SI8810742A - Process for the preparation of the new nitrogen-containing cyclic ligands,metallic complexes formed by these ligands and diagnostic composition containing these 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

GUERBET S.A. FR-1/237

FRANCE

PROCEDURE FOR THE PURCHASE OF NEW CYCLIC NITROGEN LIGANDS AND METAL COMPLEXES BASED ON LIGANDS

Technical field of the invention

The invention relates to the field of synthetic chemistry and relates to the production of new metal complexes with cyclic organic ligands.

A technical problem

A technical problem that is solved by the present invention is the process of obtaining new metal complexes with cyclic organic ligands.

The process provides the recovery of complexes formed from ligands of the general formula:

Ra

HOOC HOOC -

r ₅ 1 * 5 I 1 CH I 1 CH - I l N - (R ₄ - l - N) n _x N - R ₂ - I - Z 1 CH J r ₅

COOH ^R 1 where represents a radical of the formula:

- ( ^CH 2) m - ^CH - ^CH "

R ₆ R7

Rg is selected from the group consisting of: C1-C14 alkyl, C1-C4 hydroxy alkyl,

C1-C4 polyhydroxyalkyl and the group of the formula:

^r 5 ^r 5

I I

CH-CCOH CH-COOH l t

^X Z - R ₂ - NO

CH - COOH l

^r 5

Ril consists of group A and group of the formula:

- (CH ₂ ) _t -YAY- (CH ₂ ) _t Λ is selected from the group consisting of:

C1-Cg alkylene, C1-C3 hydroxyalkylene and C1-C3 polyhydroxyalkylene

Υ is -C-0 | and t is from 1 to 4

Oh

R7 is selected from the group consisting of:

H, C 1 -C 4 alkyl group, C 1 -C 4 hydroxyalkyl group, and C 1 -C 4 polyhydroxyalkyl group, m is 0 or 1

R2, R3 and R4 are the same or different and represent a radical of the formula:

- (CH) p - CH -

II ^r 8 ^r 9

Rg and Rg are identical or different and are selected from the group consisting of H, ^ - ^ 4 alkyl, CJ-C4 hydroxyalkyl group and a ^C l ^-c 4 polihidroksialkilno group, p is 1 or 2 n is 0, 1 or 2 and R5 is selected from the group consisting of:

H, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, and a C1-C4 polyhydroxyalkyl group, and

Z is selected from the group consisting of: H, O and a group of the formula:

r = NR ₁₀

R ^ O is selected from the group consisting of:

H, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, and a C1-C4 polyhydroxyalkyl group, and a group of the formula: -CH-COOH, wherein R5 is as indicated above | ^r 5 and a group of the formula:

R ₅

I

CH-COOH l

JN - R ₄ ) _n

- R ₁₂ - N - R ₂ ^r 5

I

CH-COOH ' ^N \

- N

I

CH - COOH

R ^R 12) ^is selected ^{from the} group consisting of C-Ce alkylene group, a C -C hidroksialkilenske group and a ^C l ^-C 8 polihidroksialkilenske groups and with metal ions selected from lanthanide ions with atomic numbers 57 to 71, from transition metal ions with an atomic number of 21 to 29, from metal ions with an atomic number of 55, 56, 82 and 83, as well as to obtain salts of these complexes with mineral bases, or with organic pharmaceutically acceptable bases or basic amino acids.

The state of the art

Cyclic nitrogen ligand-formed metal complexes of the above general formula (I) have never been described in the literature to date, and therefore no data are available for their production.

Description of solution to a technical problem

The procedure was implemented as follows. First, we made the ligands of formula (I) above by reacting a compound of formula:

X-CH-COOH

I II ^R 5 where R 5 is as described above and X represents a labile group such as chlorine, bromine or iodine or a tosyloxy group or a mesyloxy group, with a cyclic amine of formula

H H

I 1 / N - ( ^r 4 - N \ n

R ₃ R'i III ^ N - R ₂ t

H where R ₂ , R 3, R ₄ and n are as described above:

R 1 represents a radical of the formula:

- (CH ₂ ) m-CH-CHR'6 ^r 7

R'g is selected from the group consisting of a C 1 -C ₄ alkyl group ^c 1 ' ^c 4 hydroxyalkyl group, a C 1 -C 4 polyhydroxyalkyl group, and a group of the formula:

(N

R ₇ - CH

RH- CH

Z '~

where R ₂ , R 3, R 4, above, and Z 'is

R ₇ , R 11 m and n are as described 0 or a group of the formula:

N-R'io

R 10 is H, a C1-C14 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 polyhydroxyalkyl group or a group of the formula:

- (R ₄ - N) _n ^R 1 X

- R _i2 - N - R ₂ - NO

H where Ri _# R ₂ , R 3, R 4, Ri ₂ and n are as described above.

The ligands of formula I can also be obtained by means of a Strecker reaction by reaction of a cyclic amine of formula III with an aldehyde of formula:

R5-CHO Ila wherein Rg has the meaning described above, in the presence of hydrocyanic acid or a cyano ion (KCN, NaCN) in general.

Compound of Formula III wherein Z 'is a group = N - Rio can be obtained:

a) by reaction of a polyamine of formula R '

I

R'HN - (R ₄ - N) _n - R ^ -NHR 'IV wherein n, R'i, and R ₄ are as described above, and R' represents a sulphonyl, mesyl or benzene sulfonyl group of the formula

XR ₂ -NR ₃ -XV

R 'where R ₂ , R ₃ , and R' are as described above, and X represents a labile group such as tosyloxy, mesyloxy or chlorine, bromine or iodine atom, or

b) by reaction of an amine of formula

R'HN - R *! - NH - R X where R'i and R 'are as described above with the compound of the formula:

R 'R'

X- (R ₄ - N) _n - R ₃ -NR ₂ -X

XI

This cyclization is preferably carried out in the presence of a phase shift catalyst.

Polyamines of formula IV can also be obtained by starting with dihydroxylamine according to the following scheme:

H

I

HO - (R ₄ - N) _n - R'i - OH VI

R'Cl / pyridine

R '

I

R'0 - (R ₄ - N) _n - R ¹ ! - OH 'VII

NaN3 / CH ₃ CN / H ₂ O

R '

I

N ₃ - (R ₄ - N) _n - R *! - N ₃ VIII reduction of H ₂ Pd / C

R '

H ₂ N - (R ₄ - N) _n - R *! - NH ₂ IX

R'Cl / pyridine

R '

R'HN - (R ₄ - N) _n

R ¹ ! - NHR '

IV

In one embodiment, the phthalimide compounds of formula VII are reacted with the compounds of formula IX.

The compound of formula II contains two nitrogen atoms in the ring and can be obtained by the procedure described above.

For example by reaction of a polyamine of the formula:

XII

CHo - CH CHo - CH / 1 l \

R'NH NHR 'R'NH NHR' where A and R 'have the meaning described above, with a compound of formula XI, to give a compound of formula III, wherein R 1 is group A.

The polyamine of formula XII can be obtained by starting at the tetrahalogen derivative by nucleophilic substitution in the presence of sodium azide and then by reduction in the presence of hydrogen and palladium on carbon.

Compounds of formula I having two oxygen atoms in the ring and where there is a group can be obtained by condensation of the compounds of formula.

