DD293113A5 - PROCESS FOR THE PRODUCTION OF COMPLEXES - Google Patents

Abstract

Ligands and complexes of the title and the applications of these complexes in magnetic resonance imaging, in X-ray radiology and as in-vivo chemical shift agents.

Description

R R '

X- [R ₄ -N] _n -R ₃ -NR ₂ -X (XI),

in which n, R ₂ , R ₃ , R ₄ and R 'have the stated meaning and X is a labile group is prepared.

Field of application of the invention

The invention relates to a process for the preparation of novel nitrogen-containing ring-shaped ligands and their metal complexes, which are used in medical technology.

Characteristic of the known state of the art

For the preparation of the new compounds, no prior art to be considered could be determined.

Object of the invention

The aim of the invention are novel compounds which are useful in medical technology as a contrast agent in the optical imaging by means of magnetic electron resonance u.a. used, better evaluation results as well as better compatibility with the examinee result.

Explanation of the essence of the invention

The invention relates to a process for the preparation of compounds which are nitrogen-containing ring-shaped ligands and capable of forming complexes with metals. It has been found that for the preparation according to the invention of the ligands of the formula I.

HOOC

COOH

HOOC

in the

R _{1 is} a radical of the formula

(D

- (CH ₂ L-CH-CH-R ₆ R ₇

R _{6 represents} an alkyl group with C ₁ -C ₁₄ , a hydroxyalkyl group with C ₁ -C ₄ and a polyhydroxyalkyl group with Ci-C ₄ and a group of the formula

? ⁵

CH - COOH

InX

U. _> _r

CH - COOH

CH

- CH

11 - (%> m Z

R.

CH - COOH

is selected, R ₁₁ A or

- (CH ₂ I ₁ -YAY- (CH ₂ ), -

means,. ....

where A is an alkylene group with C ₁ -C ₈ , a hydroxyalkylene group with C ₁ -C ₈ or a polyhydroxyalkylene group with C ₁ -C ₈ ,

Y is selected from - C - 0 - and - 0 -

andt is 1 to 4, R ₇ is either a hydrogen atom, an alkyl group having C ₁ -C _4, a Hydroxyalkyigruppe with C ₁ -C _4, or a polyhydroxyalkyl group having Ci-C _4, m = 0 or 1, R2 / R3, R _{4 are the} same or different and are a radical of the formula

- (CH) p-CH-R ₈ R 9

represent R ₈ and R ₉ are identical or different and either a hydrogen atom, an alkyl group with C ₁ -C _4, a Hydroxyalkyigruppe with C ₄ and a polyhydroxyalkyl group having Ci-C ₄ may be, ρ = 1 or 2, η = 0,1 or 2 and R _{5 is} a hydrogen atom, an alkyl group with C ₁ -C ₄ , a hydroxyalkyl group with Ci-C ₄ or a polyhydroxyalkyl group with C ₁ -C ₄ , and Z is an oxygen atom or a group of formula

'10

wherein R10 is either a hydrogen atom, an alkyl group with Ci-C ₄ , a Hydroxyalkyigruppe with C ₁ -C ₄ , a Polyhydroxyaikylgruppe with C ₁ -C ₄ , a group of the formula -CH-COOH, wherein R _{5 has} the meaning already mentioned , or

R _{5 is} a group of the formula

ΐ ^{5 R} l N _ COOH ^R 5 ^R 3 - N CH - -R ₄ - - ¹ η CH - COOH L- IN \ -R ₂ -

CH - COOH

^R 5

is selected when Ri ₂ of the alkylene group by C _8, the Hydroxylalkylengruppe with C ₁ -C ₈ and the Polyhydroxylalkylengruppe with Ci-C _8, and the salts, a compound of formula

X-CH-COOH (II) ₍

R ₅

wherein R _{5 has} the meaning given above and X represents a labile group such as a chlorine, bromine or iodine atom or a toxyloxy or mexyloxy group, with an annular amine of the formula

R ₃

in which in turn R2, R3, R4 and η have the already given meaning, R ', a radical of the formula

- (CH ₂ L-CH-CH-R ₆ R ₇

, wherein R _{'6 is} either an Al ky! group with C ₁ -C _4, a ky Hydroxya I! group with C _4, a poly hy droxyalkylgruppe with C ₁ -C ₄ or a group of formula

wherein R ₂ , R ₃ , R ₄ , R 7, R ₁ , m and η are each as defined above and Z 'is an oxygen atom or a group of the formula

is, in the R ' _1O a hydrogen atom, an alkyl group with C ₁ -Cu, a hydroxyalkyl group with C ₁ -C ₄ , a polyhydroxyalkyl group with Ci-C ₄ or a group of the formula

may be, in which R ₁ , R ₂ , R ₃ , R ₄ , R 12 and η have the meaning given above, is reacted. The ligands of the formula I are according to the invention also according to a multi-stage process by the action of an aldehyde of the formula

R ₅ -CHO (Ma) ₁

wherein R _{5 has} the previously given meaning to produce an annular amine of formula (III) in the presence of hydrogen cyanide or more generally of cyanide ions (KCN, NaCN)

 The compounds of the formula (III) in which Z 'is a group

> - ^R io

is can be manufactured:

a) by reaction of a polyamide of the formula

R '

R ¹ HN- [R ₄ -N] _n -RVNHR '(IV)

in which n, RS and R _{4 have} the abovementioned meaning and R 'represents a tosyl, mesyl or benzenesulfonyl group, with a compound of the formula ........

XR ₂ -NR ₃ -X (V) ₍

wherein R ₂ , R ₃ and R 'have the previously given meaning and X represents a labile group such as a tosyloxy or mesyloxy group or a chlorine, bromine or iodine atom, or -....

b) by reaction of a diamine of the formula. , , : '.>:.

R'HN-R'-i-NH-R '(X)

in which R'1 and R 'have the abovementioned meaning, with a compound of the formula

R 'R' X- [R ₄ -N] -R ₃ -NR ₂ -X (XI)

This ring-forming reaction is advantageously carried out in the presence of a phase-change catalyst. The polyamines of the formula (IV) are to be prepared on the basis of dihydroxylamines according to the following scheme:

HO

R ¹ O

N-

H ₂ N

R ¹ HN

[ ^R 4 ν] ^R 'l ^0H

R'Cl / pyridine

] ^R 'j. ^0R1

NaN ₃ / CH ₃ CN / H ₂ O

R < ^N

R ^f

R '

1 - ^N 3 reduction

R · N

J - ^R1 i -

NH,

R'Cl / pyridine

R 'N

_N | -V ₁

NHR '

(Vl)

(VIl) (VIII)

(IX)

(IV)

As an embodiment, it is possible to act on the compounds of formula (VII) phthalimide and a hydrazinolysis

to get from the compounds of formula (VII) to the compounds of formula (IX).

The compounds of the formula (III) containing two nitrogen-containing rings may be used as defined above

Process are produced.

Thus, one can use a polyamine of the formula

CH,

CH

R ¹ NH

NH R '

CH

R'NH

CH,

(XII),

NH R ¹

in which A and R 'are as defined above, reacting with a compound of formula (XI) to form a compound

of the formula (III) in which Rn is a group A.

The polyamine of formula (XII) is prepared from a tetrahalogen derivative by nucleophilic substitution in the presence of sodium nitride followed by reduction in the presence of hydrogen and palladium over carbon.

As an alternative embodiment, the compounds of formula (I) containing two nitrogen-containing rings and in which

Ri _{1 is} a Α group, by condensation of a compound of the formula

(XIII)

et ooc COO et \ / CH A - - CH \ et ooc COO et with a polyamine of the formula

HHH

H ₂ NR ₂ -NR ₃ -N- [R ₄ -N] -H (XIV)

with subsequent diborane reduction according to a method described by Tabushi and Mitarb (Tetra Letters 12, 1049, 1977).

