 1991].

Compounds of general formula III can be prepared by reaction of α-halocarboxylic acid esters or acids of general formula IV

in which

Z<1> has the meanings given above, and Hal denotes chlorine, bromine or iodine,

with compounds of general formula V

in which

R<5> denotes a hydrogen atom or an acid protecting group, and

X<1>, Y<1> and f have the meanings given above.

When both Z<1> and R<5> denote an acid protecting group, these can be different, so that Z<1> (e.g. benzyl) can possibly be selectively cleaved off (e.g. by hydrogenolysis) in the presence of R< 5->protecting groups (eg t-butyl) .

When Z<1> denotes an acid protecting group, the reaction is preferably carried out in solvents such as methylene chloride, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, chloroform; lower alcohols such as methanol, ethanol and isopropanol; as well as mixtures of the above solvents with water.

When using a halocarboxylic acid, the reaction is preferably carried out in water.

Organic bases such as pyridine, triethylamine or diisopropylethylamine are used as acid-attracting agents; or inorganic bases such as sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide or sodium carbonate, potassium carbonate, sodium hydrogen carbonate or lithium carbonate. The alkylation is carried out at temperatures between 0 and 100 °C, for example at 20-80 °C.

Compounds of general formula V are prepared by reacting cyclic compounds (formula VI)

with compounds of general formula VII

in which

X1,Y1,R<5>and f have the meanings given above, and Nu denotes a nucleus donor. Chloride, bromide, iodide, mesylate, tosylate or triflate can be mentioned as nucleus donors.

The reaction is carried out in solvents such as chloroform, methylene chloride, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide or also in water, at temperatures from 0 to 100 °C, however preferably at 20-60 °C. If desired, an organic or inorganic base can be added. Examples of these are triethylamine, pyridine, sodium carbonate, sodium hydroxide or potassium hydroxide.

Compounds of general formula VII are prepared by reacting compounds of general formula VIII

in which

Nu and X<1> have the meanings given above, with compounds of general formula IX

in which

Y<1>, f and R<5> have the meanings indicated above.

The conversion is carried out according to known methods from peptide chemistry. From an acid of general formula VIII, it can thus e.g. a derivative is produced, such as e.g. an acid chloride, acid bromide or an active ester (such as, for example, NHS ester), which is condensed with an amino acid (possibly terminally protected).

Compounds of general formula VIII, as well as their acid chlorides and acid bromides, are commercially available. Compounds of general formula IX are also commercially available as free amino acids or in protected form.

Alternatively, compounds of general formula III can be prepared by reacting compounds of general formula X

in which Z<1> has the above meaning (see e.g.

EP 0255471), with compounds of general formula VII, after cleavage of any acid protecting groups present.

The turnover is carried out in solvents such as e.g. acetonitrile, dimethylformamide, tetrahydrofuran, dioxane; or lower alcohols such as methanol, ethanol or i-propanol; as well as mixtures thereof with water; however, clean water can also be used. The reaction is usually carried out at temperatures of 20-100 °C.

Organic or inorganic bases are used as acid-attracting agents. Examples include triethylamine, pyridine, 4-dimethylaminopyridine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate. Metal hydrides such as sodium hydride, calcium hydride can also be used, however only when aprotic solvents are used.

Addition of catalytic amounts of an iodide has proven beneficial. Examples include sodium iodide, potassium iodide, lithium iodide or tetrabutylammonium iodide.

The purification of the metal complexes of general formula II is carried out e.g. by chromatography on silica gel or RP-18.

Most of the metal complexes of general formula II can be crystallized from alcohols such as methanol, ethanol or isopropanol, or from their mixtures with water.

It has proven beneficial to dissolve the metal complexes in alcohols or mixtures of alcohols with water and precipitate the complexes by adding acetone drop by drop.

Drying of the metal complex carboxylic acids is advantageously carried out in vacuum at temperatures of 20-200 °C, preferably 50-130 °C, for approx. 6 hours to 3 days.

The thus prepared metal complex carboxylic acids of general formula II are stored under moisture exclusion and can be directly used in a coupling reaction.

In the present method, it is preferred that the metal complex carboxylic acid mixture is formed in situ by adding dissolution mediating compound/compounds to the DMSO suspension of the metal complex carboxylic acid, a water splitting reagent and possibly a coupling aid. It is also preferred that the metal complex carboxylic acid mixture is first prepared and isolated, followed by this mixture then being pre-treated by adding a water-splitting reagent and possibly a coupling aid in DMSO.

Furthermore, it is preferred that the amine is added without solvent to the DMSO solution of the pretreated metal complex carboxylic acid mixture or that the amine is added in dissolved form to the DMSO solution of the pretreated metal complex carboxylic acid mixture or that the amine is added in dissolved form to the DMSO solution of the pretreated metal complex carboxylic acid mixture. More preferably, the amine is dissolved in DMSO, water or in water-miscible solvents.

It is also further preferred that a mixture of the gadolinium complex of 10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1-2 equivalents of sodium bromide are first prepared and isolated, followed by this mixture then being pre-treated with the addition of 4-nitrophenol and dicyclohexylcarbodiimide in DMSO at room temperature and reaction times between 3 and 12 hours, and followed by the mixture, optionally with the addition of water, being reacted with the 24-mer polyamine based on N,N,N',N',N' ', N1 1-hexakis[2- (triamino)ethyl]trimesic acid triamide, at 20-60 °C and reaction times between 8 and 24 hours. Furthermore, it is preferred that a mixture of the gadolinium complex of 10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1 -2 equivalents of lithium chloride are first prepared and isolated, followed by this mixture then being pretreated with the addition of 4-nitrophenol and dicyclohexylcarbodiimide in DMSO at room temperature and reaction times between 3 and 12 hours, and followed by the mixture, optionally with the addition of water, reacted with The 24-mer polyamine based on N,N,N',N',N' 1,N' 1-hexakis[2- (triamino)ethyl]trimesic acid triamide, at 20-60 °C and reaction times between 8 and 24 hours.

The method according to the present invention is distinguished by practically complete coupling of the amine with the metal complex carboxylic acids, so that no problems arise with regard to the separation of unreacted or partially reacted reagents. The amide conjugates thus formed also contain practically no metal-free complexing units. This leads to physiologically better compatible compounds than the conjugates that can be prepared according to the state of the art.

Because in the method according to the present invention no protective groups have to be introduced or removed, and because the molecularly taxing (high temperature, low pH value) incorporation of the metal in the last reaction step is avoided, the product is obtained with high purity. The yield from the method according to the present invention is also surprisingly high.

A further advantage of the method according to the present invention is that the method is also suitable for conversions on an industrial scale because the conversion can be carried out in a highly concentrated solution.

The following examples 1-11 serve to illustrate the synthesis of metal complex carboxylic acids of general formula II:

Example 1

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

To 100 g (296.4 mmol) glycine benzyl ester p-toluene sulfonic acid salt and 33.0 g (326.1 mmol) triethylamine in 400 ml methylene chloride are added dropwise at 0 oC 55.9 g (326.1 mmol) 2-bromopropionic acid chloride. The temperature is not allowed to rise above 5 oC. After the addition is complete, the mixture is stirred for 1 hour at 0 °C and then for 2 hours at room temperature. 500 ml of ice water is added, and the water phase is adjusted to pH 2 with 10% aqueous hydrochloric acid. The organic phase is separated, washed once with 300 ml of 5% aqueous soda solution and 400 ml of water. The organic phase is dried over magnesium sulfate and evaporated in vacuo to dryness. The residue is recrystallized from diisopropyl ether.

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

Melting point: 69-70 °C.

Elemental analysis:

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

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

Yield: 40.0 g [63% of the theoretical value with respect to the amount of compound la)] of a slightly yellowish viscous oil.

Elemental analysis:

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

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

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

Melting point: 116-117 °C.

Elemental analysis:

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

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

Melting point: 225 °C (decomposition).

Elemental analysis:

e) 10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid 77 g (103.1 mmol) of the title compound from example ld) is dissolved in 500 ml of trifluoroacetic acid and stirred for 3 hours at room temperature. The mixture is evaporated to dryness, the residue is dissolved in 300 ml of water, and the solution is applied to a column filled with "Reillex" 425 PVP. The elution is carried out with water. The product-containing fractions are combined and evaporated to dryness, and the residue is recrystallized from methanol/acetone.

Yield: 44.04 g (84% of theory) of a colorless, hygroscopic solid.

Water content: 6.5%.

Elemental analysis (calculated on anhydrous material):

f) Gadolinium complex of 10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

To 40 g (84.12 mmol) of the title compound from example le), dissolved in 400 ml of water, 15.27 g (42.06 mmol) of gadolinium oxide is added, and the mixture is heated for 3 hours at 90 °C. The mixture is evaporated to dryness (vacuum), and the residue is recrystallized from 90% aqueous ethanol. The crystals are suctioned off, washed once with ethanol, then with acetone and finally with diethyl ether and dried in a vacuum oven at 130 °C (24 hours).

Yield: 50.53 g (93% of the theoretical value) of a colorless crystalline powder.

Water content: 2.5%.

Elemental analysis (calculated on anhydrous material):

Example 2

Dysprosium complex of 10-[ 4- carboxyl- l- methyl- 2- oxo- 3-azabutyl]- 1, 4, 7, 10- tetraazacyclododecane- 1, 4 , 7- triacetic acid

To 20 g (42.06 mmol) of the title compound from example le), dissolved in 200 ml of water, add 7.84 g

(21.03 mmol) of dysprosium oxide, and the mixture is heated for 3 hours at 90 °C. The mixture is evaporated to dryness (vacuum), and the residue is recrystallized from 90% aqueous ethanol. The crystals are suctioned off, washed once with ethanol, then with acetone and finally with diethyl ether and dried in a vacuum oven at 130 oC (24 hours).

Yield: 24.98 g (91% of the theoretical value) of a colorless crystalline powder.

Water content: 2.7%.

Elemental analysis (calculated on anhydrous material):

Example 3

Ytterbium complex of 10-[ 4- carboxyl- 1- methyl- 2- oxo- 3- azabutyl]-1, 4, 7, 10- tetraazacyclododecane- 1, 4, 7- triacetic acid

To 20 g (42.06 mmol) of the title compound from example le), dissolved in 200 ml of water, 8.29 g (21.03 mmol) of ytterbium oxide is added, and the mixture is heated for 3 days at 90 °C. The mixture is evaporated to dryness (vacuum), and the residue is recrystallized from 90% aqueous ethanol. The crystals are suctioned off, washed once with ethanol, then with acetone and finally with diethyl ether and dried in a vacuum oven at 130 °C (24 hours).

Yield: 21.79 g (78% of the theoretical value) of a colorless crystalline powder.

Water content: 2.8%.