EtOOC COOEt

XIII

CH-A-CH

EtOOC COOEt with polyamide of formula,

H H H l l I

H ₂ NR ₂ -NR ₃ -N- (R ₄ -N) -H

XIV followed by reduction in diborane, following the procedure of Tabushi et.al. (Tetra Letters 12, 1049, 1977).

Compounds of formula I having at least two nitrogen atoms in the ring can also be prepared by starting with the compound of formula III in the two steps described above.

Compounds of formula I having two nitrogen atoms in the ring can also be obtained by condensation of a compound of formula I wherein R1 is a radical of formula:

- (CH ₂ ) _m -CH-CHR ₆ R 7 where R 8 is a hydroxyl group, with a compound having a bifunctional activity of the formula:

Χχ-Λ-Χΐ where X is ^ COOH, COC1 or an anhydrous acid.

A compound of formula I wherein two nitrogen atoms are present in the ring can also be obtained by condensation of a compound of formula:

HOOC-CH

R ₅ where R 6 is a radical of formula

- (CH ₂ ) _m - CH - CH JJR ₆ r ₇ where m and R _{7 have} the aforementioned meaning, R 8 is selected from the group consisting of C 1-4, hydroxyalkyl group C 3-4, polyhydroxyalkyl group C ^ _4:

with a compound of the formula:

X-R _'12 -X XVI where X is as described above and R'i ₂ represents a protected group R ^ _{2 The} compounds of the formula are thus obtained:

R ₅ r ₅ ^r 5 ^r 5

HOOC-CH

CH-COOH

HOOC-CH l

CH-COOH

HOOC-CH

-CH-COOH ^r 5 ^r

The present invention also provides a process for the production of complexes formed by ligands of formula I with metal ions selected from lanthanide ions with an atomic number of 57 to

71, of transition metal ions with an atomic number of 21 to 29, of ions Mn ²⁺ , Fe ³⁺ and Cr ³⁺ , of metals with an atomic number of 55, 56, 82 and 83, as well as for the salts of these complexes with mineral or organic pharmaceutically acceptable bases or basic amino acids.

In these complexes, the desired ions are gadolinium, Europe, dysprosium, iron (Fe ³⁺ ) and manganese (Mg ²⁺ ).

Suitable salts, for example, are those which are upgraded with sodium hydroxide, N-methylglucamine, diethylamine, lysine and arinine.

The complexes can be obtained by reacting the ligand with the salt or oxides of the metals in aqueous solution and possibly neutralizing them due to the formation of the salt.

It can be said that the present invention encompasses only ligands of formula I and previously defined complexes in the form of a racemic mixture, and equally stereoisomers of these ligands and complexes.

The complexes of the present invention may be attached to another macromolecule capable of fixation as desired to an organ. This means that the complexes of the present invention can be protein-bound and in particular antibodies.

They are also easily encapsulated, especially in liposomes.

The complexes of the present invention upgraded with paramagnetic ions and their salts with pharmaceutically acceptable bases can be used as contrast agents for magnetic resonance imaging and as agents for chemical changes in vivo.

Complexes of the present invention superimposed with lanthanide ions (order numbers 57-71) or metal ions with the sequence numbers 55, 56, 82 and 83 or their salts with pharmaceutically acceptable bases can be used for contrast in X-ray radiography. For this effect, especially desired complexes are upgraded with ions of the following metals: Gd,

Er, Dy, Tb, Ce, La, Ba, and Cs.

In addition, the present invention includes a method for the preparation of a diagnostic tool, which is introduced into the human body, characterized in that it is essentially a complex upgraded with a Formula I ligand with metal ions selected from lanthanide ions, ions transition metals and metal ions with the sequence numbers 55, 56, 82 and 83, as well as salts of these complexes with meineral or organic bases, pharmaceutically acceptable or base acids in pharmaceutically acceptable form.

According to the present invention, these preparations can be prepared in the form of aqueous solutions where water is a solvent of a physiologically acceptable complex.

The diagnostic preparations obtained by the present invention can be administered in the following ways:

- parenterally, intravenously, intraarterially, intralymphatically and subcutaneously

- orally

- intrabronchial in aerosol form

- interconnected

- Local for visual observation of openings (such as uterus)

In magnetic resonance imaging, dosages are highly variable depending on the route of administration.

For intravenous or intraarterial administration, the dose is about 0.01 to 2 mM / kg.

In oral administration, the dose may be up to 10 mM / kg.

For other forms of administration, doses below 1 mM / kg are used, and for administrations under arachoid brain membrane, doses are below 0.05 mM / kg.

When used for in vivo chemical change agents and contrast agents in radiology using X-rays, the doses are the same, whereas for intravenous and intra-arterial administration, the doses are less than or equal to 5 mM / kg.

In addition, the complexes of the present invention are upgraded with ligands of formula I with radioactive ions whose salts with bases are pharmaceutically acceptable, useful as diagnostic agents or in therapy in nuclear medicine. Examples of radioactive ions are radioisotopes of elements such as copper, cobalt, gallium, germanium, indium and especially technetium (Tc 99 m).

The following examples illustrate the preparation of a compound of the present invention.

In the following cases, the terms and designations used shall mean:

NMR spectra recorded on a 60 MHz Varian EM 360 apparatus with TMs internal reference. The solvent is CDC1 ₃ unless otherwise noted.

The IR spectra were recorded on a Perkin-Elmer 1320 apparatus.

Solid substitution spectra are recorded in the form of KBr lozenges. In the case of liquid (oil), the spectra are recorded without solvent.

The term buffer as used herein, in the description of thin layer chromatography, means a mixture of 1.5 M NH ₄ OH and 1.5 (NH ₄ ) ₂ CO ₃ .

The melting points were determined on a Kofler apparatus. The terms used for doses during complexation the absence of Gd ³⁺ free and the free ligand indicate the detection limits of the methods used, that is, between 4 and 5 ppm (parts per million) for Gd ³⁺ and the ligand.

1. Example

2,6-Dimethyl-1,4-7,10-tetraazacyclododecane-N, N ', N, N' tetraacetic acid

a) N-Tosyl-bis (2-tosyloxy) amine

A solution of 53.2 g (0.4 mol) was added dropwise to a solution of 248 (1.3 mol) chloride sulphated in 200 cm ^{3 of} pyridine at 0 ^e C.

O dsopropanolanol in 50 cm, at a temperature between 0 and 5C.

The mixture was left at this temperature for 72 hours and then poured into two liters of water-ice mixture containing o

250 cm of concentrated HCl.

The suction derivative was extracted with 2 L of methylene chloride. The organic phase was poured onto sodium sulfate, filtered and decolorized on black 3SA, not filtered again on a layer of silica. The solvent was evaporated to leave 193.8 g of a yellow oil (81% yield; Rf = 0.7 silica / CH2Cl2 / acetone / 98/2), which was used in the following reactions without first purification.

η

Η NMR (nuclear magnetic resonance imaging) 6H CH3 (doublet 1.2 in 1.3 ppm); 9H CH3 sued (2.5 ppm singlet); 4H CH2 (center multiplet at 3.3 ppm); 2H CH (quadriplet between 4.7 and 5.1 ppm); 12H aromatics (multiplet 7.3 and 8 ppm).

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

In 193.8 g (0.032 mol) of the compound obtained in step a), 1.2 l acetonitrile and 300 cm ³ , 65.1 g sodium azide (1 mol) was added. The mixture was stirred and heated at 75 ^e C for 48 hours. After cooling, the acetonitrile was evaporated in vacuo.