The compounds of formula (I) having two nitrogen-containing rings are then prepared as the compounds of formula (III) having two rings as described above.

As one embodiment, the compounds of formula (I) having two nitrogen-containing rings by condensation of a compound of formula (I) wherein R _{1 is} a radical of formula

- {CH ₂ ) _m -CH-CH-

R _{6 is} again a hydroxylalkyl group having an activatable bifunctional group of the formula X ₁ -AX ₁ ,

in which X _{1 is} a COOH, COCI group or an acid anhydride.

The compounds of formula (I) having two nitrogen-containing rings are also by condensation of a compound of formula

HOOC - CH

I -h.

N R_ N H

R ₃ R '"(XV)

HOOC - CH

^R 5

in which R "i is a radical of the formula - (CH ₂ ) _m -CH-CH-

-CH-CH R e R ₇

and m and R _{7 have} the abovementioned meaning, while R " _{6 is} an alkyl group with C ₁ -C ₄ , a hydroxyalkyl group with C ₁ -C ₄ OdCr a polyhydroxyalkyl group with C ₁ -C ₄ ISt, with a compound of formula

X-R _'12 -X (XVI) ₍

where X is as previously given and R _{'12 is} a possibly protected R ₁₂ group.

These are the compounds of the formula

HOOC - CH I

(XVII)

- COOH

receive.

For the preparation of complexes consisting of the ligands of the formula (I) with metal ions such as the ions of the lanthanides (atomic numbers 57 to 71), the ions of the transition metals (atomic numbers 21 to 29), in particular Mn ²⁺ , Fe ³⁺ and Cr ^{3 +} , and the ions of the metals of atomic numbers 55, 56, 82 and 83 are formed, and the salts of these complexes with pharmaceutically acceptable inorganic or organic bases or basic amino acids, the ligands with a salt or an oxide of the metals in one reacted aqueous solvent and optionally neutralized to form a salt.

In these complexes, the metal ions are preferably gadolinium, europium, dysprosium, iron (Fe ³⁺ ) and manganese (Mn ²⁺ ).

Examples of salts are those formed with sodium hydroxide, N-methylglucamine, diethanolamine, lysine and arginine.

Of course, this invention encompasses not only the ligands of formula (I) and the complexes defined above in the form of racemic mixtures, but also the stereoisomers of these ligands and complexes.

The complexes of the invention may also be bound to a macromolecule, which may preferably be fixed on a support. Consequently, the complexes according to the invention can be bound to proteins and in particular to antibodies.

In addition, they may in particular be encapsulated in liposomes.

The complexes according to the invention formed by the ligands of the formula (I) with paramagnetic ions and their salts with pharmaceutically acceptable bases can be used as contrast agents in optical magnetic resonance imaging and as a chemical displacer in vivo.

The complexes formed by ligands of the formula (I) with the ions of the lanthanides (atomic numbers 57 to 71) or the ions of the metals of atomic numbers 55, 56, 82 and 83 and their salts with pharmaceutically acceptable bases are known as contrast agents to use in X-rays. In particular, the complexes formed with the ions of the following metals are preferred: Gd, Er, Dy, Tb, La, Ba and Cs.

At least one complex formed from a ligand of formula (I) with metal ions such as the ions of the lanthanides, the ions of the transition metals and the ions of the metals of atomic numbers 55, 56, 82 and 83 is taken for the preparation of a human-administrable diagnostic composition and the salts of these complexes with pharmaceutically acceptable inorganic or organic bases or basic amino acids in a pharmaceutically acceptable form.

These compositions may in particular consist of solutions of a complex according to the invention in a physiologically compatible, aqueous solvent.

The prepared diagnostic compositions can be administered:

- parenteral and intravenous, intraarterial, intralymphatic, subcutaneous

- orally

- subarachnoidal

- intrabronchially in the form of an aerosol

- intra-articular

- local for the visualization of cavities (for example uterus).

In optical imaging by means of magnetic resonance, the doses depend strongly on the mode of administration.

Intravenous or intra-arterial, the dose is about 0.01 to 2mM / kg.

When administered orally, the dose may be up to 10mM / kg.

In the other modes of administration, the efficacy doses are generally less than 1 mM / kg and, in subarachnoid administration, generally less than 0.05 mM / kg.

When used as a chemical displacer in vivo and as a contrast agent in X-rays the same doses are taken. An exception is the intravenous or intra-arterial administration, where the doses are smaller than or

equal to 5mM / kg.

In addition, the complexes according to the invention which are formed by the ligands of the formula (I) with radioactive ions and their salts with pharmaceutically acceptable bases are to be used as diagnostic or therapeutic agents in nuclear medicine. Examples of radioactive ions are the radioisotopes of elements such as copper, cobalt, gallium, germanium, indium and especially technetium (Tc99m).

embodiments

The following examples illustrate the preparation of the compounds according to the invention. In these examples

the NMR spectra were generated with a Varian EM 360 to 60MHz instrument with the TM as internal reference,

the IR spectra were made with a Perkin Elemer 1320 device.

The spectra of the solids were recorded on the KBr platelets. For the liquids (oils) they were recorded without solvent.

The term "buffer" used in thin-layer chromatography refers to a mixture of NH ₄ OH 1.5M and (NH ₄ J ₂ CO ₃ 1.5M.

The melting points were recorded on the Kofier bench.

The terms used in the complexation determinations: "Absence of free Gd ³⁺ and free ligands" are understood to be the detection limits of the methods used, ie, <4 ppm and <5 ppm for Gd ³⁺ and ligand, respectively.

Example 1: Preparation of 2,6-dimethyl-1,4,7,10-tetraazacyclododecane-N.NV-N ", N" -tetraacetic acid

a) Preparation of N-tosyl-bis (2-tosyloxypropyl) -amine

To a solution of 248g (1,3MoI) of tosyl chloride in 200 cm ³ of pyridine at 0 ⁰ C a solution of 53,2g (0,4MoI) diisopropanolamine in 50 cm ³ of pyridine is added dropwise, and cooled in the process, so that the temperature between 0 and 5 ° C is held. The mixture is left at this temperature for 72 h. Subsequently, the mixture is poured onto 21 of ice water and 250 cm ³ of concentrated hydrochloric acid.

The tosyl derivative is extracted with 21% methylene chloride. The organic phase is dried over sodium sulphate, filtered, then destained with carbon black 3SA and filtered again over silica gel. After evaporation of the solvent remain 193,8g of a yellow oil (yield 81%, Rf = 0.7 silica gel / CH ^^ / acetone / GE ^), which is used without further purification in the following reactions.

Spectrum NMR ¹ H: 6H CH ₃ (doublet 1.2 and 1.3 ppm); 9 H ToSyI-CH ₃ (singlet 2.5 ppm); 4H CH ₂ (multiple centered at 3.3ppm); 2 H CH (quadruplet between 4.7 and 5.1 ppm); 12H aromatics (multiple «7.3 and 8ppm).

b) Preparation of N-tosyl bis (2-azidopropyl) amine

To 193.8 g (0.32 mol) of the compound prepared under a) in 1.21 acetonitrile and 300 cm ^{3 of} water are added 65.1 g of sodium nitrite (1 mol). The mixture is stirred for 48 h and heated to 75 ° C. After cooling, acetonitrile is evaporated in vacuo.

The residue is mixed with 11 methylene chloride. The organic phase is washed in water, dried and filtered through silica gel (200 g).

After evaporation, 82 g of light yellow oil (yield 75%, Rf = 0.85 silica gel CH ₂ Cl ₂ / acetone / 92: 2) remain, which is sufficiently pure to be used directly.