Elemental analysis (calculated on anhydrous material):

Example 4

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

To 100 g (296.4 mmol) glycine benzyl ester p-toluenesulfonic acid salt and 89.98 g (889.2 mmol) triethylamine in 500 ml methylene chloride are added dropwise at 0 °C 65.96 g (355.7 mmol) aPbromobutyric acid chloride. The temperature is kept between 0 and 5 °C. 1000 ml of 5% aqueous hydrochloric acid is added to the mixture, and the organic phase is separated. The organic phase is extracted again with 500 ml of 5% aqueous hydrochloric acid, dried over magnesium sulfate and evaporated in vacuo to dryness. The residue is recrystallized from diisopropyl ether.

Yield: 75.43 g (81% of the theoretical value) of a colorless crystalline powder.

Elemental analysis:

b) 10-[4-(benzyloxycarbonyl)-1-ethyl-2-oxo-3-aza-butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-tri-acetic acid-tri-tert. - butyl ester

To 50 g (159.14 mmol) of the title compound from Example 4a), 36.98 g (79.6 mmol) of 1,4,7-tris(tert.-butoxycarbonylmethyl)-1,4,7,10-1etraazadodecane ( = D03A-1ri - tert.-butyl ester), 44 g (318.4 mmol) potassium carbonate and 1 g

(6 mmol) of potassium iodide is added to 500 ml of acetonitrile, and the mixture is refluxed for 12 hours. The salts are filtered off, and the filtrate is evaporated in vacuo to dryness. The residue is dissolved in 800 ml of dichloromethane and extracted twice with 300 ml of 5% aqueous sodium carbonate solution. The organic phase is dried over magnesium sulfate and evaporated. After chromatography on silica gel (eluent: dichloromethane/methanol = 20:1) 19.11 g of the title compound (31.2% of the theoretical value) are obtained as a colorless foam.

Elemental analysis:

c) 10-(4-carboxy-1-ethyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tri-tert-butyl ester 19 g (25 .40 mmol) of the title compound from example 4fc) are dissolved in 300 ml of isopropanol and 2 g of palladium catalyst (10% Pd/C) are added. The mixture is hydrated overnight at room temperature. The catalyst is filtered off, and the filtrate is evaporated to dryness.

Yield: 16.54 g (99% of the theoretical value) of a viscous oil.

Elemental analysis:

d) 10-(4-carboxy-1-ethyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

16 g (24.32 mmol) of the title compound from example 4c) are dissolved in 100 ml of trifluoroacetic acid and stirred for 3 hours

at room temperature. The mixture is evaporated to dryness, the precipitate is dissolved in 50 ml of water, and the solution is applied to a column filled with "Reillex" 425 PVP. The elution is carried out with water. The product-containing fractions are combined and evaporated to dryness, and the precipitate is recrystallized from methanol/acetone.

Yield: 10.10 g (79% of theory) of a colorless, hygroscopic solid.

Water content: 6.9%.

Elemental analysis (calculated on anhydrous material):

e) Gadolinium complex of 10-(4-carboxy-1-ethyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

To 9 g (18.38 mmol) of the title compound from

-example 4d), dissolved in 70 ml of water, add 3.33 g

(9.19 mmol) of gadolinium oxide, and the mixture is heated for 3 hours at 90 oC. The mixture is evaporated to dryness (vacuum), and the residue is recrystallized from 90% aqueous ethanol. The crystals are suctioned off, washed once with ethanol, then with acetone and finally with diethyl ether and dried in a vacuum oven at 130 °C (24 hours).

Yield: 11.44 g (94% of the theoretical value) of a colorless crystalline powder.

Water content: 2.8%.

Elemental analysis (calculated on anhydrous material):

Example 5

Dysprosium complex of 10-(4-carboxyl-1-ethyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

To 10 g (20.43 mmol) of the title compound from example 4d), dissolved in 80 ml of water, add 3.81 g

(10.21 mmol) of dysprosium oxide, and the mixture is heated for 3 hours at 90 oC. The mixture is evaporated to dryness (vacuum), and the residue is recrystallized from 90% aqueous ethanol. The crystals are suctioned off, washed once with ethanol, then with acetone and finally with diethyl ether and dried in a vacuum oven at 130 oC (24 hours).

Yield: 12.40 g (91% of the theoretical value) of a colorless crystalline powder.

Water content: 2.7%.

Elemental analysis (calculated on anhydrous material):

Example 6

a) N-[2-bromo-2-phenylacetyl] glycine tert-butyl ester To 50 g (296.5 mmol) glycine tert-butyl ester hydrochloride salt and 90 g (889.5 mmol) triethylamine in 500 ml methylene chloride 72.69 g (311.3 mmol) of α-bromophenylacetic acid chloride are added dropwise at 0 °C. The temperature is kept between 0 and 5 °C. 1000 ml of 5% aqueous hydrochloric acid is added to the mixture, and the -organic phase is separated. The organic phase is extracted again with 500 ml of 5% aqueous hydrochloric acid, dried over magnesium sulfate and evaporated in vacuo to dryness. The residue is recrystallized from diisopropyl ether/n-hexane.

Yield: 78.8 g (81% of the theoretical value). Elemental analysis:

b) 1-[4-(tert.-butoxycarbonyl)-oxo-1-phenyl-3-azabutyl]-4,7,10-tris(tert.-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane

To 50 g (159.14 mmol) of the title compound from Example 6a), 53.12 g (114.3 mmol) of 1,4,7-tris(tert.-butoxycarboxymethyl)-1,4,7,10-tetraazadodecane ( = D03A-tri-tert-butyl ester), 63.16 g (457.0 mmol) of potassium carbonate and 1 g (6 mmol) of potassium iodide are added to 500 ml of acetonitrile, and the mixture is refluxed for 12 hours. The salts are filtered off, and the filtrate is evaporated in vacuo to dryness. The residue is dissolved in 1000 ml of dichloromethane and extracted twice with 400 ml of 5% aqueous sodium carbonate solution. The combined organic phases are dried over magnesium sulfate and evaporated. After chromatography on silica gel (eluent: dichloromethane/methanol = 20:1) 27 g of the title compound (31% of the theoretical value) are obtained as a colorless foam.

Elemental analysis:

c) 1-(4-carboxy-2-oxo-1-phenyl-3-azabutyl)-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

26 g (34.12 mmol) of the title compound from example 6b) are dissolved in 300 ml of trifluoroacetic acid and stirred for 3 hours

at room temperature. The mixture is evaporated to dryness, the precipitate is dissolved in 80 ml of water, and the solution is applied to a column filled with • "Reillex" 425 PVP. The elution is carried out with water. The product-containing fractions are combined and evaporated to dryness, and the residue is recrystallized from methanol/acetone.

Yield: 16.22 g (81% of theory) of a colorless, hygroscopic solid.

Water content: 8.4%.

Elemental analysis (calculated on anhydrous material):

d) Gadolinium complex of 1-(4-carboxy-2-oxo-1-phenyl-3-azabutyl)-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

To 15 g (27.90 mmol) of the title compound from example 6c), dissolved in 200 ml of water, 5.06 g (13.95 mmol) of gadolinium oxide is added, and the mixture is heated for 3 hours at 90 °C. The mixture is evaporated to dryness (vacuum), and the residue is recrystallized from 90% aqueous ethanol. The crystals are suctioned off, washed once with ethanol, then with acetone and finally with diethyl ether and dried in a vacuum oven at 130 °C (24 hours).

Yield: 18.27 g (92% of the theoretical value

di) of a colorless, crystalline powder.

Water content: 2.8%.

Elemental analysis (calculated on anhydrous material):

Example 7

a) N-(2-bromopropionyl)-ft-alanine

To 40 g (448.98 mmol) β-alanine and 90 g (889.5 mmol)

triethylamine in 500 ml methylene chloride is added dropwise at 0 °C 72.69 g (311.3 mmol) α-bromopropionic acid chloride. The temperature is kept between 0 and 5 °C. 1000 ml of 5% aqueous hydrochloric acid is added to the mixture, and the organic phase is separated. The organic phase is extracted once more with 500 ml of 5% aqueous hydrochloric acid, dried over magnesium sulphate and evaporated in vacuo to dryness. The residue is recrystallized from acetone/diisopropyl ether.

Yield: 62.37 g (62% of the theoretical value). Elemental analysis:

b) 10-(5-carboxy-1-methyl-2-oxo-3-azapentyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

To 60 g (267.80 mmol) of the title compound from example 7a), dissolved in 300 ml acetonitrile/200 ml water, is added 46.38 g (133.9 mmol) 1,4,7-tris(carboxymethyl)-1, 4,7,10-tetraazacyclododecane (= D03A), 129.54 g (937.3 mmol) potassium carbonate and 1 g (6 mmol) potassium iodide. The mixture is refluxed for 12 hours. The mixture is evaporated in vacuo to dryness, the residue is dissolved in 500 ml of methanol, and the salts are filtered off. The filtrate is evaporated to dryness, the residue is dissolved in 300 ml of water and adjusted with 5 N hydrochloric acid to pH 1. The product is purified through a column filled with "Reillex" 425 PVP. The elution is carried out with water. The product-containing fractions are evaporated to dryness, and the residue is recrystallized from methanol/acetone.

Yield: 19.19 g (27% of the theoretical value) of a colorless solid.

Water content: 7.8%.

Elemental analysis (calculated on anhydrous material):

c) Gadolinium complex of 10-(5-carboxy-1-methyl-2-oxo-3-azapentyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

To 18 g (36.77 mmol) of the title compound from example 7b) dissolved in 300 ml of water, 6.66 g (18.38 mmol) of gadolinium oxide is added, and the mixture is heated for 3 hours at 90 °C. The mixture is evaporated to dryness (vacuum), and the residue is recrystallized from 90% aqueous ethanol. The crystals are suctioned off, washed once with ethanol, then with acetone and finally with diethyl ether and dried in a vacuum oven at 130 oC (24 hours).

Yield: 21.6 g (89% of the theoretical value) of a colorless crystalline powder.

Water content: 2.5%.

Elemental analysis (calculated on anhydrous material):

Example 8

a) N-(2-bromopropionyl)-11-aminoundecanoic acid

To 30 g (149 mmol) of 11-aminoundecanoic acid and 45.24 g

(447.1 mmol) of triethylamine in 600 ml of methylene chloride are added dropwise at 0 °C to 30.65 g (178.8 mmol) of α-bromopropionic acid chloride. The temperature is kept between 0 and 5 °C. 800 ml of 5% aqueous hydrochloric acid is added to the mixture, and the organic phase is separated. The organic phase is extracted once more with 300 ml of 5% aqueous hydrochloric acid, dried over magnesium sulfate and evaporated in vacuo to dryness. The residue is recrystallized from acetone/dipropyl ether.

Yield: 25.55 g (51% of the theoretical value). Elemental analysis:

b) 10-(13-carboxy-1-methyl-2-oxo-3-azatridecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tritriacetic acid

To 25 g (74.35 mmol) of the title compound from example 8a), dissolved in 250 ml acetonitrile/150 ml water, is added 12.88 g (37.18 mmol) 1,4,7-tris(carboxymethyl)-1, 4,7,10-tetraazacyclododecane (= D03A), 35.97 g (260.3 mmol) potassium carbonate and 1 g (6 mmol) potassium iodide. The mixture is refluxed for 12 hours. The mixture is evaporated in vacuo to dryness, the residue is dissolved in 300 ml of methanol, and the salts are filtered off. The filtrate is evaporated to dryness, the residue is dissolved in 300 ml of water and adjusted with 5 N hydrochloric acid to pH 1. The product is then purified through a column filled with "Reillex" 425 PVP. The elution is carried out with water. The product-containing fractions are evaporated in vacuo to dryness, and the residue is recrystallized from methanol/acetone.