The residue was taken up in methylene chloride and the organic phase was washed with water, dried, filtered on a layer of silica (200 g), and after evaporation 82 g of a pale yellow oil (75% yield; Rf = 85 silica) were left

CH2Cl2 / acetone / 92/2) which was sufficiently pure for immediate further use.

IC N3 spectrum = 2100 cm ^- ! · Intense.

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

82.2 g (0.244 mol) of the compound obtained in step b) was poured _3 into 500 cm3 ethanol containing 8g of carbon on palladium (5% at 50% humidity).

The mixture was thoroughly stirred and hydrogen (evacuation of nitrogen released) was passed through. After 8 hours at room temperature, CCM showed us the absence of nitrogen function. The mixture was then filtered and evaporated to give 68.4 g of a light yellow oil (yield 98.5%, Rf =

0.6 silica / MeOH / NH ^ H 95/5), which was used in the next step without further purification.

NMR: 6H CH3 (doublet 0.9 in 1 ppm); 3H CH3 sued (singlet at 2.4 ppm); 6H CH2 and CH (massive complex between 2.7 and 3.2 ppm); 4H aromatics (multiplet between 7.1 and 7.7 ppm).

d) N-tosyl-bis / 2 (tosylamino) propyl / amine

In 68.4 g (0.24 mol) of the amine from step c) in 500 cm ^{3 of} methylene chloride and 700 cm ³ (0.5 mol) of triethylamine at 0C, 93 g (0.5 mol) of sulphide of chloride were added in doses. After complete addition, the mixture was left at room temperature for 6 hours, stirring. The reaction mixture was washed with 600 cm ³ of water, the organic phase is dried, evaporated to dryness and the residue chromatographed on a silica gel column with methylene chloride, then with a mixture of methylene chloride: methanol 98: 2nd the desired fractions were evaporated and the residue in solid form was recrystallized in ethanol. Filtration and drying gave 99.1 g of the final product (70%).

NMR: 6H CH3 (doublet 0.9 in 1 ppm); 9H CH3 sued (singlet at 2.4 ppm); 4H 0¾ and CH (triplet centered at 2.9 ppm); 2H CH (doublet 3.3 and 3.5 ppm); 12H aromatics (multiplet centered at 7.4 ppm).

e) N-tosyl-bis {2-tosyloxy ethyl) amine

A solution of 32.5 g (0.31 mol) was added to a solution of 185g (0.97 mol) of sulphide of chloride in 200 cm ^{3 of} pyridine at 0 ° C.

O Diethanolamine in 60 cm of pyridine at such a rate that the temperature did not exceed 5'C. After addition, the temperature of the mixture was maintained at this temperature for 1 hour and then poured into 20 cm ^{3 of} ice water during thorough stirring. After filtration, washing and drying, 148.4 g of sediment were obtained (85% yield; R _f = 0.6 silica / CH2Cl2 / acetone / 98/2).

NMR: 9H CH ₃ sued (singlet at 2.4 ppm); 4H CH ₂ (triplet centered at 3.4 ppm); 4H CH ₂ O (triplet 4.1 ppm); 12H aromatics (multiplet centered between 7.1 and 7.7 ppm).

f) Tetratosyl-2-6-dimethyl-1,4,7,10-tetraazacyclododecane g (0.11 mol) of the compound obtained in step d) in 500 cm3 of dry DMF was maintained at room temperature under controlled release of hydrogen was added dropwise to a vessel containing 8.8 g of 90.22 mol) of 60% NaH in oil in 50 cm ^{3 of} DMF. After the addition was complete, the mixture was heated to 100 “C and a solution of 68.1 g (0.12 mol) of the compound was added dropwise.

O obtained in step e) in 500 cm of dry DMF. The reaction mixture was maintained at this temperature for 24 hours with thorough stirring.

The solvent was then evaporated in vacuo and the residue re-introduced into a mixture of CH ₂ Cl ₂ / H ₂ O. The organic phase was washed with water, dried and evaporated to dryness. The residue (100 g) was recrystallized in isopropanol then in propanol to give 36 g of a white solid after filtration, washing with isopropyl ether, (yield 40%; Rf - 0.5-0.6 silica / CH ₂ Cl ₂ / acetone / 98/2).

NMR: 6H CH ₃ (doublet at 1 and 1.2 ppm); 12H CH ₃ sued (2.4 ppm singlet); 14H CH ₂ and CH (massive between 3 and 4.5 ppm); 16H aromatics (multiplet centered between 7.1 and 7.7 ppm).

g) N, N ', N, N ^, -tetratosyl-2-6-dimethyl-1,4,7,10-tetraazacyclododecane (variant)

To a suspension of 17 g (28.7 mmol) of the compound obtained in step d)

A solution of freshly prepared sodium ethylate (60 mmol) was quickly added to 100 mL of ethanol at reflux temperature.

About 200 cm dry DMF. The resulting turbid mixture was left at reflux for half an hour and then the solvents were evaporated to dryness and the residue was taken up in 200 cm < ³ > DMF and the solution was heated to 100C. To this solution, a solution of 17 g (30 mmol) of the compound from step e) in 100 o cm DMF was added over a half hour. The reaction mixture was maintained at 100C overnight and the organic phase product was chromatographed on a silica gel column with the eluant Cl2Cl2 / ethyl acetate 98/2.

The product was recrystallized from isopropyl ether and measured after drying. 13.5 g of product were obtained (yield 58%; Rf = 0.5-0.5 silica / CH ₂ Cl ₂ / acetone / 98/2).

The NMR spectrum is the same as in step f).

h) the 2,6-dimethyl-1,4,7,10-tetraazacyclododecane g compounds of step f) or of step g) were suspended

O in 80 cnr of 98% sulfuric acid and the suspension was heated for 72 hours at 100 ° C under argon. After cooling, the reaction mixture was added dropwise to 1 liter of ethyl ether at 0 ^e C. The resulting 2.6-dimethyl-1,4,7,10-tetraazacyclododecane sulfate was filtered, put into water, neutralized with Na ₂ CO ₃ and extracted with CH 2 Cl 2. The organic phase was evaporated to dryness, 6 g of the obtained product was used in the following steps without further purification.

(Yield 74%; Rf = 0.65 alum / butanol / water / acetic acid / 50/25/11.

NMR: (D ₂ O) 6H CH ₃ (doublet at 0.9 to 1 ppm); 14H CH ₂ and CH (center multiplet at 2.5 ppm).

i) 2,6-Dimethyl-1,4-7,10-tetraazacyclododecane-N, N ', N ⁿ , N' -acetic acid

To a solution of 3 g (15 mmol) of the compound obtained in step h) v

A mixture of 5.7 g (mmol) of monochloro acetic acid and 3.4 g (60 mmol) of potassium hydroxide in water was added to the water.

About cnr water. The resulting mixture was heated to 60C and a solution of KOH 2.4 g (60 mmol) n 25 cm ^{3 of} water was added while maintaining the pH between 9 and 10. The addition was continued for 8 hours, while maintaining the temperature unchanged for 24 hours after addition. After cooling, the pH was adjusted to 2.5 with concentrated HCl. The resulting precipitate was filtered off, washed with ice water and measured after drying. 3 g of product were obtained. (Yield 35%; Rf = 0.33 silica / ethyl acetate / isopropanol / ammonia / 12/35/30.

This compound corresponds to the 2,6-dimethyl-1, 4-7,10tetraazacyclododecane-Ν, Ν ', N, N'-tetra acetic acid complex with 2KC1.