IR spectrum N ₃ = 2100cm " ¹ dense

c) Preparation of N-tosyl bis (2-aminopropyl) amine

82.2 g (0.244 mol) of the compound prepared under b are dissolved in 500 cm ^{3 of} ethanol with 8 g 5% palladium soot with 50% moisture content.

The mixture is stirred vigorously, allowing a small flow of hydrogen to flow through (to remove the liberated nitrogen). After 8 h at ambient temperature, thin layer chromatography indicates the absence of the azido group. The mixture is filtered and evaporated. This gives 68.4 g of a light yellow oil (yield 98.5%, Rf = 0, 6 silica gel / MeOH / NH ₄ OH.95: 5), which is used without further purification.

NMR spectrum: 6HCH ₃ (doublet 0.9 and 1 ppm); 3HToSyI-CH ₃ (singlet at 2,4ppm); 6H CH ₂ and CH (complex mass between 2.7 and 3.2 ppm); 4H aromatics (multiples between 7.1 and 7.7 ppm).

d) Preparation of N-Tosyl bis / 2 (tosylamino) propylamine

To the lower) obtained 68.4 g (0.24 mol) of amine in 500 cm ^{3 of} methylene chloride and 70cm ³ (0.5MoI) triethylamine at 0 ⁰ C 93g (0.5 mol) of tosyl chloride are added little by little. After adding, the mixture is stirred at ambient temperature for 6 h. The reaction mixture is then washed with 600 cm ^{3 of} water, dried the organic phase, brought to dryness and the residue on silica gel with the pure methylene chloride and then with the methylene chloride-methanol mixture (98: 2) chromatographies. The essential fractions are evaporated, the solid residue is recrystallized in ethanol. After filtering and drying, 99.1 g of mass are obtained (yield 70%).

NMR spectrum: 6H CH ₃ (doublet 0.9.1 ppm); 9H ToSyI CH ₃ (singlet 2.4ppm); 4H CH ₂ (triplet centered at 2.9 ppm); 2H CH (doublet 3.3 and 3.5 ppm); 12 H Aromat (multiplet centered at 7.4ppm).

e) Preparation of N-tosyl-bis (2-tosyloxyethyl) amine

To a solution of 185 g (0.97 mol) of tosyl chloride in 220 cm ^{3 of} pyridine at ^{0 0} C is slowly added a solution of 32.5 g (0.31 mol) of diethanolamine in 60 cm ^{3 of} pyridine, so that the temperature is not higher than 5 ° C is. After adding, the mixture is left for 1 h at this temperature and then poured over 220 cm ^{3 of} ice water with sufficient stirring. 148.4 g of precipitate formed after filtering, washing and drying (yield 85%, Rf = 0.6 silica gel / CH ₂ Cl ₂ / acetone / 98: 2).

Nuclear Magnetic Resonance Spectrum: 9H ToSyI-CH ₃ (Singuiett 2.4ppm); 4H CH ₂ N (triplet at 3.4 ppm); 4H CH ₂ O (triplet at 4.1 ppm); 12H Aromat (multiplet between 7.1 and 7.7ppm).

f) Preparation of N ^ '^^ Nyy

65 g (0.11 mol) of the compound obtained under d) dissolved in 500 cm ^{3 of} dry DMF are added dropwise 8.8 g (0.22 mol) of NaH

added to 60% in oil in 50 cm ³ DMF. The compound is added at ambient temperature so that hydrogen is released regularly. After the addition the mixture is heated to 100 ^c C, and a solution of 68.1 g (0,12MoI) of the compound lower) obtained and dissolved in 500cm ³ of dry DMF was added dropwise. For 24 hours, this reaction mixture is sufficiently stirred at this temperature.

The solvent is then brought to dryness and the residue is redissolved in a CH ₂ Cl ₂ ZH ₂ O-Ge (TIiSCh) The organic phase is washed in water, dried and brought to dryness The residue (100 g) is recrystallized in isopropanol and then in toluene to yield, after filtering, washing in isopropyl ether and dry, 36 g of solid white cloth (yield 40%; R f = 0.5-0.6 silica gel / CH ₂ CL ₂ / acetone / 98: 2). ,

NMR spectrum: 6HCH ₃ (doublet and 1.2 ppm); 12HTosyl-CH ₃ (Singuiett2,4ppm); 14HCH _{2 and} CH (massive between 3 and 4.5 ppm); 16H aromatics (multiple "between 7.1 and 7.7ppm).

g) Preparation of N, N ', N ", N'" - tetratosyl-2,6-dimethyl-1,4,7,10-tetraazacyclododecane (embodiment)

To a suspension of 17 g (27.7 mmol) of the compound obtained under d) in 100 cm ^{3 of} ethanol in the reflux, a freshly prepared solution of sodium ethylate (6OmMoI) in 200 cm ^{3 of} dry DMF is added rapidly. The mixture is left clear and refluxed for half an hour. The solvents are brought to dryness; the residue is again heated with 200 cm ³ DMFversetztundauf 100 ⁰ C. This solution is added in the course of half an hour, a solution of 17g (3OmMoIJ of the compound obtained under e) in 100cm ³ DMF. One night, the reaction mixture is kept at 100 ° C. Subsequently, the DMF is evaporated, the residue is again treated with a H ₂ O / CH ₂ CI ₂ mixture. The product from the organic phase is chromatographed over silica gel with the mixture of CH ₂ Cl ₂ and ethyl acetate (98: 2) as extractant. The product is recrystallized in isopropyl ether and, after drying, gives 13.5 g. (Yield 58%, R f = 0.5-0.6 silica gel / CH ₂ Cl ₂ / acetone / 98: 2)

 The spectrum is similar to that under f).

h) Preparation of 2,6-dimethyl-1,4,7,10-tetraazacyclododecane

33 g of the compound obtained under f) or g) are brought into suspension in 80 cm ³ 98% sulfuric acid and kept at 100 ° C under an argon atmosphere for 72h. After cooling the reaction mixture, 11 ethyl ether is added dropwise at 0 ° C. The resulting 2,6-dimethyl-1,4,7,10-tetraazacyclododecane sulfate is filtered, redissolved in water, neutralized with NaOH and then extracted with CH ₂ Cl ₂ . The organic phases are brought to dryness and the resulting 6 g of solid are used without further purification (yield 74%, R f = 0.65 alumina / butanol / water / acetic acid / 50: 25: 11).

Nuclear Magnetic Resonance Spectrum (D ₂ O): 6H CH ₃ (doublet 0.9 to 1 ppm); 14H CH ₂ and CH (multiple centered at 2.5ppm).

i) Preparation of 2,6-dimethyl-1,4,7,10-tetraazacyclododecane-N, N ', N ", N"' - tetraacetic acid To a solution of 3 g (15 mmol) of the compound prepared under h) in 25 cm ³ water is added to a mixture of 5.7 g (6OmMoI) monochloroacetic acid and 3.4 g (6OmMoI) in 25cm ^{3 of} water. The mixture is heated to 6O ⁰ C, and a potassium carbonate solution (3.4g, 6OmMoI) in 25cm ^{3 of} water is added so that the pH remains between 9 and 10. It is added for 8 hours. After the addition of potassium carbonate is heated for 24 h. After cooling, the pH is lowered to 2.5 using concentrated sulfuric acid. The resulting precipitate is filtered, washed in ice-water and gives 3g after drying. (Yield 35%, R f = 0.33 silica gel / ethyl acetate / isopropanol / ammonia / 12: 35: 30). This compound corresponds to the complex of 2,6-dimethyl-1,4,7,10-tetraazacyclododecane-N, N ', N ", N"' - tetraacetic acid with 2KCl. 9.5 g of this complex are eluted with 200 cm ³ 10% acetic acid over an ion exchange resin IRA958 <OH), which was previously regenerated with 1 η NaOH and washed to neutrality with water. The fractions obtained are brought to dryness and treated three times with 50 cm ^{3 of} water to eliminate the traces of acetic acid. The residue is triturated in ethyl ether (100 cm ³ ) and, after filtering and drying, yields 6.3 g of a white solid. Yield: 89%. NMR spectrum: (D ₂ O) 6H CH ₃ (doublet 1.4 and 1.5 ppm); 14H CH ₂ and CH (massive complex centered at 2.6ppm); 8H CH ₂ COOH (doublet at 3.8 ppm).