Yield: 6.63 g (27% of the theoretical value) of a colorless solid.

Water content: 8.9%.

Elemental analysis (calculated on anhydrous material):

c) Gadolinium complex of 10-(13-carboxy-1-methyl-2-oxo-3-azatridecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tritriacetic acid

To 6 g (9.97 mmol) of the title compound from example 8b) dissolved in 80 ml of water, 1.81 g (4.98 mmol) of gadolinium oxide is added, and the mixture is heated for 3 hours at 90 °C. The mixture is evaporated to dryness (vacuum), and the precipitate is recrystallized from 90% aqueous 2-propanol. The crystals are suctioned off, washed once with ethanol, then with acetone and finally with diethyl ether and dried in a vacuum oven at 130 °C (24 hours).

Yield: 6.75 g (87% of the theoretical value) of a colorless crystalline powder.

Water content: 2.9%.

Elemental analysis (calculated on anhydrous material):

Example 9

a) N-(2-bromopropionyl)alanine

To 30 g (336.7 mmol) alanine and 102.2 g (1010.2 mmol)

triethylamine in 600 ml methylene chloride is added dropwise at 0 °C 69.26 g

(404 mmol) α-bromopropionic acid chloride. The temperature is kept between 0 and 5 °C. 1000 ml of 5% aqueous hydrochloric acid is added to the mixture, and the organic phase is separated. The organic phase is extracted again with 400 ml of 5% aqueous hydrochloric acid, dried over magnesium sulfate and evaporated in vacuo to dryness. The residue is recrystallized from acetone/diisopropyl ether.

Yield: 52.05 g (69% of the theoretical value). Elemental analysis (calculated on anhydrous material):

b) 10-(4-carboxy-1-methyl-2-oxo-3-azapentyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

To 50 g (223.2 mmol) of the title compound from example 9a), dissolved in 300 ml acetonitrile/200 ml water, add 38.65 g (111.6 mmol) 1,4,7-tris(carboxymethyl)- 1,4,7,10-tetraazacyclododecane (= D03A), 108 g (781.2 mmol) potassium carbonate and 1 g (6 mmol) potassium iodide. The mixture is refluxed for 12 hours. The mixture is evaporated in vacuo to dryness, the residue is dissolved in 500 ml of methanol, and the salts are filtered off. The filtrate is evaporated to dryness, the residue is dissolved in 300 ml of water and adjusted with 5 N hydrochloric acid to pH 1. The product is purified through a column filled with "Reillex" 425 PVP. The elution is carried out with water. The product-containing fractions are evaporated in vacuo to dryness, and the residue is recrystallized from methanol/acetone.

Yield: 17.72 g (30% of the theoretical value) of a colorless solid.

Water content: 7.5%.

Elemental analysis (calculated on anhydrous material):

c) Gadolinium complex of 10-(4-carboxy-1-methyl-2-oxo-3-azapentyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

To 15 g (30.64 mmol) of the title compound from example 9b) dissolved in 150 ml of water, 5.55 g (15.32 mmol) of gadolinium oxide is added, and the mixture is heated for 3 hours at 90 °C. The mixture is evaporated to dryness (vacuum), and the residue is recrystallized from 90% aqueous ethanol. The crystals are suctioned off, washed once with ethanol, then with acetone and finally with diethyl ether and dried in a vacuum oven at 130 oC (24 hours).

Yield: 18.22 g (90% of the theoretical value) of a colorless crystalline powder.

Water content: 2.6%.

Elemental analysis (calculated on anhydrous material):

Example 10

a) N-(2-bromopropionyl)valine

To 40 g (341.4 mmol) valine and 103.7 g (1024 mmol)

triethylamine in 600 ml methylene chloride is added dropwise at 0 °C 70.2 g -(409.7 mmol) α-bromopropionic acid chloride. The temperature is kept between 0 and 5 °C. 1000 ml of 5% aqueous hydrochloric acid is added to the mixture, and the organic phase is separated. The organic phase is extracted again with 500 ml of 5% aqueous hydrochloric acid, dried over magnesium sulfate and evaporated in vacuo to dryness. The residue is recrystallized from acetone/diisopropyl ether.

Yield: 59.39 g (69% of the theoretical value). Elemental analysis (calculated on anhydrous material):

b) 10-(4-carboxy-1,5-dimethyl-2-oxo-3-azahexyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

To 55 g (218.2 mmol) of the title compound from example 10a), dissolved in 200 ml acetonitrile/200 ml water, is added 37.8 g (109.7 mmol) 1,4,7-triscarboxymethyl-1,4,7 ,10-tetraazacyclododecane (= D03A), 106.13 g (767.9 mmol) potassium carbonate and 1 g (6 mmol) potassium iodide. The mixture is refluxed for 12 hours. The mixture is evaporated in vacuo to dryness, the residue is dissolved in 500 ml of methanol, and the salts are filtered off. The filtrate is evaporated to dryness, the residue is dissolved in 300 ml of water and adjusted with 5 N hydrochloric acid to pH 1. The product is purified through a column filled with "Reillex" 425 PVP. The elution is carried out with water. The product-containing fractions are evaporated in vacuo to dryness, and the residue is recrystallized from methanol/acetone.

Yield: 17.57 g (29% of the theoretical value) of a colorless solid.

Water content: 6.3

Elemental analysis (calculated on anhydrous material):

c) Gadolinium complex of 10-(4-carboxy-1,5-dimethyl-2-oxo-3-azahexyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

To 15 g (28.98 mmol) of the title compound from example 10b) dissolved in 150 ml of water, 5.25 g (14.49 mmol) of gadolinium oxide is added, and the mixture is heated for 3 hours at 90 °C. The mixture is evaporated to dryness (vacuum), and the residue is recrystallized from 90% aqueous ethanol. The crystals are suctioned off, washed once with ethanol, then with acetone and finally with diethyl ether and dried in a vacuum oven at 130 °C (24 hours).

Yield: 18.57 g (93% of the theoretical value) of a colorless crystalline powder.

Water content: 2.5%.

Elemental analysis (calculated on anhydrous material):

Example 11

a) N-(2-bromoacetyl) glycine tert.-butyl ester

To 50 g (296.5 mmol) glycine tert-butyl ester hydrochloride salt and 90 g (889.5 mmol) triethylamine in 500 ml methylene chloride, 77.8 g (385.5 mmol) bromoacetic acid bromide is added dropwise at 0 °C. The temperature is kept between 0 and 5 °C. 1000 ml of 5% aqueous hydrochloric acid is added to the mixture, and the organic phase is separated. The organic phase is extracted again with 500 ml of 5% aqueous hydrochloric acid, dried over magnesium sulfate and evaporated in vacuo to dryness. The residue is recrystallized from diisopropyl ether/n-hexane.

Yield: 30.5 g (61% of the theoretical value). Elemental analysis:

b) 10-[4-(tert-butoxycarbonyl)-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tri-tert-butyl ester

To 20.35 g (80.70 mmol) of the title compound from Example 11a), 25 g (53.8 mmol) of 1,4,7-tris(tert.-butoxycarboxymethyl)-1,4,7,10- tetraazadodecane (= D03A-tri-tert.-butyl ester), 29.74 g (215.8 mmol) of potassium carbonate and 1 g (6 mmol) of potassium iodide are added to 200 ml of acetonitrile, and the mixture is refluxed for 12 hours. The salts are filtered off, and the filtrate is evaporated in vacuo to dryness. The residue is dissolved in 800 ml of dichloromethane and extracted twice with 200 ml of 5% aqueous sodium carbonate solution. The organic phase is dried over magnesium sulfate and evaporated. After chromatography on silica gel

(eluent: dichloromethane/methanol = 20:1) 25.09 g of the title compound (68% of the theoretical value) are obtained as a colorless foam.

Elemental analysis:

c) 10-[4-carboxy-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

25 g (36.45 mmol) of the title compound from example 11b) are dissolved in 300 ml of trifluoroacetic acid and stirred for 3 hours at room temperature. The mixture is evaporated to dryness, the residue

is dissolved in 80 ml of water, and the solution is applied to a column filled with "Reillex" 425 PVP. The elution is carried out with water. The product-containing fractions are combined and evaporated to dryness, and the residue is recrystallized from methanol/acetone.

Yield: 15.24 g (84% of theory) of a colorless, hygroscopic solid.

Water content: 7.3%.

Elemental analysis (calculated on anhydrous material):

d) Gadolinium complex of 10-[4-carboxy-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid To 15 g (32.50 mmol) of the title compound from Example lic), dissolved in 200 ml of water, 5.86 g (16.25 mmol) of gadolinium oxide are added, and the mixture is heated for 3 hours at 90 °C. The mixture is evaporated to dryness (vacuum), and the residue is recrystallized from 90% aqueous ethanol The crystals are suctioned off, washed once with ethanol, then with acetone and finally with diethyl ether and dried in a vacuum oven at 130 °C (24 hours).

Yield: 18.92 g (92% of the theoretical value) of a colorless crystalline powder.

Water content: 2.7%.

Elemental analysis (calculated on anhydrous material):

The following examples 12-37 serve to illustrate the method according to the present invention.

Examples 12-24: Formation in situ of the metal complex carboxylic acid mixture consisting of metal complex carboxylic acid and dissolution mediating compound:

Example 12

a) Bis [2-(benzyloxycarbonylamino)ethyl]amine

51.5 g (500 mmol) diethylenetriamine and 139 ml (1 mol)

triethylamine is dissolved in dichloromethane, 161 g of benzyl formate (Fluka) are added in dichloromethane at -20 °C and then stirred overnight at room temperature. After the reaction is complete, the mixture is evaporated under suction, the residue is dissolved in diethyl ether, the organic phase is washed with sodium carbonate solution and dried with sodium sulfate. Hexane is added to the filtrate, the precipitate is filtered off and dried.

Yield: 163.4 g (88% of the theoretical value). Elemental analysis:

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

13.27 g (50 mmol) trimesic acid trichloride (Aldrich) and 34.7 ml (250 mmol) triethylamine are dissolved in dimethylformamide (DMF) and added at 0 °C 65.0 g (175 mmol) of the amine described in example 12a) and then stirred overnight at room temperature. The solution is evaporated in vacuo, and the residue is chromatographed on silica gel

with ethyl acetate.

Yield: 39.4 g (62% of the theoretical value).