9.5 g of the complex were eluted with 200 cm ^{3 of} 10% acetic acid on an ion-exchange resin IRA 95 (OH), which was previously regenerated with IN NaOH and washed with water until neutral. The resulting fractions were evaporated to dryness and taken 3 times

About 50 cnr of water to eliminate acetic acid traces. The resulting residue was treated with ether to give 6.3 g of a solid product after filtration and drying.

Yield 89%.

NMR: (D ₂ O) 6H CH ₃ (doublet 1.4 in 1.5 1 ppm); 14H CH ₂ and CH (massive complex centered at 3.6 ppm); 8H CH ₂ COOH (doublet at 3.8 ppm).

2. Example

21.

The Gadolini Complex

2,6-dimethyl-1,4,7,10-tetraazacyclododecane-Ν, Ν ', N, N' tetraacetic acid (methylglucamine salt)

A suspension of 5.425 g (12.54 mmol) of 2,6-dimethyl-1,4,4,7,10tetraazacyclododecane-Ν, Ν ', N, N ¹ -tetraacetic acids obtained in Example 1 and 2.27 g of Gd2C> 3 (6.27 mmol) in 125 cm ^{3 of} water was heated to 65'C within 24 hours. Then, by adding methylglucamine, the pH was adjusted to 7. After evaluating free Gd ³⁺ (using xineol / orange / EDTA) 650 mg of 2,6-dimethyl-l, 4,7, 10-tetraazacyclododecane-Ν, Ν 'were added. , N, N'tetraacetic acids (1.5 mmol) to complex the remaining Gadolini. The end of complexation is determined by the absence of free Gd ³⁺ (evaluated using xineol orange) and free complex (complexometric evaluation are.

Cu *). The total presence of Gadolini in the solution was evaluated by emission atomic spectroscopy on DCP using a Spectrospan 4 Beckman apparatus.

Quantitative yield Rf = 0.49 silica / ethyl acetate / isopropanol / ammonia / 12/35/30.

3. Example

2-Hexyl-1,4,7,10-tetraazacyclododecane-N, N ', N, N'-tetra of acetic acid

a) N- (2-hydroxyethyl) -N- (2-hexyl-2-hydroxyethyl) amine g (0.39 mmol) epoxy-1,2-octane was added dropwise

O in 250 cm (4 mol) of ethanolamine at 100C. The temperature was maintained for 1 hour after completion of the addition, and then the excess ethanolamine was distilled off in vacuo. The residue was recrystallized from 600 cnr hexane and then filtered m dried. 69 g of a solid were obtained (mp (melting point; translation) <45'C; yield 93%; Rf = 0.82 silica / butanol / H ₂ O / acetic acid / 50/25/11).

NMR: 3H CH3 (triplet 0.9 ppm); 10H CH ₂ (broad singlet

2.2 ppm); 7H CH ₂ and CH (small singlet at 2.8 and 3.8 ppm).

b) N-tosyl-N- (2-tosyloxy ethyl) -N- (2-hexyl-2-tosyloxy-ethyl) amine

To a solution of 156 g (0.82 mol) of sulphurous chloride in 300 cm ^{3 of} pyridine at 0 ° C was added 47.3 g (0.25 mol) of the compound obtained in step a) of this case in small doses for one hour. The temperature of the mixture was maintained at 0 ° C for 2 days, then poured into a 2: 1 mixture of ice and HCl. The product was extracted with CH ₂ C1 ₂ is then chromatographed on a silica gel column with CH ₂ C1 _2nd 118 g of product were obtained. (Yield 72%; Rf = 0.6 silica / CH ₂ Cl ₂ / acetone / 98/2).

NMR: 3H CH3 chain (triplet at 0.9 ppm); 10H CH ₂ chain (broad singlet at 1.3 ppm); 9H CH3 sued (singlet at 2.4 ppm); 4H CH2N (triplet at 3.4 ppm); CH ₂ O and CH (massive at

4.2 ppm); 12H aromatics (massive between 7 and 7.7 ppm).

c) N-tosyl-N- (2-azidoethyl) -N- (2-hexyl-2-azidoethyl) amine g (0.133 mol) of compound b) of this example and 29.25 g (0.45 mol) of sodium azide were mixed with 350 cm acetomtril m 80 cm water. The mixture was maintained at 65 &lt; 0 &gt; C for three days and then the acetonitrile was evaporated. The residue was mixed with CH ₂ C1 ₂ ; The organic phase was washed in water, dried and evaporated to give 50% yellow oil, which was used in the following steps without further purification. (Yield 95%; Rf = 0.75 silica / CH ₂ Cl ₂ / acetone / 98/2).

NMR: 3H CH3 chain (triplet at 0.9 and 0.9 ppm); 10H CH ₂ chain (massive at 1.4 ppm); 3H CH3 sued (singlet at 2.4 ppm); 5H CH ₂ and CH (massive complex at 3.4 ppm); 4H aromatics (massive between 7.1 and 7.7 ppm).

IR (infrared spectrum; Transl.); N3 = 2100 cm ^-1 strong.

d) N-tosyl-N (2-tosylaminoethyl) -N- (2-hexyl-2-tosylaminoethyl) amine

To a solution of 61.5 g (0.18 mol) of the compound of this example step d) in 500 cm &lt; ³ &gt; CH ₂ C1 ₂ and 52.5 cm &lt; ³ &gt; (0.38 mol) of triethylamine at 0 &apos; C was added 68.6 g (0.36 mol) of sulphurous chloride. After stirring for two hours at room temperature. . . . . At 1 temperature, the reaction mixture was treated with 500 cm3 of water. The organic phase was washed with water, dried and evaporated, and the oily residue was chromatographed on a silica gel column with CH ₂ Cl ₂ . The resulting oil was evaporated after evaporation of the solvent with isopropyl ether to give 60 g of solid (mp 120'C; yield 51%; R _f = 0.6 silica / CH ₂ Cl ₂ / MeOH 98/2).

NMR: 3H CH3 chain hexyl (mass poorly explained with center at 1 ppm); 9H CH3 sued (singlet at 2.4 ppm); 7H CH ₂ and CH (massive centered at 3.1 ppm).

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

A mixture of 46.5 g (71.5 mmol) of the compound of Example 2 step d),

41.5 g (73 mmol) of the compound of Example 1, step e) and 24 g (70 mmol) of tetrabutylammonium hydrosulfate were added to a suspension of 400 cm ³ toluene and 200 cm ³ 20% Na ₂ CO ₃ . The suspension was stirred vigorously for 24 hours at 70 * C. After cooling, the organic phase was washed with water, dried and evaporated. The residue was recrystallized in ethanol and then chromatographed on a silica gel column with CH2C1 _second 35 g of solid (mp 154-161 ^e C) were obtained. Yield 56%; Rf = 0.55 silica / CH ₂ Cl ₂ / acetone 98/2).

NMR: 3H CH ₃ chain (triplet at 0.9 ppm); 10H CH ₂ chain (massive at 1.3 ppm); 12H CH ₃ sued (singlet at 2.4 ppm);

15H CH ₂ and CH rings (massive at 3.3 ppm); 16H aromatics (multiplet between 7.1 and 7.7 ppm).

g) 2-hexyl-1,4,7,10-tetraazacyclododecane g (13 mmol) of the compound obtained in step f) of this example

O was heated at 100'Cv 40 cm for 98 hours with 98% sulfuric acid in an argon atmosphere. After cooling, the mixture was added dropwise into 500 ml of ethyl ether at 0 ° C. The resulting sulfate was filtered and then neutralized with 10% sodium carbonate solution and extracted with CH ₂ Cl ₂ . The organic phase was dried with sodium sulfate, then evaporated to give 2g of a firm cream. (Yield 57%; R _f = 0.75 alumina / butanol / water / acetic acid 50/25/11).