Example 2 Preparation of the Gadolinium Complex of 2,6-Dimethyl-1,4,7,10-Tetraazacyclododecane-N, N ', N ", N" ", Tetraacetic Acid, Methyl Glucamine Salt)

A suspension of 5.425 g (12.54 mmol) of the 2,6-dimethyl-1,4,7,10-tetraazacyclododecane-N, N ', N ", N" -tetraacetic acid prepared in Example 1 i) and 2.27 g Gd ₂ O ₃ (6.27 mmol) in 125cm ³ of water is heated 24 h at 65 ⁰ C. The pH is adjusted to 7.4 by adding methylglucamine. After determination of free Gd ³⁺ by xylenol orange / EDTA, 650 mg of 2,6-dimethyl-1,4,7,10-tetraazacyclododecane-N, N ', N ", N"' - tetraacetic acid (1.5 mmol) are used to complex the added to remaining Godaliniums. Complexation is complete when there is no longer free Gd ³⁺ (determination with xylenol orange) and no free ligands (complexometric determination with Cu ²⁺ ). The total content of gadolinium in the solution is determined by atomic emission spectroscopy on a Spectrospan-4 Beckman apparatus. Quantitative yield Rf = 0.49 silica gel / ethyl acetate / isopropanol / ammonia / 12: 35: 30.

Example 3: Preparation of 2-hexyl-1,4,7,10-tetraazacyclododecane-N, N ', N ", N"' - tetraacetic acid

a) Preparation of N- (2-hydroxyethyl) -N- (2-hexyl-2-hydroxyethyl) amine

50g (0.39 mmol) are epoxy-1,2-octane dropwise 250cm ³ (4MoI) of ethanolamine was added at 100 ⁰ C into. After adding is heated for an hour, then the excess ethanolamine is distilled under vacuum. The residue is recrystallized after filtering and drying in 600 cm ^{3 of} hexane. 69 g of solid material are obtained (melting point <45 ^° C., yield 93%, R f = 0.62 silica gel / butanol / H ₂ O / acetic acid / 50: 25: 11).

NMR spectrum: 3H CH ₃ (triplet 0.9 ppm); 10H CH ₂ chain (broad singlet at 2.2ppm; 7H CH ₂ and CH (2 poorly resolved masses at 2.8 and 3.8ppm).

b) Preparation of N-tosyl-N- (2-tosyloxyethyl) -N-2-hexyl-2-tosyloxyethyl) amine:

To a solution of 156 g (0.82 mol) of tosyl chloride in 300 cm ^{3 of} pyridine at 0 ⁰ C are added within 1 h gradually 47.3 g (0.25 mol) of the compound obtained under a). The mixture is kept for 2 days at 0 ⁰ C, and then poured onto a mixture of ice and HCl (2: 1). The product is extracted with CH ₂ Cl ₂ and then chromatographed on silica gel column with CH ₂ Cl ₂ as extractant. You get 118g mass. (Yield 72%; R f = 0.6 silica gel / CH ₂ Cl ₂ / acetone / 98: 2). NMR spectrum: 3H CH ₃ chain (triplet at 0.9 ppm); 10H CH ₂ chain (broad singlet at 1.3 ppm); 9H tosyl-CH ₃ (singlet at 2.4ppm); 4H CH ₂ N (poorly resolved triplet at 3.4 ppm); 3H CH ₂ O and CH (mass at 4.2ppm); 12H aromatics (massive between 7 and 7.7ppm).

c) Preparation of N-tosyl-N- (2-azidoethyl) -n '(2-hexyl-2-azidoethyl) -amine

87 g (0.133 mol) of the compound obtained under b) and 29.25 g (0.45 mol) of sodium nitrite are mixed with 350 cm ^{3 of} acetonitrile and 80 cm ^{3 of} water. This mixture is kept at 65 ⁰ C for 3 days. Subsequently, the acetonitrile is evaporated under vacuum; the residue is redissolved in CH ₂ Cl ₂ ; the organic phase is washed in water, dried and evaporated; 50% of the yellow oil is collected and used without further purification (yield: 95%, Rf = 0.75

NMR spectrum: 3H CH ₃ chain (triplet at 0.9 ppm); 1 OH CH ₂ chain (mass 1.4 ppm); 3H ToSyI-CH ₃ (singlet at 2.4ppm); 5H CH ₂ and CH (massive complex at 3.4 ppm); 4H aromatics (massive between 7.1 and 7.7ppm). IR spectrum N ₃ = 2100cm " ¹ dense.

d) Preparation of N-tosyl-N (2-aminoethyl) -N- (2-hexyl-2-aminoethyl) -amine

71 g (0.18 mol) of the diazide obtained under c) are dissolved in 500 cm ^{3 of} ethanol, to which 5 g of palladium black with 50% moisture are added. The suspension is stirred vigorously for 24 hours at ambient temperature and hydrogen flow. The catalyst is removed by filtering; After evaporation of ethanol gives 61.5 g of diamine, which is used without further purification. (Yield: quantitative, R f = 0.51 silica gel / MeOH: NH ₄ OH / 95: 5).

e) Preparation of N-tosyl-N (2-tosylaminoethyl) -N- (2-hexyl-2-tosylarninoethyl) -amine

To a solution of 61.5 g (0.18 mol) of the compound obtained under d) in 500 cm ³ CH ₂ Cl ₂ and 52.5 cm ³ (0.38 mol) of triethylamine at 0 ⁰ C are gradually added 68.6 g (0 , 36MoI) tosyl chloride. After stirring for 2 h at ambient temperature, the reaction mixture is treated with 500 cm ^{3 of} water. The organic phase is washed in water, dried and evaporated; the oily residue is chromatographed on silica gel column with CH ₂ Cl ₂ as extractant. The oil gives after evaporation of the solvent and addition of isopropyl ether 60 g of a white solid substance (melting point 120 ⁰ C; yield 51%, Rf = 0.6 silica gel / CHsCb / MeOH / gS ^).

NMR spectrum: 13H chain (poorly resolved mass centered at 1 ppm); 9H tosyl-CH ₃ (singlet at 2.4ppm); 7H CH ₂ and CH (mass centered at 3.1 ppm).

f) Preparation of N, N ', N ", N"' - tetratosyl-2-hexyl-1,4,7,10-tetraazacyclododecane

A mixture of 46.5 g (71.5 mmol) of the compound obtained under d), 41.5 g (73 mmol) of the compound obtained in Example 1e) and 24 g (7OmMoI) of tetrabutylammonium hydrogen sulfate are dissolved in 400 cm ³ toluene and 200 cm ³ % sodium hydroxide in suspension. The mixture is stirred vigorously at 70 ^° C. for 24 hours. After cooling, the organic phase is washed in water, dried and evaporated. The residue is crystallized in ethanol and chromatographed on silica gel column with CH ₂ Cl ₂ as extractant. This gives 35 g of solid material (mp 154/161 ⁰ C). Yield 56%; Rf = 0.55 silica gel / CH ₂ Cl ₂ / acetone / 98: 2).

