EP1430036A1

EP1430036A1 - Novel method of preparing nitrogen macrocycles

Info

Publication number: EP1430036A1
Application number: EP02783226A
Authority: EP
Inventors: Frédéric BOSCHETTI; Franck Denat; Roger Guilard; Henry Ledon; Hervé CHOLLET; Jean-Louis Babouhot
Original assignee: Centre National de la Recherche Scientifique CNRS; Commissariat a lEnergie Atomique CEA
Current assignee: Centre National de la Recherche Scientifique CNRS; Commissariat a lEnergie Atomique et aux Energies Alternatives CEA
Priority date: 2001-09-28
Filing date: 2002-09-27
Publication date: 2004-06-23
Also published as: JP4699693B2; CA2461344A1; US20040206940A1; WO2003029228A1; FR2830253A1; US7312327B2; FR2830253B1; JP2005508930A

Abstract

The invention relates to a method of preparing nitrogen macrocycles having formula (I). The inventive method comprises a step involving the reaction of compounds (II) and (III) in order to form a compound having formula (IV). Said compound is subsequently made to react with a compound having formula (V) in order to form a compound having formula (VI). The latter compound is then subjected to an acid treatment.

Description

New process for the preparation of C-functionalized nitrogen macrocycles and new intermediates obtained.

The chemistry of cyclic polyamines, and in particular of tetraazacycloalkanes whose two main representatives are 1, 4,7,10-tetraazacyclododecane (cyclene) and 1, 4,8,11-tetraazacyclotetradecane (cyclame), a experienced considerable development. The derivatives of these polyazamicrocycles find applications in fields as varied as the purification of liquids, catalysis or medicine. Cyclene is, for example, the basic motif of many contrast agents in medical imaging. The N-functionalization of these macrocycles and the study of the complexing properties of the new ligands thus obtained have been the subject of numerous works.

The selectivity of the macrocycle with respect to a given substrate depends on the nature, the number and the relative position of the chelating arms. Most applications require the attachment of macrocycles, either on a solid support or on an antibody. The synthesis of molecules containing both a complex site, such as a nitrogenous macrocycle carrying adequate chelating arms, and a reactive termination allowing grafting onto an antibody or onto a solid support has been the subject of numerous publications and requests. patent over the past decade. However, such bifunctional chelating agents (BCA or BFC) are difficult to prepare, in particular when it is necessary to condense different functional groups with the nitrogen atoms of the cycle.

Many more or less selective N-functionalization methods of tetraazacycloalkanes have been described. However, most of them require either the use of a large excess of the basic macrocycle, which is still relatively expensive, or the tedious implementation of successive sequences of protection and deprotection of reaction sites.

Another approach consists in introducing the arm allowing grafting on a carbon atom of the macrocyclic skeleton then the chelating arms on the nitrogen atoms. The latter seems better suited to the synthesis of these bifunctional chelating agents because it allows on the one hand to conserve the four secondary amino functions without altering the properties of the macrocycle and on the other hand easily attach four chelating arms during a stage of total functionalization. This approach was applied in the synthesis of numerous bifunctional chelating agents, some of which, represented in FIG. 1, are used in clinical trials on human and / or marketed beings (BAT, p-NCS-Bz-DOTA, p -NH ₂ -Bz-DOTA). However, it remains limited by the delicate synthesis of C-functionalized macrocycles.

Indeed, a synthesis by formation of a C-C bond on the macrocycle is not possible. It necessarily involves the use of a synthon carrying the desired functional group or an intermediate allowing access to it. Several cyclization methods have been developed. None are general and do not allow access to cyclam, cyclene or other macrocycles.

In the case of cyclam derivatives, the method most used to date is that of Tabushi et al., Represented by scheme 1, based on the condensation of a linear tetraamine with a functionalized diethyl malonate ¹ . The acidity of the hydrogen atoms of the methylenic group allows an easy functionalization of the diester. The diamide obtained is then reduced to yield the C-functionalized cyclam. Many C-substituted cyclams at the carbon atom in position 6 have been synthesized by this ^{2 "11} pathway. This approach has also made it possible to obtain biscyclams linked by ^{12" 14} carbon atoms and the synthesis of 1, 4,7,10-tetraazatridecanes (2223) C- functionalized ³ ' ¹⁵ ' ¹⁶ . Finally, the anchoring of cyclic tetraamines to organic polymers was carried out according to this reaction scheme ^17,18 . The main advantage of this method is the possibility of introducing very diverse functional groups onto the macrocycle. However, it has many drawbacks: it cannot be applied to the cyclene series, it requires a step of reduction of the intermediate diamide carried out with a large excess of borane, and the reaction times are long, up to 20 days for the 'cyclization step. Furthermore, the reaction yields remain low despite the optimization of the cyclization conditions ^19,20 .