The compound was kept in the form of oxalate, which was obtained by reacting the ethanolic solution of oxalic acid with 2-hexyl1,4,7,10-tetraazacyclododecane overnight at room temperature. Oxalate appeared as a solid white precipitate.

h) 2-Hexyl-1,4,7,10-tetraazacyclododecane-N, N ¹ , N ', N' tetra of acetic acid

A solution of 1.09 g (2 mmol) of oxalate obtained in step g (neutralized with 470 mg (8.4 mmol) of KOH in 13 cm of water in 20 ml of ethanol was added to this solution. Potassium monochloroacetate freshly prepared from 1.063 g (11.25 mmol) was added to this solution. acetic acid monochloro, 630 mg (11.25 mmol) KOH in 20 cm ^{3 of} water.

The reaction mixture was heated to 60 &lt; 0 &gt; C and the pH was maintained between 8 and 10 by the addition of KOH. Within 3 hours, 100 cm ^{3 of} water containing 630 mg KOH was added. After 3 hours of reaction, 141 mg (1.5 mmol) of chloro acetic acid and 84 g (1.5 mmol) of KOH were added. The temperature of the mixture was maintained at 60 ^e C. for two more days. After cooling and acidifying to pH

2.5 (HJC1 6N) solution was introduced through a column of OH resin IRA 958 (Trademark). Elution with 100 cm ^{3 of} 10% formic acid gave 700 mg of product. Directly discharged water was concentrated and treated again on identical choline.

After the same treatment, 2.5 g of product were obtained. (Yield 38.4%;

Rf = 0.65 silica / ethanol / buffer 2/1).

NMR: (D2O) 3H CH3 chain (triplet 0.9 ppm); 10H CH2 chain (massive at 1.4 ppm); 15H CH2 and CH cyclic (massive at 3.3 ppm); 8H CH2COOH (singlet at 3.9 ppm).

4. Example

Gadolinium complex 2-hexyl-1,4,7-tetraazacyclododecane-N, N ', N', N tetraacetic acid

488.6 mg (1 mmol) of the compound obtained in Example 3 and 181.3 mg (1 molar metal) of gadolinium oxide were suspended in 40

Leave m cm water at 65C for 2 days. During the reaction, evaluation of free gadolinium allowed us to monitor the complexation flow. After the complexation was complete, the solution was filtered on Millipore paper and then evaporated to dryness and crystallized in ethyl ether. 550 mg of white solid were obtained (Yield 85.5%; R _f = 0.65 EtOH / buffer 2/1).

5. Example

Gadolinium 2-hexyl-1,4,4,7,10-tetraazacyclododecane-N, N ', N', N 'tetraacetic acid complex (methylglucamine salt)

486.6 mg (1 mmol) of the compounds of Example 3 and 181.3 mg (1 meq. Metal) of gadolinium oxide were suspended in 40 cm ^{3 of} water and left at 65 C C for 12 hours. Methylglucamine was added to the clear solution so that the pH was 7.4. To make it easier to monitor the complexation process, methylglucmin is added after the ligand is added. completion of complexation was determined by the absence of free Gd ³⁺ (evaluation with xylene phenol) and free ligand (evaluation with copper). The total Gadolini content of the solution was evaluated by atomic emission spectroscopy on a Spectrospan 4 Beckman apparatus. Rf = 0.65 in EtOH / buffer 2/1.

6. Example

2-Methyl-1,4,7,10-tetraazacyclododecane-N, N ', N ¹ , N' tetra of acetic acid

a) N, N'-Ditosyl-1,2-diaminopropane

In a three-pan vessel equipped with a magnetic stirrer, thermostat and chlorine protection, 14.8 g of 1.2diaminopropane were dissolved in 500 ml of CH 2 Cl 2 and 58 cm ^{3 of} Et ³ N.

Within one hour, 80 grams of sulphurous chloride were added in doses. Keeping the temperature at 20 “C required cooling, which was provided with an ice bath.

The reaction mixture was then stirred overnight at room temperature, then transferred to an ampoule of 1 l capacity and washed with 2 x 250 cm ^{3 of} water.

The organic phase was dried over Na ₂ SO ₄ , evaporated to dryness and crystallized in isopropyl ether.

66 g of product were obtained (Yield 86%; m.p. 98-100 ° C).

NMR ppm doublet (3H) 3.1

2.4 ppm singulet (6H) 5.5 2.9 ppm doublet (2H) 7.1-7 ppm massive (1H) ppm singulet variable (2H) 8 ppm aromatic (8H)

CCM SIO ₂ (silica); eluent CH ₂ Cl ₂ / MeOH 90/10 R _f = 0.75

b) N, N'-Ditosyl-bis- (2-tosyloethoxyethyl) ethylene diamine

In a 500 cm ^{3 three-} pan vessel equipped with a magnetic stirrer, thermostat and chlorine protection, a solution of 162 g of sulphurous chloride in 3200 ml of pyridine was cooled to 0'C using an ice bath.

Within two hours, 29.6 g of bis (hydroxyethyl) ethyldiamine were added in doses. The temperature was kept below 5'C. The reaction mixture was stirred at this temperature for 4 hours, allowed to stand in the refrigerator at 6-8 ° C for 48 hours, and then at room temperature for 4 hours.

The reaction mixture was placed in 1 liter of ice, water and 300 ml of concentrated acid. The product was extracted with Na ₂ SO ₄ and then evaporated to dryness. The residue was placed in warm water.

250 cm of ethanol. The product was crystallized, filtered through a porous glass and dried at 60C for 48 hours. We got

107.5 g of product (Yield 70%; m.p. 138-140C).

NMR

2.4 ppm singlet (12H)

3.3 ppm singlet + triplet (8H) 4.2 ppm triplet (4H)

7.2-7.8 ppm massive (16H)

CCM: SIO ₂ (plate) eluent: toluene / acetone 80/20. R _f = 0.6

c) N, Ν ', N', N '”- tetratosyl-2-methyl-l, 4,7,10-azacyclododecane

A solution of 17.5 g of N, N'ditosylamino-1,2-propane in 500 ml of dry DMF was stirred for 15 minutes in a triplicate container of volume 1 L at room temperature and then 33 g of the CS2CO3 in question were added. In an inert atmosphere, the suspension was heated to 55C using an oil bath

At this temperature, a solution of 35 g of N, N'-ditosyl-bis (2-tosylethyl) ethylene dismine in 500 ml of dry DMF was added dropwise over two hours. After the addition was complete, the temperature was kept constant for 48 hours. The DMF was then removed by vacuum distillation. The residue was obtained in a mixture of water / CH ₂ Cl ₂ .

The organic phase was dried with Na ₂ SO ₄ . The solvent was removed by distillation on a rotary evaporator.

The residue was mixed in warm 200 ml of ethyl acetate and the product was allowed to crystallize. After drying, it was dried in vacuo at 60 ° C for 24 hours.

We obtained 22.5 g of product (Yield 61%; m.p. 274-275'C).