NMR spectrum: 3H CH ₃ chain (triplet at 0.9 ppm); 10H CH ₂ chain (massive at 1.3 ppm); 12H tosyl-CH ₃ (singlet at 2,4ppm); 15H CH ₂ and CH cycle (massive at 3.3ppm); 16H aromatics (multiple "between 7.1 and 7.7ppm).

g) Preparation of 2-hexyl-1,4,7,10-tetraazacyclododecane

12 g (13 mmol) of the compound obtained under f) are kept for 24 h at 100 ⁰ C in 40 cm ³ 98% sulfuric acid under argon. After cooling, the mixture is poured dropwise onto 500 ml of ethyl ether at ⁰ ° C. The resulting sulfate is filtered and then neutralized with a 10% sodium hydroxide solution and extracted with CH ₂ Cl ₂ . The organic phase is dried over sodium sulfate, brought to dryness and gives 2 g of a cream-colored solid. (Yield: 57%, R f = 0.75 alumina / butanol / water / acetic acid / 50: 25: 11).

The compound is stored in the form of oxalate, allowing an ethanol-containing oxalic acid solution to react with 2-hexyl-1,4,7,10-tetraazacyclododecane for one night at ambient temperature. Oxalate precipitates in the form of a white solid.

h) Preparation of 2-hexyl-1,4,7,10-tetraazacylododecane-N, N ', N ", N"' - tetraacetic acid A solution of 1.09 g (2.8 mmol) under g) of oxalate in 13 cm ³ Water and 10ml ethanol are neutralized with 470mg (8.4mMol) potash. This solution is added Kaliummonochloroacetat which (11.25 mmol) potassium carbonate was prepared in 20cm ³ water from 1,063g (11,25mMol) and monochloroacetic 630 mg.

The reaction mixture is brought to 60 ⁰ C, and the pH is maintained by addition of potash between 8 and 10. It is added within 3 h, with 10 cm ^{3 of} water containing 630 mg of potash. After 3 h of reaction, 141 mg (1.5 mmol) of chloroacetic acid and 84 mg (1.5 mmol) of potash are added.

The mixture is kept at 60 ^° C. for a further 2 days. After cooling and acidification to a pH of 2.5 (6n-HCl), the solution is passed through column of strong OH "resin IRA958.The elution with 100 cm ^{3 of} 10% formic acid leads to 700 mg

Product. The direct flow waters (unbound product) are concentrated and re-treated over the same column. After the same treatment, 2.5 g of product are obtained. (Yield: 38.4%, Rf = 0.65 silica gel / ethanol / buffer / 2: 1). NMR spectrum: 3HCH ₃ chain (triplet 0.9 ppm); 10H CH ₂ chain (massive at 1.4 ppm); 15HCH ₂ and CH ring (massive at 3.3ppm); 8H CH ₂ COOH (singlet at 3.9ppm); Spectrum in D ₂ O obtained.

Example 4: Preparation of the gadolinium complex from 2-hexyl-1,4,7,10-tetraazacyclododecane-N, N ', N ", N'-tetraacetic acid

488mg (1 mmol) of the compound obtained in Example 3 and 181,3mg (1 meq metal) of gadolinium oxide are placed in suspension in water ³ 40 cm and maintained at 65 ° C for 2 days. After 2 hours, the solution is limpid. During the reaction, development and complexation can be traced by the terms of free gadolinia. When the complexation is complete, the solution is filtered through Millipore paper, then brought to dryness and crystallized in ethyl ether. This gives rise to 550 mg of a solid white substance. (Yield: 85.5%, Rf = 0.65EtOH / buffer / 2: 1).

Example 5 Preparation of the Gadolinium Complex from 2-Hexyl-1,4,7,10-tetraazacyclododecane-N, N ', N ", 1'-T'-tetraacetic Acid (Methyl Glucamine Salt)

488,6mg (1 mmol) of the compound obtained in Example 3 and 181,3mg (1 meq metal) of gadolinium oxide are placed in suspension in water ³ 40cm and 12 held h at 65 ° C. The solution is added to methylglucamine to adjust the pH to 7.4. Depending on the determination results, ligands are added. The complexation is completed when no free Gd ³⁺ (determination with xylenol orange) and no free ligand (complexometric determination by means of copper) are no longer present. The determination of the total content of gadolinium in the solution is carried out by means of atomic emission spectroscopy on the Spectrospan ^ Beckman apparatus. Rf = 0.65 in EtOH / buffer / 2: 1.

Example 6: Preparation of 2-methyl-1 _/ 4,7,10-tetraazacyclododecane-N, N ', N ", N"' - tetraacetic acid

a) Preparation of N, N'-ditosyl-1,2-diaminopropane

In a 11-neck, 3-neck round bottom flask equipped with a magnetic stirrer, thermometer, and a chloride guard, 14.8 g of 1,2-diaminopropane are dissolved in 500 ml of CH ₂ Cl ₂ and 58 cm ^{3 of} Et ₃ N.

Within one hour, 80g of tosyl chloride are added gradually. With the help of an ice bath must be cooled so that the temperature remains at 20 ⁰ C.

Subsequently, the reaction mixture is stirred for one night at ambient temperature.

The reaction mixture is passed into a 11-decanting funnel and then washed twice with 250 cm ^{3 of} water.

The organic fraction is dried over Na ₂ SO ₄ , brought to dryness and then crystallized in isopropyl ether.

Mass obtained = 66g yield = 86%

Melting point = 98/100 ° C.

1 ppm doublet (3H) 3.1 ppm massive (1H)

2.4ppm Singlet (6H) 5.5ppm Replaceable Singlet (2H)

2.9ppm doublet (2H) 7.1 to 7.8ppm aromatics (8H)

TLC:

SiO ₂ extractant CH ₂ Cl ₂ 90 Rf = 0.75 MeOH 10

b) Preparation of N, N'-Ditosylbis (2-tosyloxyethyl) ethylenediamine

In a three-necked round bottom flask of 500cm ^3, which is equipped with a thermometer, a chloride guard and a magnetic stirrer, a solution of 162 g of tosyl chloride in 300 ml of pyridine by means of an ice bath and salt to 0 ⁰ C is cooled.

At this temperature, 29.6 g of bis (2-hydroxyethyl) methylenediamine are gradually added over a period of 2 hours. The temperature must never exceed 5 ° C. The reaction mixture is stirred for 4 hours at this temperature, stored for 48 hours at 6-8 ° C in the refrigerator and then for 4 hours at ambient temperature.

The reaction mixture is added to 11x ice + water and 300 ml concentrated HCl. The product is extracted with 500 ml of CH ₂ Cl ₂ . This organic phase is dried over Na ₂ SO ₄ and then brought to dryness. The residue is added hot in 250 cm ^{3 of} ethanol. The product is crystallized. It is spun on sintered glass and then dried for 48 h at 6O ⁰ C.

Mass obtained = 107.5g yield = 70%

Melting point = 138/140 ° C NMR:

2,4ppm Singlet (12H)

3,3ppm Singlet + Triplet (8 H)

4.2 ppm triplet (4H)

7.2 to 7.8ppm massif (16H)

TLC:

SiO ₂ -Plaque Extraction Agent Toluene 80 Rf = 0.6

Acetone 20

c) Preparation of N, N'SN-tetratosyl-methyl-1-10-tetraazacyclododecane

In a 11-neck three-neck round bottom flask, a solution of 17.5 g of N, N'-ditosyldiamino-1,2-propane in 500 ml of dry DMF is stirred at ambient temperature for a quarter of an hour. 33 g of previously pulverized Cs ₂ CO ₃ are added in suspension of this solution. This suspension is brought to 55 ^C by means of an oil bath in an inert atmosphere.