Elemental analysis:

c) Naa,NE-bis (N,N'-dibenzyloxycarbonyllysyl) lysine, protected "trilysine"

Dissolve 3.6 g (20 mmol) lysine hydrochloride and 6.95 ml (50 mmol) triethylamine in DMF, add 26.8 g (50 mmol) Na<a>,N<E->dibenzyloxycarbonyllysine p-nitrophenyl ester (Bachem) and stirred for 2 days at room temperature. After the reaction is complete, the mixture is evaporated in vacuo, the residue is dissolved in ethyl acetate and shaken with dilute hydrochloric acid. The organic phase is dried with sodium

sulfate, the solvent is evaporated, and the residue is chromatographed with stepwise gradients of ethyl acetate/ethanol.

Yield: 10.7 g (57% of the theoretical value). Elemental analysis:

d) Fully protected benzyloxycarbonyl-24-mer polyamine based on N,N,N',N',N' 1,N' '-hexakis [2-(trilysylamino)-ethyl] trimesic acid triamide

1.27 g (1 mmol) of the hexabenzyloxycarbonylamine described in example 12b) is dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid is added while stirring. After 60 minutes, the initial precipitation with diethyl ether is completed, the hexaamine hydrobromide formed is washed with 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 "trilysine" described in Example 12c), 1.2 g (7.5 mmol) of 1-hydroxytriazole and 2.4 g (7.5 mmol) of 2-(lH -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU; Peboc Limited, UK) is dissolved in DMF and stirred for 15 minutes. 5.16 ml (30 mmol) of N-ethyldiisopropylamine and 0.95 g (1

■mmol) of the hexaamine hydrobromide described above and stirred overnight at room temperature. After the reaction is complete, the mixture is evaporated in vacuo, and the residue is chromatographed with ethyl acetate/ethanol (2:1) on silica gel.

Yield: 4.55 g (76% of the theoretical value). Elemental analysis: e) 24-mer polyamine based on N,N,N',N',N' ',N' 1 - hexakis[2-(trilysylamino)ethyl]trimesic acid triamide,

tetracosa hydrochloride

5.99 g (1 mmol) of the 24-mer-benzyloxycarbonylamine described in the previous example 12d) are dissolved in 500 ml

methanol, add under nitrogen 1 g of palladium on active carbon (10%) and 24 ml (24 mmol) of 1 N HCl and hydrate with hydrogen. After the reaction has finished, the catalyst is filtered off, and the filtrate is evaporated to dryness.

Yield: 3.65 g (quantitative). The tetracosa hydrochloride was readily soluble in water.

Elemental analysis:

f) Tetracosamide conjugate of the 24-mer polyamine based on N,N,N',N',N' 1,N' 1-hexakis[2- (trilysylamino)ethyl]trimesic acid triamide with the gadolinium complex of 10-(4- carboxyl-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid 31.74 g (50.4 mmol, 3-fold excess) of the Gd complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, described in example 1f), 5.19 g of sodium bromide (50.4 mmol) and 8.7 g (75.6 mmol) of N-hydroxysuccinimide are dissolved in 250 ml of dimethyl sulfoxide at 50 oC. After cooling to room temperature, 15.6 g (75.6 mmol) of N,N<1->dicyclohexylcarbodiimide are added, and the mixture is preactivated for 60 minutes. A solution of 2.55 g (0.7 mmol) of the tetracosa hydrochloride described in example 12e) and 8.5 g of triethylamine in 25 ml of water is added to the N-hydroxysuccinimide ester solution thus prepared, and the mixture is stirred overnight at room temperature. Sufficient acetone is then added to the resulting suspension for complete precipitation, the precipitate is filtered off with suction, dried, dissolved in water, insoluble dicyclohexylurea is filtered off, and the filtrate is desalted and purified from low molecular weight components through an "AMICON" YM-3 ultrafiltration membrane (molecular weight cut-off 3000 Da ). The retentate is then freeze-dried.

Yield: 11.8 g (88% of the theoretical value). H20 content (Karl-Fischer): 9.0%.

Gd determination (AAS): 19.6%.

MALDI-TOF mass spectrum: 17.476 (M + Na + ). Elemental analysis (calculated on anhydrous material):

Example 13

a) 1,4,7-tris[N2,N6-bis (benzyloxycarbonyl)lysyl] - 1, 4, 7, 10- tetraazacyclododecane

49.07 g (95.9 mmol) di-Z-lysine-N-hydroxysuccinimide ester and 5 g (29 mmol) cyclene (= 1,4,7,10-tetraazadodecane) are dissolved in a mixture of 200 ml toluene/100 ml dioxane. 9.7 g (95.9 mmol) of triethylamine is added to the mixture and heated for 12 hours at 70 °C. The mixture is evaporated to dryness, the residue is dissolved in 600 ml of dichloromethane and extracted three times with 200 ml of 5% aqueous potassium carbonate solution. The organic phase is dried over magnesium sulfate and evaporated in vacuo to dryness. The residue is chromatographed on silica gel (eluent: ethyl acetate/ethanol = 15:1).

Yield: 29.61 g (75% of the theoretical value) of a colorless solid.

Elemental analysis:

b) 1-(4-carboxybutyryl)-4,7,10-tris[N2,N6-bis(benzyl-oxycarbonyl)lysyl]-1,4,7,10-1tetraazacyclododecane

To 28 g (20.56 mmol) of the title compound from example 13a) (dissolved in 200 ml tetrahydrofuran) are added 3.5 g (30.8 mmol) glutaric anhydride (Fluka) and 6.24 g (61.72 mmol) triethylamine. The mixture is heated for 6 hours at 50 °C. The solution is evaporated in vacuo to dryness, dissolved in 300 ml of dichloromethane and extracted twice with 150 ml of 5% aqueous hydrochloric acid. The organic is dried over magnesium sulfate, evaporated in vacuo to dryness, and the residue is chromatographed on silica gel (eluent: dichloromethane/methanol = 20:1).

Yield: 27.65 g (91% of the theoretical value) of a colorless solid.

Elemental analysis:

c) 1-(4-nitrophenoxy)glutaryl)-4,7,10-tris[N2,N6-bis-(benzyloxycarbonyl)lysyl]-1,4,7,10-tetraazadodecane

14.76 g (10 mmol) of the carboxylic acid described in example 13b), dissolved in 150 ml of dichloromethane, is first added 1.53 g (11 mmol) of 4-nitrophenol and then 2.27 g (11 mmol) of dicyclohexylcarbodiimide at 0° C. After stirring overnight at room temperature, dicyclohexylurea is filtered off with suction, the filtrate is evaporated and reprecipitated from isopropanol. The mother liquor is decanted from the oily product, the oil is dissolved in dichloromethane and evaporated in a vacuum. 15.4 g (96.3%) of a foamy solidified solid is obtained.

Elemental analysis:

d) Fully protected benzyloxycarbonyl-36-mer polyamine, built up from a N,N,N' ,N' ,N' 1 ,N' ' -hexakis (2-aminoethyl)trimesic acid triamide core and six amine-protected hexaamine monocarboxylic acids described in example 13b) 1.27 g (1 mmol) of the hexakisbenzyloxycarbonylamine described in example 12b) is dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid is added while stirring. After 60 minutes, the initial precipitation is completed with diethyl ether, the hexaamine hexahydrobromide formed is washed with ether, dried in vacuo and reacted further without further purification.

Yield: 0.95 g (quantitative).

The hexaamine hexahydrobromide is dissolved in 150 ml DMF, 15.99 g (10 mmol) of the 4-nitrophenyl active ester described in example 13c) and 4.05 g (40 mmol) triethylamine are added, stirred overnight at room temperature and then evaporated in vacuo to dryness . The residue is dissolved in ethyl acetate and washed successively with water, diluted caustic soda and saturated NaCl solution. The organic phase is dried over sodium sulphate, the filtrate is evaporated to dryness, and the residue is chromatographed on silica gel (eluent: dichloromethane/methanol 18:2).

Yield: 6.55 g (71% of the theoretical value) of a colorless solid.

Elemental analysis:

MALDI-TOF mass spectrum: molecular peak at 9235 (M + Na + ).

e) Hexatriacontoquisamide conjugate of the 36-mer polyamine from example 13d) with the dysprosium complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4, 7- triacetic acid

1.84 g (0.2 mmol) of the 3 6-mer-benzyloxycarbonylamine described in example 13d) is dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid is added while stirring. After 5 hours, the initial precipitation is completed with diethyl ether, the 36-meramine hydrobromide formed is washed with ether, dried in vacuo and used without further purification in the reaction described below.

Yield: 1.5 g (quantitative).

13.6 g (21.6 mmol, 3-fold excess) of the dysprosium complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4 ,7-triacetic acid, described in example 2), and 3.73 g (32.4 mmol) of N-hydroxysuccinimide are dissolved in 100 ml of dimethyl sulfoxide at 90 °C. After cooling to room temperature, 6.7 g (32.4 mmol) of N,N'-dicyclohexylcarbodiimide are added, and the mixture is preheated for 60 minutes. A solution of 1.5 g (0.2 mmol) of the above-described hexatriacontahydrobromide and 3.5 g of triethylamine in 10 ml of water is added to the N-hydroxysuccinimide ester solution thus prepared, and the mixture is stirred overnight at room temperature. Sufficient acetone is added to the resulting suspension for complete precipitation, the precipitate is filtered off with suction, dried, dissolved in water, insoluble dicyclohexylurea is filtered off, and the filtrate is desalted and purified from low molecular weight components through an "AMICON" YM-3 ultrafiltration membrane (molecular weight cut-off 3000 Da). The retentate is then freeze-dried.

Yield: 4.7 g (79% of the theoretical value). H20 content (Karl-Fischer): 10.5%.

Dy determination (AAS): 19.7%.

MALDI-TOF mass spectrum: 26.616 (M + Na + ). Elemental analysis (calculated on anhydrous material):

Example 14

Polyamide conjugate of polylysine with the gadolinium complex of 10-(4-carboxyl-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetradodecane-1,4,7-triacetic acid

3.15 g (5 mmol) of the Gd complex described in example 1f) and 0.58 g (5 mmol) of N-hydroxysuccinimide are dissolved in 25 ml of dimethyl sulfoxide while heating. After cooling to room temperature, 1.03 g (5 mmol) of N,N'-dicyclohexylcarbodiimide is added, and the mixture is stirred for 60 minutes. A solution of 523 mg (2.5 mmol) polylysine hydrobromide (Sigma) and 506 mg (5 mmol) triethylamine in 5 ml of water is added to the N-hydroxysuccinimide ester solution thus prepared, and the mixture is stirred overnight at room temperature. Sufficient acetone is added to the resulting suspension for complete precipitation, the precipitate is filtered off with suction, dried, dissolved in water, insoluble dicyclohexylurea is filtered off, and the filtrate is desalted and purified from low molecular weight components through an "AMICON" YM-3 ultrafiltration membrane (molecular weight cut-off 3000 Da). The retentate is then freeze-dried.

Yield: 1.8 g (82% of the theoretical value).

H20 content (Karl-Fischer): 10.2%.

Gd determination (AAS): 19.0%.