NMR ppm doublet (2H)

2.2 ppm singulet (12H)

3-3.8 ppm massive (15H)

7.2-7.9 ppm massive (16H) aromatic

CCM: SIO ₂ eluent: toluene / acetone 80/20. Rf = 0.56

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

In a three-lattice tank of 1 l capacity, equipped with a magnetic stirrer, thermostat and argon inlet, we heated in an inert atmosphere with an oil bath for 48 hours at 100'C, a solution of 72.5 g of the compound of step c) of this example in 300 ml 98 % H ₂ SO ₂ .

The reaction mixture was then cooled to room temperature and 800 ml of Et ₂ O cooled to 0 ° C was added after 1 hour using ethylene glycol and solid CO ₂ .

The precipitate, which is a very hygroscopic sulphate, was deposited on a porous glass, in a nitrogen atmosphere, and then quickly dissolved in 200 ml of water. This solution was alkylated with NaOH lozenges and then extracted with 5 x 100 ml CH ₂ Cl ₂ .

The combined organic phases were dried with Na ₂ SO4 and then evaporated to dryness to give 15 g of the crude product, in the form of a highly viscous liquid, which crystallized over time. 90% yield.

NMR CDC1 ₃ 1.1 ppm doublet (2H)

NMR D ₂ 0 2.7 ppm 2 singulets massive 4 variable

CCM Boards A1 ₂ O ₃ eluent BuOH 50 R _f = 0.8 h ₂ o 25 ACOH 11

e) 2-methyl-1,4,4,7,10-tetraazacyclododecane-N, N ', N, N'-tetra acetic acid complex with 2KC1

In a 250 ml three-necked vessel, cooled to a solution of 34 g of chloroacetic acid in 150 cm of water at 10′C using an ice bath. At this temperature, 20 g of KOH was added to build up the acid salt.

Then, the compound of step d) of this example was dissolved in this solution. The reaction mixture was heated to 65 ° C using an oil bath. The temperature was then maintained at this temperature for 6 hours and the pH was adjusted between 8 and 10 thereafter

However, a solution of 20 g of KOH in 50 cm of water was added.

The sediment-forming complex was deposited on a porous glass and dried in an oven for 18 hours at 60 ° C.

30 g of product were obtained (Yield 30 g; m.p. 300 “C).

f) purification of 2-methyl-1,4,4,7,10-tetraazacyclododecane-N, N ', N, N ¹ -tetra acetic acid g of the complex obtained in step e) of this example is

The suspension was suspended in the presence of 150 cm IRA 958 resin, which was previously regenerated.

After the complex was dissolved, the suspension was placed on top

O column containing 150 cm of IRA 958 resin. The elution was carried out using acetic acid solution in 5% water.

The fractions containing the product were evaporated to dryness to remove the initial acetic acid. We got

18.4 g of product (Yield 89%; Acidity 100.3 (4 equivalents)

it was determined using 0.1 M NaOH. CCM S1O2 eluent ACOET 12 isopropanol 35 nh ₃ , h ₂ o 30 FAB mass spectrum top of mass at M + 1 = 149

7.Example

Gadolinium complex solution 2-methyl-l, 4,7,10tetraazacyclododecane -N, N ', N, N'-tetra acetic acid (methylglucamine salt)

By degassing at 70 ° C, 21 g (50 mmol) of the compound of Example 6 and 9.05 g (25 mmol) of gadolinium oxide in 50 ml of bidestilled water were dissolved. After one hour, the dissolution was complete, the pH was close to 3, and after cooling it was adjusted to 7.3 with methylglucamine. 100 ml of the solution was filtered on a membrane with pores of 0.00022 mm. A solution was obtained, with a viscosity at 20 ^e C below 4 mPa containing 0.5 mol / 1 Gadolinium. We didn't detect Gadolini alone.

8. Example

a) N, N'-Ditosyl-2,3-diaminopropionic acid

To a solution of 46 g of Na ₂ CO ₃ in 500 cm ^{3 of} water, 40 g of 2,3-diano-propionic monochlorhydrate were added with thorough stirring.

O acids. After that, 200 cm of ethyl ether was added, followed by 110.5 g sulphurous chloride suction doses over one hour. Stirring was continued for 12 hours and the resulting precipitate was solidified, washed with water and ethyl ether. The resulting solid was suspended in 1 liter of water and acidified with 6N HCl. After filtration and washing with water and ethyl ether, the solid was dried under vacuum at 60C for 24 hours. Yield 76 g (Yield 65%; mp 200-201C. CCM: SiO ₂ CH ₂ C1 ₂ 80 / MeOH 20. R _f = 0.5 NMR

2.4 ppm singulet (6H) (CH ₃ groups of suits)

2.8 ppm massive (3H) (CH ₂ CH diamino chain)

3.5-5 ppm massive expanded 3H interchangeable with D ₂ O

7.2-7.8 ppm multiplet 8H aromatic

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

A suspension was stirred in a 3 l pan of 2 l capacity

O g of compound a) from this example in 600 cm THF at 20′C under an inert atmosphere (argon) without water.

THF IM was added to a solution of 500 ml of BH ₃ in an inert atmosphere over 1 hour and the temperature of the reaction mixture was raised to 30 ° C. Stirring was continued for a further 48 hours. Hydrolysis was performed carefully with 20 ml of water. THF was removed by vacuum distillation. The residue was extracted in a water / ether mixture. The organic phase was washed with water and dried with

At ₂ SO ₄ , then evaporated to dryness. The residue was crushed in isopropyl ether until crystallization. After drying and drying, 35 g of product were obtained. Yield 90%; mp 126-127'C;

CCM: Sio ₂ CH ₂ C1 ₂ 90 / MeOH 10; R _f = 0.6

NMR

2.7 ppm singulet (6H) (CH ₃ sues)

3-3.7 ppm multiplet (7H of which two are interchangeable)

6.9 ppm multiplet 8H aromatics

c) N, Ν ', N', N'-tetratosyl-2-hydroxymethyl-l, 4,7,10-azacyclododecane

In a nitrogen atmosphere atmosphere, 35 g of the compound b) from this example were dissolved in 1 liter of DMF anhydride, then 58.6 g of Cs ₂ CO ₃ anhydride was added.

This suspension was stirred for 1 hour at room temperature and then heated to 65'C using an oil bath. At this temperature, a solution containing 69 g of N, N′-ditosyl-bis (2-tosyloxy) ethylene was added dropwise over 6 hours.

O diamma in 600 cm DMF anhydride. The temperature was kept overnight at 65'C and the DMF removed in vacuo. The residue was taken up in 400 ml of water and 400 cm of dichloromethane. Organic phase o

was poured, washed with 200 cm3 of water, dried with Na ₂ SO ₄ and evaporated to dryness. The oil residue was dissolved at 80 ° C

O in 200 cm of toluene and then allowed to cool in the refrigerator for 48 hours. 24 g of product were obtained; Yield 32%; mp 143-145'C; CCM SiO ₂ , CH ₂ C1 ₂ 90 / AcOEt 10 R _f = 0.5.