At this temperature, a solution of 35 g of N, N'-ditosyl-bis (2-tosyloxyethyl) ethylenediamine in 200 cm ^{3 of} DMF is added dropwise within 2 h. After the addition is further heated for 48 h. Subsequently, the DMF is removed by vacuum distillation. The residue is poured into a water-CH ₂ Cl ₂ mixture.

The organic phase is dried over Na ₂ SO ₄ . The solvent is removed by distillation in a rotary evaporator.

The residue is stirred hot in 200 ml of ethyl acetate. The resulting product is crystallized. It is spun and then dried for 24 h at 60 ⁰ C and under vacuum.

Mass obtained = 22.5g yield = 61%

Melting point = 274/275 ° C.

1ppmDublett (2H)

2.2ppm Singlet (12H)

3 to 3.8 ppm massive (15 H)

7.2 to 7.9ppm Massive (15H) Aromat

TLC:

SiO ₂ extractant toluene = 80 Rf = 0.56 acetone = 20

d) Preparation of 2-methyl-1,4,7,10-tetraazacyclododecane

In a 11-necked, 3-neck round bottom flask equipped with a thermometer, an argon flask and a magnetic stirrer, a solution of 72.5 g of the lower compound obtained in 300 ml of 98% H ₂ SO _{4 for} 48 h by means of an oil bath heated to 100 ° C in inert atmosphere.

The reaction mixture is cooled to ambient temperature and within one hour of 800ml Et ₂ O, cooled to 0 ⁰ C, was added using a Glycolethylenbades and compressed dry ice.

The highly hygroscopic sulfate is precipitated. Under nitrogen, it is carefully thrown over sintered glass, and then quickly dissolved in 200 ml of water. This solution is made alkaline (with NaOH plates) and then extracted five times with 100 ml CH ₂ Cl ₂ .

All organic phases are dried over Na ₂ SO ₄ , brought to dryness and give 15 g of highly viscous crude product which crystallizes over time.

Yield = 90%

CDCI ₃ 1.1ppm doublet (2H)

Spectrum in + D ₂ O 2,7ppm2Singuletts

in the massif (19H, 4 interchangeable)

TLC:

Al ₂ O ₃ -Plaque extractant BuOH 50 Rf = 0.8

H ₂ O 25 ACOH 11

e) Preparation of the 2-methyl-1,4,7,10-tetraazacyclododecane-N, N ', N ", N"' - tetraacetic acid complex with 2KCl

In a 250 ml three-neck round bottom flask, a solution of 34 g of chloroacetic acid in 150 cm ^{3 of} water is cooled to 10 ° C. in an ice bath. At this temperature, 20 g of potash are added to produce the salt from the acid.

Subsequently, the compound prepared under d) is dissolved in the solution. The reaction mixture is brought to 65 ⁰ C by means of an oil bath.

At this temperature and at a pH between 8 and 10, a solution of 20 g KOH in 50 cm ^{3 of} water is added very carefully within 6 h.

The mixture is then further heated for 72 h, then the reaction medium is acidified by means of concentrated HCl to the pH of 2.5.

The complex fails. It is spun on sintered glass, rinsed with 50 cm ^{3 of} water and then dried at 60 ⁰ C for 18 hours in a drying oven.

Mass obtained = 30g yield = 66%

Melting point> 300 ° C

f) Purify the 2-methyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

30 g of the complex obtained under e) are brought into suspension in the presence of 150 cm ^{3 of} the previously regenerated resin IRA958.

After dissolution of the complex, this suspension is added to the top of a column of 150 cm ³ resin IRA958.

With the aid of a 5% acetic acid solution in water is eluted.

The fractions containing the expected pure product are brought to dryness to completely remove the acetic acid.

Received mass = 18.4g

Yield = 89%

Acidity = 100.3% (4 equivalents) Determination with NaOH 0.1M.

TLC:

SiO ₂ extractant ACOET 12 Rf = 0.36

Isopropanol 35

NH ₃₁ H ₂ O 30 mass spectrum FAB mass peak M + 1 = 419

Example 7 Preparation of a solution of the gadolinium complex of 2-methyl-1,4,7,10-tetraazacyclododecane-N, N ', N ", N"' - tetraacetic acid (methylglucamine salt)

21 g (50 μmol) of the compound obtained in Example 6 and 9.05 g (25 mmol) of gadolinium oxide are dissolved in 50 ml of double-distilled water which has been degassed at 70 ° C. After one hour, the dissolution is complete, the pH is close to 3. After cooling, the pH is adjusted to 7.3 with methylglucamine. It is made up to 100 ml and filtered over a Millipore membrane of 0.22 μιη. The result is a solution with a Gd content of 0.5 mol / l. This solution has a viscosity below 4mPa · s at BJ ⁰ C (free Gd was not detected).

Example 8: Preparation of 2-hydroxymethyl-1,4,7,10-tetraazacyclododecane-1,4,7,1-triacetic acid

a) Preparation of N, N'-ditosyl-2,3-diaminopropionic acid

To a solution of 46 g of sodium hydroxide in 500 cm ^{3 of} water, 40 g of monochlorohydrate of 2,3-diaminopropionic acid are added with constant stirring. There are 200 cm ³ of ethyl ether and then added over one hour gradually 110,5gTosylchlorid. It is stirred for 12h. The precipitate formed is spun dry and then clarified in water and ethyl ether. The solid is suspended in one liter of water and then acidified with 6N HCl. After filtering and washing in water and ethyl ether, the solid material is dried for 24 hours at 6O ⁰ C and under vacuum.

Received mass: 76 g Yield: 65% Melting point: 200-201 ° C TLC: SiO ₂ CH ₂ Cl ₂ 80 / MeOH 20 Rf: 0.5

- 2.4ppm singlet 6H (CH _{3 of the} tosyl group)

- 2.8 ppm massive 3 H (CH ₂ , CH of the diamine chain)

- 3.5 to 5ppm solid mass 3H exchangeable with D ₂ O.

- 7.2 to 7.8 ppm of multiple 8H aromatics

b) Preparation of N, N'-Ditosyl-2,3-diaminopropanol

In a 21-necked ^three- necked round bottom flask, a suspension of 40 g of the compound obtained under b) in 600 cm ^{3 of} THF at 20 ⁰ C in anhydrous and inert atmosphere is stirred (argon).

A solution of 500 ml of BH ₃ : THF 1 M in the course of half an hour in an inert atmosphere is added. The temperature of the reaction mixture increases to 30 ⁰ C. It is stirred for 48 h. The hydrolysis is carried out very gently with 20 ml of water. The THF is removed by distillation in vacuo. The organic phase is washed in water, dried over Na ₂ SO ₄ and brought to dryness. The residue is triturated in isopropyl ether until crystallization. After spinning and drying, 35 g of product are obtained.

Yield: 90%

Melting point: 126-127 ⁰ C

Thin Layer Chromatography: SiO ₂ CH ₂ Cl ₂ 90 / MeOH 10

Rf: 0.6

- 2.7ppm singlet ,, CI) ₃ "of tosyl (6H)

- 3 to 3.7ppm multiple «(7H, 2 of them interchangeable)

- 6.9ppm triplet OH alcohol interchangeable (1 H)

- 7.3 to 7.9ppm Multiple Aromatics (8H)

c) Preparation of N, N ', N ", N"' - tetratosyl-2-hydroxymethyl-1,4,7,10-tetraazacyclododecane

In a 2 l three-necked round bottom flask under argon 35 g of the compound obtained under b) are dissolved in 11 anhydrous DHF and then mixed with 58.6 g of anhydrous Cs ₂ CO ₃ .