Elemental analysis (calculated on anhydrous material):

Example 15

Dotriacontakisamide conjugate of the 32-mer dendrimeramine "DAB( PA) 4( PA) 8( PA) 16( PA) 32" and the dysprosium complex of 10-( 4-carboxyl- l- ethyl- 2- oxo- 3- azabutyl)- 1 , 4, 7, 10 - tetracyclododecane-1, 4, 7- triacetic acid

3.25 g (5 mmol) of the Dy complex of 10-(4-carboxy-1-ethyl-2-oxo-3-azabutyl)-1,4,7,10-tetracyclododecane-1,4,7-tri -

Acetic acid, described in example 5, and 0.58 g (5 mmol) of N-hydroxysuccinimide are dissolved in 25 ml of dimethyl sulfoxide while heating. After cooling to room temperature, 1.03 g (5 mmol) of N,N'-dicyclohexylcarbodiimide are added, and the mixture is stirred for 1 hour. To the N-hydroxysuccinimide ester solution thus prepared, 275 mg (0.078 mmol) of the 32-mer dendrimeramine described in Example VIII in WO 93/14147 and 506 mg (5 mmol) of triethylamine in 5 ml of water are added, and the mixture is stirred overnight at room temperature. Sufficient acetone is added to the resulting suspension for complete precipitation, the precipitate is filtered off with suction, dried, dissolved in water, insoluble dicyclohexylurea is filtered off, and the filtrate is desalted and purified from low molecular weight components through an "AMICON" YM-3 ultrafiltration membrane (molecular weight cut-off 3000 Da). The retentate is then freeze-dried.

Yield: 1.62 g (82.7% of the theoretical value). H20 content (Karl-Fischer): 7.3%.

Dy determination (AAS): 20.5%.

Elemental analysis (calculated on anhydrous material):

Example 16

Amide conjugate of daunomycin with the gadolinium complex of 1- ti-methyl- 2- oxo- 3- aza- 4- carboxybutyl]- 4, 7, 10- tris(carboxymethyl)-- 1, 4, 7, 10- tetraazacyclododecane

1 g (1.588 mmol) of the gadolinium complex of 1-[1-methyl-2-oxo-3-aza-4-carboxybutyl]-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, 134.6 mg (3.176 mmol) of lithium chloride and 365.8 mg (3.176 mmol) of N-hydroxysuccinimide are dissolved in 10 ml of dimethylsulfoxide under gentle heating and then cooled to 10 °C. The mixture is added at 10°C with 393 mg (1.906 mmol) of dicyclohexylcarbodiimide and stirred for 45 minutes at room temperature. 812.3 mg (1.588 mmol) of daunomycin dissolved in 5 ml of dimethylsulfoxide and then 321.4 mg (3.176 mmol) of triethylamine are added to the N-hydroxysuccini midester solution thus prepared. The mixture is stirred overnight at room temperature. 200 ml of acetone are added dropwise to the resulting suspension, the precipitate is filtered off and washed twice with a little acetone. The precipitate is purified by column chromatography (RP18/eluent: gradient of water/acetonitrile/tetrahydrofuran).

Yield: 1.76 g (85% of the theoretical value) of a colorless, fluffy powder after freeze-drying.

Water content: 6.3%.

Elemental analysis (calculated on anhydrous material):

Example 17

Amide conjugate of adriamycin with the gadolinium complex of 1-[ 1-methyl- 2- oxo- 3- aza- 4- carboxybutyl]- 4, 7, 10- tris(carboxymethyl)-1, 4, 7, 10- tetraazacyclododecane 1 g (1.588 mmol) of the gadolinium complex of 1-[1-methyl-2-oxo-3-aza-4-carboxybutyl]-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, 134.6 mg (3.176 mmol) of lithium chloride and 365.8 mg (3.176 mmol) of N-hydroxysuccinimide are dissolved in 10 ml of dimethylsulfoxide under gentle heating and then cooled to 10 oC. The mixture is added at 10°C with 393 mg (1.906 mmol) of dicyclohexylcarbodiimide and stirred for 45 minutes at room temperature. 812.3 mg (1.588 mmol) of adriamycin dissolved in 5 ml of dimethylsulfoxide and then 321.4 mg (3.176 mmol) of triethylamine are added to the N-hydroxysuccini midester solution thus prepared. The mixture is stirred overnight at room temperature. 200 ml of acetone are added dropwise to the resulting suspension, the precipitate is filtered off and washed twice with a little acetone. The precipitate is purified by column chromatography (RP18/eluent: gradient of water/acetonitrile/tetrahydrofuran).

Yield: 1.84 g (87% of theory) of a colorless, fluffy powder after freeze-drying.

Water content: 7.2%.

Elemental analysis (calculated on anhydrous material):

Example 18

Polyamide conjugate of human albumin with the gadolinium complex of 10- ( 5- carboxyl- l- methyl- 2- oxo- 3- azapentyl)- 1, 4, 7, 10- tetraazacyclododecane- 1, 4, 7- 1-diacetic acid

3.22 g (5 mmol) of the gadolinium complex of 10-(5-carboxy-1-methyl-2-oxo-3-azapentyl)-1,4,7,10-tetraazadodecane-1,4,7-triacetic acid (example ' 7) , 868 mg (10 mmol) of lithium bromide and 1.15 g (10 mmol) of N-hydroxysuccinimide are dissolved in 30 ml of dimethylsulfoxide under gentle heating and then cooled to 10 °C. The mixture is added at 10 oC 1.24 g (6 mmol) dicyclohexylcarbodiimide and stirred for 8 hours at room temperature. The N-hydroxysuccinic ester solution thus prepared is cooled again to 10 °C and added to a suspension of 6.6 g of human

serum albumin (Sigma), which by adding 5 ml of 1 N caustic soda is adjusted to approx. pH 10, and stirred at this temperature overnight. Sufficient acetone is then added to the resulting suspension for complete precipitation, the precipitate is filtered off with suction, dried, dissolved in water, insoluble dicyclohexylurea is filtered off, and the filtrate is desalted and purified of low molecular weight constituents through an "AMICON" YM-10 ultrafiltration membrane (molecular weight cut-off 10,000 Da) . The retentate is then freeze-dried. A colorless powder is obtained.

Yield: 7.9 g (89% of the theoretical value) with respect to a conjugate of 21 Gd complexes.

H20 content (Karl-Fischer): 10.12%.

Gd determination (AAS): 3.77%.

Elemental analysis (calculated on anhydrous material of an HSA(Gd)21 conjugate):

calculated: Gd 4,15

found: Gd 4.09.

Example 19

Hexaamide conjugate of 6 , 6 ', 6 ' ' , 6 ' ' ', 6 ' ' ' ', 6 ' ' ' ' '- hexaamino-6, 6I, 6I,, 6II', 6,,',, 6'' 1' 1- hexadeoxy-α-cyclodextrin with the gadolinium complex of 10-(13-carboxyl-1-methyl-2-oxo-3-azatridecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tritriacetic acid

3.78 g (5 mmol) of the gadolinium complex of 10-(5-carboxy-1-methyl-2-oxo-3-azatridecyl)-1,4,7,10-

tetraazacyclododecane-1,4,7-triacetic acid (Example 8c)), 868 mg (10 mmol) of lithium bromide and 1.15 g (10 mmol) of N-hydroxysuccinimide are dissolved in 30 ml of dimethylsulfoxide under gentle heating and then cooled to 10 oC. The mixture is added at 10 °C with 1.24 g (6 mmol) of dicyclohexylcarbodiimide and stirred for 8 hours at room temperature. The N-hydroxysuccinimide ester solution thus prepared is added to a suspension of 315 mg (0.25 mmol) 6,6,,6,,,6,,,,6II,,,6,,',,-hexaamino-676,, 6<I>,,6,,,,6',,,,6<I>'<I>,,-hexadeoxy-α-cyclodextrin [J. Boger, R.J. Corcoran and J.-M. Lehn, Heiv. Chim. Acta, 61, 2190-2218 (1978)] in dimethyl sulfoxide and stirred overnight at room temperature. A sufficient amount of acetone is then added to the resulting suspension for complete precipitation, the precipitate is filtered off with suction, dried, dissolved in water, insoluble dicyclohexylurea is filtered off, and the filtrate is desalted and purified from low molecular weight components through an "AMICON" YM-3 ultra-filtration membrane ( molecular weight barrier 3000 Da) . The retentate is then freeze-dried. A colorless powder is obtained.

Yield: 1.34 g (89.9% of the theoretical value). H20 content (Karl-Fischer): 9.5%.

Gd determination (AAS): 16.4%.

Elemental analysis (calculated on anhydrous material):

Example 20

Amide conjugate of 3'-amino-3'-deoxyguanosine with the gadolinium complex of 1-[1-methyl-2-oxo-3-aza-4-carboxybutyl]-4,7,10-tris(carboxymethyl)-1,4,7 , 10- tetraazacyclododecane

1 g (1.588 mmol) of the gadolinium complex of 1-[1-methyl-2-oxo-3-aza-4-carboxybutyl]-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, 476 mg (3.176 mmol) of sodium iodide and 365.8 mg (3.176 mmol) of N-hydroxysuccinimide are dissolved in 10 ml of dimethylsulfoxide under gentle heating and then cooled to 10 °C. The mixture is added at 10°C with 393 mg (1.906 mmol) of dicyclohexylcarbodiimide and stirred for 45 minutes at room temperature. To the N-hydroxysuccinimide ester solution thus prepared, 422.8 mg (1.588 mmol) of 3'-amino-3'-deoxyguanosine dissolved in 5 ml of dimethylsulfoxide and then 321.4 mg (3.176 mmol) of triamine are added. The mixture is stirred overnight at room temperature. 200 ml of acetone are added dropwise to this solution, the precipitate is filtered off and washed twice with a little acetone. The precipitate is purified by column chromatography (RP18/eluent: gradient of water/acetonitrile/tetrahydrofuran).

Yield: 1.30 g (88% of the theoretical value) of a colorless, fluffy powder after freeze-drying.

Water content: 5.3%.

Elemental analysis (calculated on anhydrous material):

Example 21

Amide conjugate of dehydroabiethylamine with the gadolinium complex of 1-[l- methyl- 2- oxo- 3- aza- 4- carboxybutyl]- 4, 7, 10- tris( carboxymethyl)- 1, 4, 7, 10- tetraazacyclododecane 1 g (1.588 mmol) of the gadolinium complex of 1-[1-methyl-2-oxo-3-aza-4-carboxybutyl]-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, 134.6 mg (3.176 mmol) of lithium chloride and 442 mg (3.176 mmol) of 4-nitrophenol are dissolved in 10 ml of dimethyl sulphoxide under gentle heating and then cooled to 10 °C. The mixture is added at 10°C with 393 mg (1.906 mmol) of dicyclohexylcarbodiimide and stirred for 45 minutes at room temperature. To the solution prepared in this way, 422.8 mg (1.588 mmol) of dehydroabiethylamine dissolved in 5 ml of dimethylsulfoxide and then 321.4 mg (3.176 mmol) of triethylamine are added. The mixture is stirred overnight at room temperature. 100 ml of acetone is added dropwise to this solution, the precipitate is filtered off and washed twice with a little acetone. The precipitate is purified by column chromatography (RP18/eluent: gradient of water/acetonitrile/tetrahydrofuran).