NMR

2.4 ppm singulet 12H CH ₃ sued

3.2- 4.1 ppm massive (17H CH ₂ rings + CH ₂ -OH

7.2- 8.1 ppm multiplet 16H aromatic

d) The 2-hydroxymethyl-1,4,7,10-tetraazacyclododecane g of the compound of c) of this example was dissolved in 100 cm ^{3 of} 98% with H2SO4. This solution was heated at 100 ° C for 48 hours under an inert atmosphere. The reaction mixture was cooled and then added dropwise to 1 liter of ethyl ether cooled using a CO2 / acetone bath. The calibrated amine sulfate was precipitated on porous glass and washed with ethyl ether. The solid was immediately dissolved in 200 cm ^{3 of} water, the solution was alkylated with NaOH at pH 12 and evaporated to dryness. After drying the solid residue in the presence of P2O5 in vacuo, the product was extracted at reflux with 2 x 100 cm THF. The extracted fractions were evaporated to give a colorless oil (4.5 g of base); Yield 90%; CCM AI2O3 BuOH 50 / water 25 / AcOH 11. Rf = 0.8; NMR (CDCl3); 2.8 ppm singlet (17H) + triplet

3.8 ppm singulet interchangeable (5H)

e) 2-Hydroxymethyl-1,4,7,10-tetraazacyclododecane-4,7,10-three acetic acid

In a 250 ml three-pan vessel equipped with a magnetic stirrer, temperature probe and pH meter electrode, the solution was neutralized using a 15.8 KOH solution in 50 cm ^{3 of} water to control the pH of the medium.

8.5 g of the compound of step d) of this example, 15.8 g

2-chloroacetic acid and 100 ml of water to pH + 9.5. The reaction mixture was then warmed to 50 ° C with oil bath for 72 hours. The pH was maintained at 9.5 by KOH. The reaction mixture was cooled, acidified to pH 5, diluted to 500 cm and applied to an anion exchange resin column IRA 958. The alkylation products were bound to the resins, washed first with water, then eluted with fractions of 5% acetic acid and evaporated to dryness. The residue is a crude powder which was purified on a 40 mm diameter HPLC column containing silica RP.18. 3.5 g of pure product are obtained; Yield 22%; m.p. 142-144'C.

CCM: SiO ₂ EcOET 12 / isopropranol 35 / NH4OH 30 Rf = 0.35. Acidity: 198.7% (reliability 2).

Evaluation on NaOH 0.1 M - H ₂ O support.

FAB mass spectrum: peak at M + l = 377.

9.Example

2-Hydroxymethyl-1,4,4,10tetraazacyclododecane-4,7,10-three acetic acid gadolinium solution

A suspension of 11.05 g of 2-hydroxymethyl-1,4,7,10tetraazacyclododecane-4,7,10-three acetic acid and 5.07 g of gadolinium oxide in bidestilled water was heated at 80 * C for 1 hour.

After cooling and adjusting the pH, the volume was adjusted to 100 ml by adding K ₂ Og. The evaluation of the total presence of gadolinium was performed by atomic emission spectroscopy (0.28 M / l).

10. Example

2-Hydroxymethyl-1,4,7,10-tetraazacyclododecane-4,7,10-three acetic acid. 3. .

A solution of 0.7 g of 2-hydroxymethyl, 4,7,10-tetraazacyclododecane-4,7,10-three acetic acid and a solution of 0.7 g of 2-hydroxymethyl, 4,7,10-tetraazacyclododecane-4,7,10-three acetic acid were heated in a 500 cm reactor equipped with a magnetic stirrer.

Oh

0.28 g of chloro acetic acid in 15 cm of water, the pH was adjusted to 10.5 by addition of KOH at a temperature of 70 C C, which was maintained unchanged for 48 hours. Towards the end of the reaction, the pH was adjusted to 5 and the solution was eluted on IRA 958 resin. The ligand was chromatographed on resin (5% acetic acid). After evaporation to dryness, the product was purified by preparative HPLC (silica RP 18).

0.15 g of ligand (Yield 18%) is obtained.

CCM (silica) eluent ethyl acetate 12 isopropanol 35 Rf = 0.25 NH ₃ , H ₂ O 30

FAB mass spectrum; peak at M + l = 435

11. Example

2- {2-Hydroxyethyl-1,4,4,7,10,13-tetraazacyclododecane, Ν ', Ν, N' '- acetic acid tetra

This ligand was obtained according to the procedure described in Examples 8 and 10, for the synthesis of 2-hydroxymethyl-1,4,7,10-tetraazacyclododecane-Ν, Ν ', N, N'-tetra acetic acid, and for the starting compound 3 , 4-diamine butyric acid (S. Kasina et.al., J. Med. Chem. 29, 1933, 1986).

12. Example

2-methyl-1, 4,7,10,13-pentazacyclopentadecane-4,7,10,13tetra acetic acid (Product 12a), and

2-Methyl-l, 4,7,10,13-pentaazacyclopentadecane-l, 4,7,10,13 penta acetic acid (Product 12b)

a) 1,4,7,10,13-Pentatosyl-2-methyl-1, 4,7,10,13 pentazacyclopentadecane

In a three-volume vessel with a capacity of 2 l equipped with a mechanical mixer, 35.7 g (0.093 mol) of N, N'-ditosyl-1,2-diaminopropane, 75.7 g (0.23 mol) of cesium carbonate and 800 ml of DMF were added. The mixture was stirred in an argon atmosphere and then heated to 75 ° C.

At 75 [deg.] C. for four hours, the mixture was stirred

ΛΑ added a solution of 83 g (0.012 mol) of 1,11-mesyloxy-3,6,9tritosyl-3,6,9-triazaundecane synthesized by the Ricman and Atkins method, Organic Synthesis 58, p. 86 in 700 ml DMF. The temperature of the reaction mixture was maintained at 75 &lt; 0 &gt; C for a further four hours and then concentrated to dryness. The residue was taken up in 700 ml of ethanol and the solid was filtered and put into 800 ml of warm toluene. The solid was filtered at room temperature and then dried. 45.4 g of product were obtained.

Yield 49%.

CCM: SiO ₂ 60 F254 Merck Eluent CH ₂ C1 ₂ / acetone 98.2 R _f = 0.45 DCI method (NH ₃ ); peak mass at 999.

b) 2-methyl-1,4,4,7,10,13-pentaazacyclopentadecane g of compound a) from this example was heated at 100'C in 130 ml of concentrated sulfuric acid for 72 hours. After cooling, the reaction mixture was poured into a mixture of 250 ml of ethyl ether and 250 ml of ethanol at 0 ° C. The solid was filtered, then dissolved in 250 ml of water and then treated with carbon. The mixture was alkylated with Na ₂ CO 3 and then extracted with CH ₂ Cl ₂ - The organic solution was dried with Na ₂ SO 4 and evaporated to dryness.

The resulting amine can be used as such or in the form of chlorohydrate. 8.4 g of base product and 13.2 g of 5HC1 product were obtained. Yield 72.8%.

Chlorohydrate analysis: CCM: Al ₂ 0 ₃ F254 Merck.

Eluent: ethanol / isopropylamine 80:20; detects iodine; R f = 0.85 NMR: 1.7 ppm 3H CH ₃ ; 3.7 ppm 19H CH ₂ and CH.

c) 2-methyl-1,4,7,10,13-pentaazacyclopentadecane-4,7,10,13 acetic acid tetra (Product 12a); and

2-Methyl-l, 4,7,10,13-pentaazacyclopentadecane-l, 4,7,10,13 pent acetic acid (Product 12b).

In a triangular vessel with a capacity of 0.5 l, at a temperature below 5 C C, a solution of 25.7 g (0.27 mol) of chloro acetic acid in 50 ml of water was neutralized to pH 5 with 5M KOH.