This suspension is stirred for one hour at ambient temperature and then heated to 65 ° C using an oil bath. At this temperature, a solution of 69g N, N'-ditosyl-bis (2-tosyloxyethyl) ethylenediamine in 600cm ^{3 of} anhydrous DMF is added dropwise over 6h. One night, the temperature is maintained at 65 ⁰ C; the DMF becomes

removed by vacuum distillation. The residue is again placed in a mixture of 400ml of water and 400 cm ³ of dichloromethane. The organic phase is decanted, washed with 200 cm ^{3 of} water, dried over Na ₂ SO ₄ and then brought to dryness. The remaining oil is dissolved at 8O ⁰ C in 200cm ³ of toluene and then allowed to crystallize in the refrigerator for 48h long. It produces 24g product.

Yield: 32%

Melting point: 143-145 ⁰ C

Thin Layer Chromatography: SiO ₂ CH ₂ Cl ₂ 90 / AcOEt 10 Rf: 0.5

2,4ppm singlet 12H CH ₃ tosyl

3.2 to 4.1 ppm Mass 17H CH ₂ Ring + CH ₂ -OH

7.2 to 8.1 ppm Multiple 16H aromatics

d) Preparation of 2-hydroxymethyl-1,4,7,10-tetraazacyclodecane

20 g of the lower) compound are dissolved in 100 cm ^{3 of} 98% H ₂ SO ₄ . This mixture is kept for 48 hours in an inert atmosphere at 100 ° C. Then, the reaction mixture is cooled and added dropwise to one liter of ether while cooling with a bath of compressed dry ice and acetone. The sulfate precipitate of the amine is thrown over sintered glass and then clarified in ethyl ether. The solid is immediately dissolved in 200 cm ³ of water; The solution is alkalized with NaOH to pH> 12 and brought to dryness. After drying the solid residue in vacuo and in the presence of P ₂ O ₅ , the product is extracted twice in 100 cm ^{3 of} THF in the reflux. The evaporation of the extraction fractions leads to a colorless oil.

Received mass: 4.5g output

Yield: 90%

Thin layer chromatography: Al ₂ O ₃ BuOH 50 / water 25 / AcOH 11

Rf: 0.8

NMR (CDCIs spectrum) 2.8ppm singlet (17H) + triplet 3.8ppm singlet interchangeable (5H)

e) Preparation of 2-hydroxymethyl-i, 4,7,10-tetraazacyclododecane ^ JJO-triacetic acid

In a three-necked round bottom flask of 250 cm ^3, equipped with a magnetic stirrer and heating device, a temperature probe and a pH Meßgerätelektrode which is again connected to a pH-analog meter and a Reagenszusatzgerät according to the pH value of the medium is a solution from 8.5 g of the compound obtained under d), 15.8 g of 2-chloroacetic acid and 100 ml of water with the aid of a solution of 15.8 g potash in 50 cm ^{3 of} water to pH 9.5 neutralized. The reaction mixture is then kept at 50 ^° C. for 72 hours by means of an oil bath, with the pH remaining being adjusted constantly to 9.5 with a potash solution. The mixture is cooled, acidified to pH 5, diluted to 500cm ^3, and extracted over a column of 500cm ³ of the previously regenerated strong anion exchange resin IRA958. The ; Alkylation products are bound by the resin. This resin is rinsed with water and then eluted with fractions of 5% acetic acid. The fractions are brought to dryness. The residue is a crude powder, which is on Präparatir HPLC column with a diameter of 40 and filled with an implanted silica gel RP. 10 is cleaned.

Weight obtained: 3,5g pure product.

  · Yield: · '. · 22%. '. - ... , '- · _

Melting point: ''. · T42-144 ° C ''. · '. · -.

Thin-layer chromatography: SiO ₂ AcOEt 12 / isopropanol 35 / NH ₄ OH 30 Rf: 0.35

Acidity: 198.7% (2 waves)

Determination with NaOH 0.1 M corrected with H ₂ O Mass spectrum FAB peak at m + 1 = 377

Example 9: Preparation of a solution of the gadolinium complex of 2-hydroxymethyl-1,4 _> 7,10-tetraazacyclododecane-4,7,10-triacetic acid

A suspension of 11.05 g 2-hydroxymethyl-1,4,7,1O-tetraazacyclododecane-triacetic acid ^ J.IO and 5.07 g of gadolinium oxide in double distilled water is maintained at 80 ⁰ C for one hour.

After cooling, the pH is adjusted to 7.3 by the addition of sodium hydroxide and the amount is made up to 100 ml. The total content of gadolinium is determined by means of atomic emission spectrometry (0.28 M / l).

Example 10: Preparation of 2-hydroxymethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid In a 50 cm ³ reactor equipped with a magnetic stirrer, a solution of 0, 7g 2-hydroxymethyl-1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid and 0.28 g of chloroacetic acid in 15 cm ^{3 of} water to 70 ⁰ C heated.

The pH adjusted to 10.5 with a potash solution is maintained at 70 ° C for 48 hours.

At the end of the reaction, the pH is brought to 5, after which the solution is eluted with a resin IRA958.

The ligand is chromatographed over resin on elution with 5% acetic acid.

After the product has been brought to dryness, it is purified by preparative HPLC (RP18 implanted silica gel).

This gives 0.15 g of ligand with a yield of 18%.

Thin Layer Chromatography (silica gel) Extractant ethyl acetate 12 isopropanol 35 Rf = 0.25

NH ₃₁ H ₂ O 30 Mass spectrum FAB peak at M + 1 logo CNRS logo INIST

Example 11: Preparation of 2- (2-hydroxyethyl) -1,4,7,10-tetraazacyclododecane-N, N ', N ", 1'-tetraacetic acid This ligand is prepared as described in Examples 8-10 Procedure in the synthesis of 2-hydroxymethyl-1,4,7,10-tetraazacyclododecane-N, N ', N ", N"' - tetraacetic acid based on 3,4-diaminobutanoic acid (see Kasina et al., J. Biol. Med. Chem., 29, 1933, 1986).

Example 12: Preparation of 2-methyl-1,4,7,10,13-pentaazacyclopentadecane-4,7,10,13-tetraacetic acid (product 12a) and the 2-methyl-1,4,7,10,13- pentaazacyclopentadecane-1,4,7,10,13-pentaacetic acid (product 12b)

a) Preparation of 1,4,7, 10JS-pentatosyl-1-methyl-1-methyl-pentaazacyclopentadecane

Into a 21-neck, 3-neck round bottom flask equipped with a cooling and mechanical stirrer are added 35.7 g (0.093 mol) of N, N'-ditosyl-1,2-diaminopropane, 75.7 g of cesium carbonate (0.23 mol) and 800 ml DMF given.

The medium is placed under argon and heated to 75 ° C.

In the course of 4 hours at 75 ° C, a solution of 83g (0.012 mol) of 1,1 i-mesyloxy-S ^^ - tritosyl-S ^^ - triazaundecan, prepared according to Richman and Atkins Organic Synthesis 58, p 86, in 700 ml of DMF.

The reaction medium is held at 75 ° C for 48 hours, then filtered and the solution concentrated to dryness.

The residue is redissolved in 700 ml of ethanol, the solid filtered and then added to hot 800 ml of toluene.

The solid is filtered at ambient temperature and then dried at 60 ⁰ C.

Manures: M: 45.4g Yield: 49% Analysis: Thin Layer Chromatography: SiO ₂ 60 F254 Merck Extractant CH ₂ Cl ₂ / acetone 98: 2 Rf = 0.45 Mass Spectrum Method DCI (NH ₃ ) Mass peak at 999.

b) Preparation of 2-methyl-1,4,7,10,13-pentaazacyclopentadecane

44 g (0.44 mol) of the compound obtained under a) are held for 72 hours in 130 ml of concentrated sulfuric acid at 100 ° C.

After cooling, the reaction mixture is poured into a mixture of 250 ml of ethyl ether and 250 ml of ethanol of ⁰ ° C.