Yield: 1.36 g (91% of theory) of a glassy solid after freeze-drying.

Water content: 4.5%.

Elemental analysis (calculated on anhydrous material):

Example 22

Amide conjugate of ampicillin with the gadolinium complex of 1-[ 1-methyl- 2- oxo- 3- aza- 4- carboxybutyl]- 4, 7, 10- tris( carboxymethyl)-1, 4, 7, 10- tetraazacyclododecane 1 g (1.588 mmol) of the gadolinium complex of 1-[1-methyl-2-oxo-3-aza-4-carboxybutyl]-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, 134.6 mg (3.176 mmol) of lithium chloride and 442 mg (3.176 mmol) of 4-nitrophenol are dissolved in 10 ml of dimethylsulfoxide under gentle heating and then cooled to 10 °C. The mixture is added at 10 °C with 393 mg (1.906 mmol) of dicyclohexylcarbodiimide and stirred for 45 minutes at room temperature. 554.9 mg (1.588 mmol) of ampicillin dissolved in 5 ml of dimethylsulfoxide and then 482 mg (4.764 mmol) of triethylamine are added to the thus prepared suspension. The mixture is stirred overnight at room temperature. 100 ml of acetone is added dropwise to this solution, the precipitate is filtered off and washed twice with a little acetone. The precipitate is purified by column chromatography (RP18/eluent: gradient of water/acetonitrile/tetrahydrofuran/0.5% trifluoroacetic acid).

Yield: 1.46 g (87% of theory) of a colorless, fluffy powder after freeze-drying.

Water content: 8.1%.

Elemental analysis (calculated on anhydrous material):

Example 23

Amide conjugate of the pentapeptide NH2- Val- Leu- Phe- Phe- Ala- OH with the gadolinium complex of 1-[ l- methyl- 2- oxo- 3- aza- 4- carboxybutyl]- 4, 7, 10- tris( carboxymethyl)- 1, 4, 7, 10- tetraazacyclododecane

1 g (1.588 mmol) of the gadolinium complex of 1-[1-methyl-2-oxo-3-aza-4-carboxybutyl]-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, 134.6 mg (3.176 mmol) of lithium chloride and 365.8 mg (3.176 mmol) of N-hydroxysuccinimide are dissolved in 10 ml of dimethylsulfoxide under gentle heating and then cooled to 10 °C. The mixture is added at 10 °C with 393 mg (1.906 mmol) of dicyclohexylcarbodiimide and stirred for 45 minutes at room temperature. To the N-hydroxysuccinimide ester solution thus prepared, 946 mg (1.588 mmol) of the pentapeptide NH2-Val-Leu-Phe-Phe-Ala-OH (prepared according to solid phase technology) dissolved in 5 ml of dimethylsulfoxide and then 321.4 mg (3.176 mmol ) triethylamine. The mixture is stirred overnight at room temperature. 200 ml of acetone are added dropwise to this solution, the precipitate is filtered off and washed twice with a little acetone. The precipitate is purified by column chromatography (RP18/eluent: gradient of water/acetonitrile/tetrahydrofuran).

Yield: 1.74 g (85% of the theoretical value) of a colorless, fluffy powder after freeze-drying.

Water content: 6.5%.

Elemental analysis (calculated on anhydrous material):

Example 24

Amide conjugate of N-methylglucosamine with the gadolinium complex of 1-[1-methyl-2-oxo-3-aza-4-carboxybutyl]-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane 1 g (1.588 mmol) of the gadolinium complex of 1-[1-methyl-2-oxo-3-aza-4-carboxybutyl]-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane and 134, Dissolve 6 mg (3.176 mmol) of lithium chloride in 10 ml of dimethyl sulphoxide under gentle heating and then cool to 10 °C. The mixture is added at 10 °C 310 mg (1.588 mmol) D(-)-N-methylglucosamine and 785.4 mg (3.176 mmol) 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ). The mixture is stirred overnight at room temperature. 200 ml of acetone are added dropwise to this solution, the precipitate is filtered off and washed twice with a little acetone. The precipitate is purified by column chromatography (RP18/eluent: gradient of water/acetonitrile/tetrahydrofuran).

Yield: 1.25 g (91% of the theoretical value) of a colorless, fluffy powder after freeze-drying.

Water content: 6.7%.

Elemental analysis (calculated on anhydrous material):

Examples 25-37: Isolation of metal complex carboxylic mixtures consisting of metal complex carboxylic acid and solvents:

Example 2 5

a) Mixture consisting of the gadolinium complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetra-azacyclo-dodecane-1,4,7-triacetic acid and 2 molar equivalents of lithium chloride

31.74 g (50.4 mmol) of the Gd complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetradodecane-1,4,7 -triacetic acid, described in example 1f), is dissolved in 200 ml of water and 4.27 g (100.8 mmol) of lithium chloride is added. The clear solution is then freeze-dried and finally dried overnight at 100 °C in a vacuum. A colorless powder is obtained.

Yield: 36.0 g (quantitative).

H20 content (Karl-Fischer): 3.5%.

Gd determination (AAS): 21.2%.

Elemental analysis (calculated on anhydrous material):

b) Tetracosakisamide conjugate of the 24-mer polyamine based on N,N,N',N',N' ',N' '-hexakis[2-(triamino)ethyl]tri-mesic acid tri-amide with the gadolinium complex of 10-( 4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid

36.0 g (50.4 mmol, 3-fold excess) of the lithium mixture salt with the Gd complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7 ,10-tetraazacyclododecane-1,4,7-triacetic acid and 8.7 g (75.6 mmol) of N-hydroxysuccinimide, described in the previous example 25a), are dissolved in 250 ml of dimethylsulfoxide at room temperature. 15.6 g (75.6 mmol) of N,N'-dicyclohexylcarbodiimide is then added and the mixture is preactivated

for 60 minutes. To the N-hydroxysuccinimide ester solution thus prepared, a solution of 2.55 g (0.7 mmol) of the tetracosa hydrochloride prepared in example 12e) and 8.5 g of triethylamine in 25 ml of water is added, and the mixture is stirred overnight at room temperature -temperature. Sufficient acetone is then added to the resulting suspension for complete precipitation, the precipitate is filtered off with suction, dried, dissolved in water, insoluble dicyclohexylurea is filtered off, and the filtrate is desalted and purified of low molecular weight components through an "AMICON" YM-3 ultrafiltration membrane (molecular weight cut-off 3000 Da ). The retentate is then freeze-dried.

Yield: 11.8 g (88% of the theoretical value). H20 content (Karl-Fischer): 9.1%.

Gd determination (AAS): 19.4%.

MALDI-TOF mass spectrum: 17.476 (M + Na + ). Elemental analysis (calculated on anhydrous material):

Example 26

a) Mixture consisting of the gadolinium complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and

1 molar equivalent of sodium bromide

31.74 g (50.4 mmol) of the Gd complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetradodecane-1,4,7 -triacetic acid, described in example 1f), is dissolved in 200 ml of water and 5.19 g (50.4 mmol) of sodium bromide is added. The clear solution is freeze-dried and then further dried overnight at 100 oC in a vacuum. A colorless powder is obtained.

Yield: 36.9 g (quantitative).

H20 content (Karl-Fischer): 3.7%.

Gd determination (AAS): 20.9%.

Elemental analysis (calculated on anhydrous material):

b) Hexatriacontoquisamide conjugate of the 36-mer polyamine from example 13d) with the gadolinium complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraaza_^cyclododecane-1, 4, 7-triacetic acid

1.84 g (0.2 mmol) of the 3 6-mer-benzyloxycarbonylamine described in example 13d) is dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid is added while stirring. After 5 hours, the initial precipitation is completed with diethyl ether, the 36-mer-amine hydrobromide formed is washed with ether, dried in vacuo and used without further purification in the reaction described below.

Yield: 1.5 g (quantitative).

15.8 g (21.6 mmol, 3-fold excess) of the sodium bromide mixture salt with the Gd complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane - 1,4,7-triacetic acid and 3.73 g (32.4 mmol) of N-hydroxysuccinimide, described in the previous example 26a), are dissolved in 100 ml of dimethyl sulfoxide. 6.7 g (32.4 mmol) of N,N'-dicyclohexyldiimide are added thereto, and the mixture is pre-activated for 60 minutes. A solution of 1.5 g (0.2 mmol) of the above-described hexatriacontahydrobromide and 3.5 g of triethylamine in 10 ml of water is added to the N-hydroxysuccinimide solution thus prepared, and the mixture is stirred overnight at room temperature. Sufficient acetone is added to the resulting suspension for complete precipitation, the precipitate is filtered off with suction, dried, dissolved in water, insoluble dicyclohexylurea is filtered off, and the filtrate is desalted and purified from low molecular weight components through an "AMICON" YM-3 ultrafiltration membrane (molecular weight cut-off 3000 Da). The retentate is then freeze-dried.

Yield: 4.8 g (82% of the theoretical value). H20 content (Karl-Fischer): 9.9%.

Gd determination (AAS): 18.6%.

MALDI-TOF mass spectrum: 26.428 (M + Na + ). Elemental analysis (calculated on anhydrous material):

Example 27

Polyamide conjugate of polylysine with the gadolinium complex of 10-(4-carboxyl-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetradodecane-1,4,7-triacetic acid

3.57 g (5 mmol) of the lithium mixture salt with the Gd complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7 -triacetic acid and 0.58 g (5 mmol) of N-hydroxysuccinimide, described in example 25a), are dissolved in 25 ml of dimethylsulfoxide. 1.03 g (5 mmol) of N,N'-dicyclohexylcarbodiimide is added, and the mixture is stirred for 60 minutes. A solution of 523 mg (2.5 mmol) polylysine hydrobromide (Sigma) and 506 mg (5 mmol) triethylamine in 5 ml of water is added to the N-hydroxysuccinic ester solution thus prepared, and the mixture is stirred overnight at room temperature. Sufficient acetone is then added to the resulting suspension for complete precipitation, the precipitate is filtered off with suction, dried, dissolved in water, insoluble dicyclohexylurea is filtered off, and the filtrate is desalted and purified of low molecular weight constituents through an "AMICON" YM-3 ultrafiltration membrane (molecular weight cut-off 3000 Da). The retentate is then freeze-dried.

Yield: 1.7 g (82% of the theoretical value). H20 content (Karl-Fischer): 9.9%.

Gd determination (AAS): 19.3%.

Elemental analysis (calculated on anhydrous material):

Example 2 8

a) Mixture consisting of the dysprosium complex of 10-(4-carboxy-1-ethyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1 molar equivalent of sodium bromide

32.71 g (50.4 mmol) of the Dy complex of 10-(4-carboxy-1-ethyl-2-oxo-3-azabutyl)-1,4,7,10-tetradodecane-1, 4,7 -triacetic acid, described in example 5, is dissolved in 200 ml of water and 5.19 g (50.4 mmol) of sodium bromide is added. The clear solution is freeze-dried and then further dried overnight at 100 °C in a vacuum. A colorless powder is obtained.