To this solution was added 10 g (10.043 mol) of compound b) of this example dissolved in 20 ml of water.

The mixture was heated to 55 'and 50 ml KOH (pH 8.59.5) was added over 48 hours. After complete addition, the temperature was kept constant overnight. The reaction mixture was cooled and acidified to pH 3. The solution was then applied to 200 ml of DOWEX 50w resin. The resin was eluted with 1 dissolved ammonia to give 20 g of crude product which was dissolved in 150 ml of water and applied to 250 ml of IRA 958 resin. The resin was then washed and eluted with 2 liters of 0.1 M acetic acid and then with two liters of 0.8 M acetic acid.

Acetic acid concentration of 0.1 M gave 9 g of crude product 12a.

Acetic acid concentration of 0.8 M yielded 12.5 g of crude product 12b.

Products 12a and 12b were then purified by preparative HPLC RP18.

We obtained: Product 12a 5 g

Product 12b 1.1 g

Yield: 30%

Analysis:

CCM SiO ₂ 60F 254 Merck

Eluent: ethyl acetate / isopropanol / NH3 (30%) / 12.35.30 /

Proves: Iodine Product 12a R _f : 0.4 Product 12b Rf 0.27 Proof water Product 12a K _f : 1.8%

Product 12b Kj: 2.8%

Acidification with 0.1 M NaOH: Product 12a: 2 Acid Functions Titr: 99.6%

Product 12b: 3 acidic functions

Titre: 97.3%

FAB mass spectrum:

Product 12a peak at M + 1 = 462

Product 12b peak at M + l = 520 for

GUERBET S.A. FR Al

J

BEST MODE OF ECONOMIC APPLICATION OF THE INVENTED INVENTION AS KNOWN TO THE APPLICANT

In the applicant's experience, the following example may serve to this end.

Preparation of the 2,6-dimethyl-l, 4,7,10tetraazacyclododecane-Ν, Ν ', N, N'-tetraacetic acid gadolinium complex (methylglucamine salt)

A suspension of 5.425 g (12.54 mmol) of 2,6-dimethyl-l, 4,7,10tetraazacyclododecane-Ν, Ν ', N, N'-tetraacetic acid obtained in Example 1 and 2.27 g of Gd ^ a (6.27 mmol) in 125 cm ^{3 of} water was heated to 65'C within 24 hours. Then, by adding methylglucamine, the pH was adjusted to 7. After free Gd ^{3+ was} evaluated (using xineol / orange / EDTA) 650 mg of 2,6-dimethyl-1,4,7,10-tetraazacyclododecaneN, N ', N were added , N'-tetraacetic acid (1.5 mmol) to complex the remaining Gadolini. We determine the end of complexation

O 'due to the absence of free Gd (evaluated using xineol orange) and free complex (complexometric evaluation with Cu). The total presence of Gadolini in the solution was evaluated by emission atomic spectroscopy on DCP using a Spectrospan 4 Beckman apparatus. Quantitative yield Rf = 0.49 silica / ethyl acetate / isopropanol / ammonia / 12/35/30.

Claims (1)

1.) The process ensures the acquisition of the complexes that are formed from ligands with general ^R 5 | ^r 5 1 1 HOOC - CH 1 CH - COOH l [ N - (R ₄ - ^N ) n Z \ R3 ^R 1 \ Z N - 1 r ₂ - Z l HOOC - CH J «5 where R1 represents a radical of the formula: (CH ₂ ) _ro - ^CH - ^CH I I «6 R? R 8 is selected from the group consisting of: C 1 -C 6 alkyl, C 1 -C ₄ hydroxy alkyl, C 1 -C ₄ polyhydroxyalkyl and the group of the formula: ^r 5 ^r 5 1 I CH-COOH CH-COOH ^R 7 R _ir CH CH - COOH l ^R 5 Rij consists of group A and group of the formula: - (CH ₂ ) _t -YAY- (CH ₂ ) _t A is selected from the group consisting of: Cj-Cg alkylene, Cj-Cg hydroxyalkylene and Cj-Cg polyhydroxyalkylene Y is -C-O- and t is from 1 to 4 liters o R7 is selected from the group consisting of: H, a C ₁ -C ₄ alkyl group, a C 1 -C ₄ hydroxyalkyl group, and a C 1 -C ₄ polyhydroxyalkyl group, m is 0 or 1 R ₂ , R 3 and R 4 are the same or different and represent a radical of the formula: - (CH) p - CH - ^r 8 ^r 9 Rg and Rg are identical or different and are selected from the group consisting of H, Cf-C ₁₄ alkyl group or a C-C ₄ hydroxyalkyl group, and A C ₁ -C ₄ polyhydroxyalkyl group, p is 1 or 2 n is 0, 1 or 2 and R 5 is selected from the group consisting of: H, _Cf-C4 alkyl group or a C-C ₄ hydroxyalkyl group, and Cf-C ₄ polihidroksialkilno group, and Z is selected from the group consisting of: H, O and a group of the formula: N-R10 RfO is selected from the group consisting of: H, _Cf-C4 alkyl group or a C-C ₄ hydroxyalkyl group, and Cf-C ₄ polihidroksialkilno group, and a group of the formula: -CH-COOH, wherein R5 is as stated above and a group of the formula CH-COOH CH-COOH - R ₁₂ - k - k ₂ « CH - COOH ^r 12 3 ^θ selected from the group consisting of C ^ -Cg alkylene groups, C ^ -Cg hydroxyalkylene groups and ^c 1 ^_c 8 polyhydroxyalkylene groups and metal ions selected from lanthanide ions with an atomic number of 57 to 71, of transition metal ions having an atomic number of 21 to 29, of metal ions of an atomic number of 55, 56, 82 and 83, as well as of producing salts of these complexes with mineral bases, or with organic pharmaceutically acceptable bases or basic amino acids, characterized by by reacting compounds of the formula: X-CH-COOH 1 II ^r 5 wherein R 1 is as described above and X represents a labile group or an aldehyde of the formula: R _{5 is} CHO wherein R 8 is as described above, in the presence of hydrocyanic acid or cyanide ion, with a cyclic amino of the formula: H H I t ~ ( ^r 4 - N \ n Rq R'-i III \ Z> N - R ₂ - Z l H where R ₂ , R ₃ , R 4 and n are as described above: R'f represents a radical of the formula: - (CH ₂ ) _m -CH-CHI JK * 6 ^r 7 R'g is selected from the group consisting of Cf-C ^ ₄ alkyl, ^C l ~ ^C 4 hydroxyalkyl group, and Cf-C ₄ polihidroksialkilno group and a group of the formula H. (N R ₇ - CH I R _X1 - CH R ₄ ) _n -N (CH 2> m Z'- where R ₂ , R ₃ , R ₄ , above, and Z 'is H R 7, R 6 and m and n are as defined 0 or a group of the formula: N-R'10 R'fO is H, Cf-C | _{A 4} alkyl group, a Cf-C ₄ hydroxyalkyl group, a Cp-C ₄ polyhydroxyalkyl group or a group of the formula: H H I I - (R ₄ - H) _n ^R 1 ^ 3 - Rl2 - N 'R ₂ - »where Rf, R ₂ , R3, R4, Rf ₂ ^{n are} as described above and then the ligand of formula I reacts with the salt or oxide of the aforementioned metals in an aqueous solvent and then, due to salt formation, neutralization is possible.