The solid material is filtered, dissolved in 250 ml of water and then treated with soot.

The solution is alkalized by means of sodium hydroxide and then extracted with CH ₂ Cl ₂ .

The organic solution is dried over Na ₂ SO ₄ and brought to dryness.

The resulting amine can be used in this form or as a hydrochloride.

One obtains: M = 8.4g starting form. M = 13.2g in the form of 5HCl. Yield: 72.8%. , . ·

Analysis of the chlorohydrate:

Thin Layer Chromatography: Al ₂ O ₃ F254 Merck Extractant: Ethanol / Isopropylamine 80:20

Iodine developer Rf = 0.85

NMR: = 1.7 ppm 3HCH ₃ = 3.7 ppm 19 H CH ₂ and CH

c) Preparation of the 2-methyl-1,4,7,10,13-pentaazacyclopentadecane-4,7,10,13-tetraacetic acid (product 12a) and the 2-methyl-1,4,7,10,13-pentaazacyclopentadecane i, 4,7,10,13-pentaacetic acid (product 12b)

In a 500 ml three-neck round bottom flask, a solution of 25.7 g (0.27 mol) of chloroacetic acid in 50 ml of water with the help of potash to pH = 5 and T <10 ⁰ C is set.

10 g of the compound (10.043 mmol) obtained under b) in solution in 20 ml of water are added to this solution.

The medium is heated to 55 ° C and 50ml 5M Potash is added within 48 hours to pH 8.5-9.5.

After the addition, the heating is maintained for one night.

The reaction mixture is cooled and acidified to pH 3.

The solution is then eluted over 200 ml DOWEX 5Ow resin.

By elution of the resin with 11 of an ammonia solution 1 M, 20 g of crude product.

The crude product dissolved in 150 ml of water is eluted over 250 ml of resin IRA958.

The resin is washed in water, then eluted with 21% acetic acid 0.1M and then with 21% acetic acid 0.8M.

Concentration of the acetic acid 0.1 M gives 9 g of crude product 12a.

Concentration of the acetic acid 0.8 M gives 2.5 g of crude product 12 b.

Subsequently, products 12a and 12b are purified by preparative HPCL over silica gel RP18.

Mana contains: Product 12a: M = 5g

Product 12b: M = 1.1g Yield: 30% Analysis: Thin Layer Chromatography: SiO ₂ 60 F254 Merck

Extractant: ethyl acetate / isopropanol / NH ₃ (30%) / 12-35-30

Developer: iodine

Product 12 a Rf: 0.4

Product 12 b Rf: 0.27

Water Determination:

Produkt12a: KF: 1.8%

Produkt12b: KF: 2.8%

Acidity determination by means of NaOH 0.1 M

Product 12a: 2 Specific Acidities

Titer: 99.6%

Produce 12 b: 3 certain acidities

Titre: 97.3%

Mass spectra FAB

12a PeakM + 1 =

12b PeakM + 1 =

Claims (3)

claims: 1. A process for the preparation of complexes formed from ligands of the formula HOOC COOH 0). HOOC in the R-I is a radical of the formula - (CH ₂ ) m-CH-CH- Rq R7 where Re is either an alkyl group with C ₁ -C ₁₄ , a hydroxyalkyl group with C ₁ -C ₄ , a polyhydroxyalkyl group with C ₁ -C ₄ or a group of the formula CH - COOH -GH. R ₄ ] N CH - COOH ι 11 *? R ₂ - ~. COOH wherein R _{11 is selected} from the Α groups and the groups of the formula - (CH ₂ ) tYAY- (CH ₂ ) t- is selected, and A is selected from the alkylene group with Ci-C ₈ , the hydroxyalkylene group with C ₁ -C ₈ and the polyhydroxyalkylene group with C ₁ -C ₈ , Y is either -C-O- or -O- and t is 1 to 4, R _{7 is} either a hydrogen atom, an alkyl group with C ₁ -C 14, a hydroxyalkyl group with C ₁ -C ₄ or a polyhydroxyalkyl group with C ₁ -C ₄ , m is 0 or 1,
R2 / F $ 3 / R ₄ are identical or different and are a radical of the formula - ((pH) p "pH Re Rg represent wherein R ₈ and R _{9 are the} same or different and represent either a hydrogen atom, an alkyl group with C ₁ -C ₁₄ , a hydroxyalkyl group with C ₁ -C ₄ or a polyhydroxyalkyl group with C ₁ -C ₄ , ρ = 1 or 2, η = 0.1 or 2 and R _{5 is} either a hydrogen atom, an alkyl group with C ₁ -C ₄ , a hydroxyalkyl group with C ₁ -C ₄ or a polyhydroxyalkyl group with C ₁ -C ₄ , and Z is either an oxygen atom or a group of the formula wherein R _{10 is} either a hydrogen atom, an alkyl group with C ₁ -C ₁₄ , a hydroxyalkyl group with C ₁ -C ₄ , a polyhydroxyalkyl group with C ₁ -C ₄ , a group of formula -CH-COOH, in turn R _{5 has the} meaning given above R ₅ , or a group of the formula CH - COOH CH - COOH H. CH - COOH I ^R 5 wherein R 1 is selected from the alkylene group with C ₁ -C ₈ , the hydroxyalkylene group with C ₁ -C ₈ and the polyhydroxyalkylene group with C ₁ -C ₈ , with metal ions such as the ions of the lanthanides (atomic numbers 57 to 71), the ions the transition metals (atomic numbers 21 to 29) and the ions of the metals with atomic numbers 55, 56, 82 and 83, and with the salts of these complexes with pharmaceutically acceptable inorganic or organic bases or basic amino acids, characterized in that a compound of the formula X-CH-COOH (II) R ₅ in which R _{5 has the} abovementioned meaning and X represents a labile group or an aldehyde of the formula R ₅ -CHO (Ha) in which R _{5 has the} above meaning, in the presence of hydrocyanic acid or cyanide ions with an annular amine of the formula HH i j _ j- _R4 _ reacts, in which R ₂ , R ₃ , R ₄ and η have the abovementioned meaning, Ri is a radical of the formula - (CH ₂ L-CH-CH-R ' ₆ R7 wherein R ' _{6 is} either an alkyl group with Ci-C ₁₄ , a Hydroxyalkyigruppe with Ci-C ₄ , a Polyhydroxyalkylgruppe with Ci-C ₄ or a group of the formula R- ^H 11 in which in turn R ₂ , R ₃ , R ₄ , R 7, R n, m and η have the above meaning and Z 'is an oxygen atom or a group of the formula / * - R ' _1O wherein FT _{10 is} a hydrogen atom, an alkyl group with C ₁ -C 14, a hydroxyalkyl group with C ₁ -C ₄ , a polyhydroxyalkyl group with C ₁ -C ₄ or a group of the formula H H R ₁ R - Π -, Μ '- --Ώ' - * Μ ^{12 2} ι in which R ₁ , R ₂ , R ₃ , R ₄ , R 12 and η have the abovementioned meaning and ligands are reacted with a salt or an oxide of the metals in an aqueous solvent and optionally neutralized to form a salt , 2. The method according to claim 1, characterized in that the compound of formula (III) by reaction of a polyamide of the formula R '
R'HN- [R ₄ -N] _n -R'i-NHR '(IV) in which R ₁ and R _{4 have} the stated meaning and with a compound of formula XR ₂ -NR ₃ -X R ' (V) in which R ₃ , R ₂ and R 'have the stated meaning and X represents a labile group is prepared. 3. The method according to claim 1, characterized in that the compound of formula (III) by reaction of a diamine of the formula R'H N-RS-NH-R '(X) in which R '•, and R' have the meaning given, with a compound of the formula