Yield: 37.9 g (quantitative).

H20 content (Karl-Fischer): 3.5%.

Dy determination (AAS): 20.7%.

Elemental analysis (calculated on anhydrous material):

b) Dotriacontakisamide conjugate of the 32-mer dendrimeramine "DAB (PA) 4 (PA) 8 (PA) 16 (PA) 32" and the dysprosium complex of 10-(4-carboxy-1-ethyl-2-oxo-3-azabutyl) -1, 4, 7, 10- tetracyclododecane- 1, 4, 7- triacetic acid

3.76 g (5 mmol) of the sodium bromide mixture salt with the Dy complex of 10-(4-carboxy-1-ethyl-2-oxo-3-azabutyl)-1,4,7,10-tetracyclododecane-1, 4.7 -triacetic acid, described in the previous example 28a), 696 mg (5 mmol) of 4-nitrophenol and 1.03 g (5 mmol) of N,N'-dicyclohexylcarbodiimide are dissolved in 25 ml of dimethyl sulfoxide and stirred for 1 hour. 275 mg (0.078 mmol) of the 32-mer dendrimeramine described in example VIII in WO 93/14147 and 506 mg (5 mmol) of triethylamine in 5 ml of water are added to the thus prepared active ester solution, and the mixture is stirred overnight at room temperature. Sufficient acetone is added to the resulting suspension for complete precipitation, the precipitate is filtered off with suction, dried, dissolved in water, insoluble dicyclohexylurea is filtered off, and the filtrate is desalted and purified from low molecular weight components through an "AMICON" YM-3 ultrafiltration membrane (molecular weight barrier 3000 Da). The retentate is then freeze-dried.

Yield: 1.62 g (83% of the theoretical value). H20 content (Karl-Fischer): 10.0%.

Dy determination (AAS): 20.3%.

Elemental analysis (calculated on anhydrous material):

Example 2 9

Amide conjugate of daunomycin with the gadolinium complex of 1-[ 1-methyl- 2- oxo- 3- aza- 4- carboxybutyl]- 4, 7, 10- tris (carboxymethyl)- 1, 4, 7, 10- tetraazacyclododecane

1.135 g (1.588 mmol) of the title compound from example 25a) and 365.8 mg (3.176 mmol) of 4-nitrophenol are dissolved in 10 ml of dimethyl sulfoxide and then cooled to 10 °C. The mixture is added at 10 °C with 393 mg (1.906 mmol) of dicyclohexylcarbodiimide and stirred for 45 minutes at room temperature. 812.3 mg is added to the thus prepared suspension

(1.588 mmol) of daunomycin dissolved in 5 ml of dimethylsulfoxide and then 321.4 mg (3.176 mmol) of triethylamine. The mixture is stirred overnight at room temperature. 200 ml of acetone are added dropwise to the resulting suspension, the precipitate is filtered off and washed twice with a little acetone. The precipitate is purified by column chromatography (RP18/eluent: gradient of water/acetonitrile/tetrahydrofuran).

Yield: 1.81 g (87% of theory) of a colorless, fluffy powder after freeze-drying.

Water content: 6.8%.

Elemental analysis (calculated on anhydrous material):

- Example 3 0

Amide conjugate of adriamycin with the gadolinium complex of 1-[ 1-methyl- 2- oxo- 3- aza- 4- carboxybutyl] - 4, 7, 10- tris (carboxymethyl) - 1, 4, 7, 10- tetraazacyclododecane

1.135 g (1.588 mmol) of the title compound from example 25a) and 442 mg (3.176 mmol) of 4-nitrophenol are dissolved in 10 ml of dimethyl sulfoxide and then cooled to 10 °C. The mixture is added at 10 °C with 393 mg (1.906 mmol) of dicyclohexylcarbodiimide and stirred for 45 minutes at room temperature. 812.3 mg (1.588 mmol) of adriamycin dissolved in 5 ml of dimethylsulfoxide and then 321.4 mg (3.176 mmol) of triethylamine are added to the thus prepared suspension. The mixture is stirred overnight at room temperature. 200 ml of acetone are added dropwise to the obtained suspension, the precipitate is filtered off and washed twice with a little

acetone. The precipitate is purified by column chromatography (RP18/eluent: gradient of water/acetonitrile/tetrahydrofuran).

Yield: 1.94 g (90% of theory) of a colorless, fluffy powder after freeze-drying.

Water content: 9.1%.

Elemental analysis (calculated on anhydrous material):

Example 31

a) Mixture consisting of the dysprosium complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 1 molar equivalent of sodium bromide

32.0 g (50.4 mmol) of the Dy complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetradodecane-1,4,7 -triacetic acid, described in example 2, is dissolved in 200 ml of water and 5.19 g (50.4 mmol) of sodium bromide is added. The clear solution is freeze-dried and then further dried overnight at 100 °C in a vacuum. A colorless powder is obtained.

Yield: 37.2 g (quantitative).

H20 content (Karl-Fischer): 3.5%.

Dy determination (AAS): 20.8%.

Elemental analysis (calculated on anhydrous material):

b) Hexatriacontoquisamide conjugate of the 36-mer polyamine from example 13d) with the dysprosium complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4, 7- triacetic acid

1.84 g (0.2 mmol) of the 36-mer-benzyloxycarbonylamine described in example 13d) is dissolved in glacial acetic acid and 33% hydrogen bromide in glacial acetic acid is added while stirring. After 5 hours, the incipient precipitation is completed with diethyl ether, the formed 36-meramine-

hydrobromide is washed with ether, dried in vacuo and used without further purification in the reaction described below.

Yield: 1.5 g (quantitative).

15.9 g (21.6 mmol, 3-fold excess) of the sodium bromide mixture salt with the dysprosium complex of 10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetradodecane-1 ,4,7-triacetic acid, described in the previous example 31a), 3.73 g (32.4 mmol) of N-hydroxysuccinimide and 6.7 g (32.4 mmol) of N,N'-dicyclohexylcarbodiimide are dissolved in 100 ml of dimethyl sulfoxide at room temperature pre-serve for 60 minutes. A solution of 1.5 g (0.2 mmol) of the above-described hexatriacontahydrobromide and 3.5 g of triethylamine in 10 ml of water is added to the N-hydroxysuccinimide ester solution thus prepared, and the mixture is stirred overnight at room temperature. Sufficient acetone is added to the resulting suspension for complete precipitation, the precipitate is filtered off with suction, dried, dissolved in water, insoluble dicyclohexylurea is filtered off, and the filtrate is desalted and purified from low molecular weight components through an "AMICON" YM-3 ultrafiltration membrane (molecular weight cut-off 3,000 Da). The retentate is then freeze-dried.

Yield: 5.0 g (84% of the theoretical value). H20 content (Karl-Fischer): 10.5%.

Dy determination (AAS): 19.6%.

MALDI-TOF mass spectrum: 26.616 (M + Na + ). Elemental analysis (calculated on anhydrous material):

Example 32

a) Mixture consisting of the gadolinium complex of 10-(13-carboxy-1-methyl-2-oxo-3-azatridecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and 2 molar equivalents of lithium chloride

38.1 g (50.4 mmol) of the Gd complex of 10-(13-carboxy-1-methyl-2-oxo-3-azatridecyl)-1,4,7,10-tetradodecane-1,4,7 -triacetic acid, described in example 8c), is dissolved in 250 ml of water and 4.27 g (100.8 mmol) of lithium chloride is added. The clear one

solution is freeze-dried and then further dried overnight at 100 °C in vacuum. A colorless powder is obtained.

Yield: 42.4 g (quantitative).

H20 content (Karl-Fischer): 3.5%.

Gd determination (AAS): 18.0%.

Elemental analysis (calculated on anhydrous material):

b) Hexaamide conjugate of 6,6',6,,,6,,,,6,,'',6,,l,,,-hexaamino-6, 6 ,,6,,,6I,,,6,, ',,6,,',,-hexadeoxy-α-cyclodextrin with the gadolinium complex of 10-(13-carboxy-1-methyl-2-oxo-3-azatridecyl)-1,4,7,10-tetraazacyclododecane-1, 4, 7-triacetic acid

4.2 g (5 mmol) of the lithium mixture salt with the gadolinium complex of 10-(5-carboxy-1-methyl-2-oxo-3-azatridecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid described in the previous example 32a), 1.15 g (10 mmol) of N-hydroxysuccinimide and 1.24 g (6 mmol) of dicyclohexylcarbodiimide are dissolved in 30 ml of dimethyl sulfoxide and stirred for 8 hours at room temperature. The N-hydroxysuccinic ester solution thus prepared is added to a suspension of 315 mg (0.25 mmol) 6,6',6'',6'<11>,-6'<1>'<1>,6'' ■''-hexaamino-6,6,,6,,,6,,,,6,,,,,6,,,,,-hexadeoxy-α-cyclodextrin [J. Boger, R.J. Corcoran and J.-M. Lehn, Heiv. Chim. Acta, 61, 2190-2218 (1978)] in dimethyl sulfoxide and stirred overnight at room temperature. To the resulting suspension is added a sufficient amount of acetone for complete precipitation, the precipitate is filtered off with suction, dried, dissolved in water, insoluble dicyclohexylurea is filtered off, and the filtrate is desalted and purified from low molecular weight components through an "AMICON" YM-3 ultrafiltration membrane (molecular weight barrier 3000 Then). The retentate is then freeze-dried. A colorless powder is obtained.

Yield: 1.35 g (90% of the theoretical value). H20 content (Karl-Fischer): 9.5%.

Gd determination (AAS): 16.6%.

Elemental analysis (calculated on anhydrous material):

Example 33

Amide conjugate of 3'- amino- 3'- deoxyguanosine with the gadolinium complex of 1-[l- methyl- 2- oxo- 3- aza- 4- carboxybutyl]- 4, 7, 10-tris (carboxymethyl)- 1, 4, 7 , 10- tetraazacyclododecane

1.163 g (1.588 mmol) of the title compound from example 26a) and 365.8 mg (3.176 mmol) of N-hydroxysuccinimide are dissolved in 10 ml of dimethyl sulfoxide and then cooled to 10 °C. The mixture is added at 10°C with 393 mg (1.906 mmol) of dicyclohexylcarbodiimide and stirred for 45 minutes at room temperature. 422.8 mg (1.588 mmol) of 3'-amino-3'-deoxyguanosine dissolved in 5 ml of dimethylsulfoxide and then 321.4 mg (3.176 mmol) of triamine are added to the N-hydroxysuccini midester solution thus prepared. The mixture is stirred overnight at room temperature. 200 ml of acetone are added dropwise to this solution, the precipitate is filtered off and washed twice with a little acetone. The precipitate is purified by column chromatography (RP18/eluent: gradient of water/acetonitrile/tetrahydrofuran).

Yield: 1.36 g (90% of theory) of a colorless, fluffy powder after freeze-drying.

Water content: 7.4%.

Elemental analysis (calculated on anhydrous material):

Example 34

Amide conjugate of dehydroabiethylamine with the gadolinium complex of 1-[1-methyl-2-oxo-3-aza-4-carboxybutyl]-4,7,10-tris(carboxymethyl)-1,4,7,10-1tetraazacyclododecane

1.163 g (1.588 mmol) of the title compound from example 26a) and 365.8 mg (3.176 mmol) of N-hydroxysuccinimide are dissolved in 10 ml of dimethyl sulfoxide and then cooled to 10 °C. The mixture is added at 10 °C with 393 mg (1.906 mmol) of dicyclohexylcarbodiimide and stirred for 45 minutes at room temperature. To the thus prepared suspension is added

422.8 mg (1.588 mmol) of dehydroabiethylamine dissolved in 5 ml of dimethyl sulfoxide and then 321.4 mg (3.176 mmol) of triamine. The mixture is stirred overnight at room temperature. 200 ml of acetone are added dropwise to this suspension, the precipitate is filtered off and washed twice with a little acetone. The precipitate is purified by column chromatography (RP18/eluent: gradient of water/acetonitrile/tetrahydrofuran).

Yield: 1.40 g (92% of the theoretical value) of a glassy solid after freeze-drying.

Water content: 6.5%.

Elemental analysis (calculated on anhydrous material):

Example 35

Amide conjugate of ampicillin with the gadolinium complex of 1-[ 1-methyl- 2- oxo- 3- aza- 4- carboxybutyl]- 4, 7, 10- tris(carboxymethyl)-1, 4, 7, 10- tetraazacyclododecane

1.135 g (1.588 mmol) of the title compound from example 25a) and 365.8 mg (3.176 mmol) of N-hydroxysuccinimide are dissolved in 10 ml of dimethyl sulfoxide and then cooled to 10 °C. The mixture is added at 10 °C 3 93 mg (1.906 mmol) of dicyclohexylcarbodiimide and stirred for 45 minutes at room temperature. 554.9 mg •-(1.588 mmol) of ampicillin dissolved in 5 ml of dimethylsulfoxide and then 482 mg (4.764 mmol) of triethylamine are added to the thus prepared suspension. The mixture is stirred overnight at room temperature. 200 ml of acetone are added dropwise to this suspension, the precipitate is filtered off and washed twice with a little acetone. The precipitate is purified by column chromatography (RP18/eluent: gradient of water/acetonitrile/tetrahydrofuran/+0.5% trifluoroacetic acid).

Yield: 1.54 g (90% of the theoretical value) of a colorless, fluffy powder after freeze-drying.

Water content: 10.0%.

Elemental analysis (calculated on anhydrous material):

Gd 16.05.

Example 36

Amide conjugate of the pentapeptide NH2-Val-Leu-Phe-Phe-Ala-OH with the gadolinium complex of 1-[l-methyl-2-oxo-3-aza-4-carboxybutyl]-4,7,10-tris(carboxymethyl)- 1,4,7,10-tetraazacyclododecane

1.135 g (1.588 mmol) of the title compound from example 25a) and 365.8 mg (3.176 mmol) of N-hydroxysuccinimide are dissolved in 10 ml of dimethyl sulfoxide and then cooled to 10 °C. The mixture is added at 10 °C with 393 mg (1.906 mmol) of dicyclohexylcarbodiimide and stirred for 45 minutes at room temperature. To the thus prepared suspension is added 946 mg (1.588 mmol) of the pentapeptide NH2-Val-Leu-Phe-Phe-Ala-OH (prepared according to solid phase technique) dissolved in 5 ml of dimethylsulfoxide and then 321.4 mg (3.176 mmol) of triethylamine. The mixture is stirred overnight at room temperature. 200 ml of acetone are added dropwise to this suspension, the precipitate is filtered off and washed twice with a little acetone. The precipitate is purified by column chromatography (RP18/eluent: gradient of water/acetonitrile/tetrahydrofuran).

Yield: 1.81 g (87% of theory) of a colorless, fluffy powder after freeze-drying.

Water content: 8.1%.

Elemental analysis (calculated on anhydrous material):

Example 37

Amide conjugate of N-methylglucosamine with the gadolinium complex of 1-[l-methyl-2-oxo-3-aza-4-carboxybutyl]-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

1.163 g (1.588 mmol) of the title compound from example 26a) are dissolved in 10 ml of dimethyl sulfoxide and then cooled to 10 °C. 310 mg (1.588 mmol) of D(-)-N-methylglucosamine and 785.4 mg (3.176 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) are added to the mixture at 10 °C. The mixture is stirred overnight at room temperature. 200 ml of acetone are added dropwise to this solution, the precipitate is filtered off and washed twice with a little

acetone. The precipitate is purified by column chromatography (RP18/eluent: gradient of water/acetonitrile/tetrahydrofuran).

Yield: 1.30 g (93% of the theoretical value) of a colorless, fluffy powder after freeze-drying.

Water content: 8.5%.

Elemental analysis (calculated on anhydrous material):

Claims (29)

1. Process for the production of metal complex carboxyamides containing the 1, 4, 7, 10-tetraazacyclodecane shell, characterized by a metal complex carboxylic acid mixture consisting of the metal complex carboxylic acid where the metal is selected from the group of lanthanides, iron, manganese, yttrium and bismuth, and at least one solubilizer compound in dimethylsulfoxide (DMSO) is pretreated with a water-splitting reagent, possibly with the addition of a coupling aid f, followed by reaction with an amine of the general formula I in which A denotes the residue of a natural or synthetic amine, wherein the amine is selected from the group of antibiotics, nucleosides, aminoterpenes, aminoporphyrins, aminosteroids, aminosugars, dendrimers, proteins, polylysines, aminopolysaccharides, polyvinylamines, polyalkylamines, poly[N(2-aminoethyl)]methacrylamides, polynucleotides and polypeptides, and ten denotes the numbers 1-100, provided that the reaction takes place in solution with a temperature of 0 to 70 °C. 2. Method according to claim 1, characterized in that the metal complex carboxylic acid mixture is formed in situ by adding a dissolution mediating compound/compounds to the DMSO suspension of the metal complex carboxylic acid, a water splitting reagent and optionally a coupling aid. 3. Method according to claim 1, characterized in that the metal complex carboxylic acid mixture is first prepared and isolated, followed by this mixture then being pre-treated by adding a water-splitting reagent and possibly a coupling aid in DMSO. 4. Method according to claim 1, characterized in that the amine is added without solvent to the DMSO solution of the pretreated metal complex carboxylic acid mixture. 5. Method according to claim 1, characterized in that the amine is added in dissolved form to the DMSO solution of the pretreated metal complex carboxylic acid mixture. 6. Method according to claim 5, characterized in that the amine is dissolved in DMSO, water or in water-miscible solvents. 7. Method according to claim 1, characterized in that the pre-treatment with the water-splitting reagent is carried out at temperatures from 0 to 50<Q>C and at reaction times between 1 and 24 hours. 8. Method according to claim 7, characterized in that the pre-treatment is carried out at room temperature and with reaction times between 3 and 12 hours. 9. Process according to claim 1, characterized in that the reaction with the amine of general formula I is carried out at temperatures from 0 to 70 °C and at reaction times between 1 and 48 hours. 10. Method according to claim 9, characterized in that the reaction is carried out at temperatures from 30 to 60 °C and at reaction times between 8 and 24 hours. 11. Method according to claim 1, characterized in that the solvents are selected from alkali, alkaline earth, trialkylammonium and tetraalkylammonium salts, urea, N-hydroxyimides, hydroxyaryltriazoles, substituted phenols and salts of heterocyclic amines. 12. Method according to claim 1, characterized in that the number 1 denotes. 13. Method according to claim 1, characterized in that the numbers 2 to 50 denote. 14. Method according to claim 1, characterized in that the numbers 12 to 36 denote. 15. Method according to claim 1, characterized in that the metal complex carboxylic acid has a cyclic structure. 16. Method according to claim 11, characterized in that the solvents are selected from the compounds lithium chloride, lithium bromide, lithium iodide, sodium bromide and sodium iodide. 17. Method according to claim 1, characterized in that the metal complex carboxylic acid denotes a gadolinium or dysprosium complex. 18. Method according to claim 1, characterized in that the metal complex carboxylic acid is a compound of general formula II in which Z° denotes a metal ion equivalent with ordinal numbers 25, 26, 39, 57-71, 83, and R denotes a CHX^CO-NH-CHY1-(CH2)f-COOH group, where X<1> and Y<1> independently of each other denotes a hydrogen atom, a straight-chain or branched C 1 -C 7 alkyl radical, a phenyl or benzyl group, and f denotes the numbers 0 to 9. 19. Method according to claim 18, characterized in that the metal complex carboxylic acid with general formula II is a gadolinium or dysprosium complex of 10-[4-carboxy-1-methyl-2-oxo-3-aza-butyl]-1,4,7,10 -tetraazacyclododecane-1, 4,7-triacetic acid. 20. Process according to claim 1, characterized in that the residue A in the amine of general formula I does not contain any protonatable amino groups. 21. Process according to claim 20, characterized in that the amine of general formula I denotes a 24-mer polyamine based on N,N,N', N', N'',N''-hexakis[2-(trilysylamino)ethyl] trimesic acid triamide. 22. Method according to claim 1, characterized in that the metal complex carboxylic acid mixture contains up to 5 molar equivalents of the solvents in relation to the metal complex carboxylic acid. 23. Method according to claim 1, characterized in that the metal complex carboxylic acid mixture contains 0.5 to 2 molar equivalents of dissolution mediating compounds in relation to the metal complex carboxylic acid. 24. Method according to claim 1, characterized in that carbodiimides or onium reagents are used as water-splitting reagents. 25. Method according to claim 24, characterized in that dicyclohexylcarbodiimide is used as carbodiimide. 26. Process according to claim 1, characterized in that 4-nitrophenol, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, 3,5-dinitrophenol or pentafluorophenol are used as coupling aids. 27. Method according to claim 26, characterized in that 4-nitrophenol is used as coupling agent. 28. Method according to claim 1, characterized in that a mixture of the gadolinium complex of 10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1, 4,7,10-tetraazacyclododecane-1,4,7- triacetic acid and 1-2 equivalents of sodium bromide are first prepared and isolated, followed by this mixture then being pretreated under N,N,N' , N' ,N1 1 , N1 ' -hexakis[2-(triamino)ethyl]trimesic acid triamide, at 20-60 oC and reaction times between 8 and 24 hours. 29. Method according to claim 1, characterized in that a mixture of the gadolinium complex of 10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7 -triacetic acid and 1-2 equivalents of lithium chloride are first prepared and isolated, followed by this mixture then being pretreated with the addition of 4-nitrophenol and dicyclohexylcarbodiimide in DMSO at room temperature and reaction times between 3 and 12 hours, and followed by the mixture, optionally with the addition of water, is reacted with the 24-mer polyamine based on N,N,N',N',N'',N''-hexakis[2-(triamino)ethyl]trimesic acid triamide, at 20-60 °C and reaction times between 8 and 24 hours.