Another method, represented by scheme 2, which consists of Michael's addition of a linear tetraamine on a coumarin or on an acrylate derivative ethyl, then a reduction in borane of the cyclic amide obtained, made it possible to obtain cyclams C - functionalized in position 5 with a phenol, ni-trophenol ^21,22 , pyridine ²³ , imidazole ^{24 group} . hydroxypyridine ²⁵ or triphenylphosphine ²⁶ . The disadvantages of this method are the same as those of the method of Tabushi et al. ; the cyclization stage lasts three weeks at reflux in ethanol, the cyclization yield is low (8 to 40%), and the intermediate amide must then be reduced.

The synthesis of 4-nitro benzyl cyclene (p-N0 ₂ -Bn-cyclene), precursor of 2- (4-nitro benzyl) 1, 4,7,10, tetrakis (carboxymethyl) cyclene (p-NH ₂ -Bn- DOTA), has been the subject of several publications and patent applications ^{5> 27 "30.} The synthesis represented by scheme 3, involves synthons N-substituted by groups of tosyle type and is directly inspired by the method d obtaining cyclene according to Richman and Atkins ³¹ Other C-fonT3 cyclenics: idealized were also obtained by this method ^{32 "36} If the cyclization yields are generally good, we find here the drawbacks of the Richman method and Atkins, the drastic detosylation conditions, the sulfonamide intermediates and the uneconomical aspect in terms of atoms involved ("non atom economy"), to which is added the difficulty of obtaining C-functionalized synthons. This approach has also been used for the synthesis of cyclams functionalized at positions 6 ^37,38 or 5 ³⁹ or of C-substituted tetraazacycloalkanes of larger dimensions ^37,38,40 .

Another access route to macrocycles consists in using an external support, usually a metal cation, to bring the building blocks into a conformation favorable to the cyclization reaction. We then speak of a "flat effect". This approach allows an efficient synthesis of cyclam ^41.42, has also been proposed for obtaining C-functionalized macrocycles. The most used synthesis, represented by diagram 4, involves intermediaries of the Schiff base type ⁴³ . Cyclization is most often carried out with nitroethane or diethyl malonate. Copper II complexes based on cyclam (2323) but also on macrocycles of different sizes (2223), (2333) or (3333), C-substituted by ester functions or nitro groups have thus been obtained ^{43 "46} . Free ligands mono- or di- C-functionalized with acid or amino groups have also been obtained from these complexes ^{47 "50.} Bismacrocycles have also been synthesized in this way ^51. The subsequent functionalization of the cyclam carrying an amino group for example allows access to new macrocycles C-substituted ^52. The yields observed during cyclization reactions vary from 15 to 75% depending on the compounds targeted.The disadvantages of the method lie in the elimination of the metal ion which requires conditions limiting the choice of functional group introduced and in its impossibility to be adapted to the cyclene series The use of Fe III as a support has recently made it possible to obtain several C-arylated cyclenes with yields of 40% to 70% ^53,54 .

Finally, some authors describe the synthesis of C-functionalized cyclenes according to high dilution conditions ^{28.55 "58.} These high dilution techniques, widely used in the field of macrocyclic chemistry, generally lead to good cyclization yields but the high dilution constitutes a major obstacle to the large-scale preparation of said macrocycles.

The inventors have therefore sought to develop a new process for the preparation of C-functionalized tetraazacycloalkanes.

The subject of the invention is a process for the preparation of a compound of formula (I):

in which: one of the groups A or B represents a radical -CH ₂ - and the other group represents, or else a radical -CH (R ') - CH ₂ - in which R' represents either a saturated aliphatic radical or unsaturated having from 1 to 12 carbon atoms, leaves a radical - (CH ₂ ) n-0-Rι \ in which n represents an integer between 0 and 4 and R-) 'represents a hydrogen atom or a radical saturated or unsaturated aliphatic having from 1 to 8 carbon atoms, i.e. a radical (CH ₂ ) _n -C (= O) -O- Ri 'in which n and Ri' are as defined above, either a radical - (CH2) _n -R2 ', in which R ₂ ' represents an unsubstituted phenyl radical or a phenyl radical substituted by one or more radicals chosen from amino, nitro, chloro, bromo, iodo or methoxy or hydroxy radicals, or else a radical -CH (R ") - in which R" represents, sojt a saturated or unsaturated aliphatic radical containing from 1 to 12 carbon atoms, ie a radical - (CH ₂ ) nO-Rι "in which n represents an integer between 0 and 4 and R- _t " represents a hydrogen atom or a saturated or unsaturated aliphatic radical containing from 1 to 8 carbon atoms, sojt a radical (CH ₂ ) _n -C (= O) -0-Rι "in which n and Ri" are as defined above, sojt is a radical - (CH ₂ ) _n - ₂ "in which R ₂ " represents a radical unsubstituted phenyl or a phenyl radical substituted by one or more radicals chosen from amino, nitro, chloro, bromo radicals , iodo or methoxy or hydroxy, and the group D represents a radical - (CH ₂ ) m-, in which m is equal to 0, or to l, comprising the following successive reaction stages:

- a step (a) during which the compound of formula (II):

in which the group (D) is as defined above, reacts with a compound of formula (III):

in which R and R1, identical or different, independently of one another represent a hydrogen atom or a radical chosen from methyl, ethyl, linear or branched propyl or butyl, linear or branched radicals and preferably represent a hydrogen atom or a methyl radical, to form a compound of formula (IV): in which D, R and R1 are as defined above;

a step (b) during which the compound of formula (IV) obtained in step (a) reacts with the compound of formula (V):

A— B

/ \

X

(V) in which A and B are as defined above and X represents a radical chosen from bromo, iodo, chloro or tosylate radicals, to form the compound of formula (VI):

in which A, B, D, R and R1 are as defined above; and

a step (c) during which the compound of formula (VI) obtained in step (b) undergoes an acid treatment to form said compound of formula (I).

By saturated or unsaturated aliphatic radical containing from 1 to 12 carbon atoms, is meant in the definitions of R ', R ", Ri' and R-i" described above, in particular alkyl radicals, and alkenyl radicals.

Among the alkyl radicals, more particularly denoted for R ', R ", Ri" and Ri ", the methyl, ethyl, propyl, 1-methyl ethyl, butyl, 1-methyl propyl, 2-methyl propyl, 1, 1- radicals. dimethyl ethyl, pentyl, 1-methyl butyl, 2-methyl butyl, 1-ethyl propyl, 1, 1-dimethyl propyl, 2,2-dimethyl propyl or 1, 2-dimethyl propyl.

Among the alkenyl radicals, more particularly denoted for R ', R ", Ri' and Ri", the vinyl, 1-propenyl, 1-methyl ethenyl, 2-propenyl, 1- butenyl, 1-methyl 1-propenyl, 2-methyl 1-propenyl, 2-butenyl, 1-pentenyl, 1- methyl 1 -butenyl, 2-methyl 1 -butenyl, 3-methyl 1 -butenyl, 1, 1-dimethyl 1- propenyl, 2,2-dimethyl 1-propenyl or 1, 2-dimethyl 1-propenyl, 2-pentenyl, 2-methyl 2-butenyl. As illustrated by the examples described below, the process as defined above allows direct synthesis of functionalized C-tetraazacycloalkanes, which are macrocycles with high added value. It proceeds in only three stages, starting from commercially available compounds. None of the three stages requires special conditions: high dilution, inert atmosphere, long reaction times, ... unlike all the syntheses described so far. It is general and allows the preparation of cyclams, cyclenes, but also of 1,4,7,10-tetraazatridecanes (2223) C- functionalized. The yields are very high (71-87% in the cyclam series) for such compounds. The mild conditions, in particular during the last "deprotection" stage, allow the introduction of very diverse organic functions, unlike the methods involving reduction, detosylation or demetallation stages. A multitude of biselectrophilic ethane or propane derivatives can thus be used, even if the examples described here are limited to commercially available compounds. After N-functionalization by suitable groups, the diversity of functions introduced at the level of a carbon atom of the cycle makes it possible to adapt the method of immobilization of the macrocycle on an antibody or on a solid support according to a given application. . Finally, new C-functionalized macrobicycles based on cyclam or cyclene can be prepared according to this method. This is why the invention also relates to the compounds of formula (VI) as defined above. The compounds of formula (VI) also allow access to the compounds of formula (VII):

in which A, B, D, R and R1, are as defined above, by a treatment suitable for the person skilled in the art.

This compound of formula (VII) constitutes another object of the present invention. According to a specific aspect, the present invention also relates to the compounds of formula (la):

namely the two compounds of formula (I) as defined above, for which A represents a group -CH ₂ -, B represents a group -CH (R ") - and for which in the definition îe D, m is equal to 0, it being understood that in the formula

(la), R "does not represent a hydroxymethyl radical.

The compounds of formula (I) resulting from stage (c) of the process of the invention (and in particular the compounds of formula (la) as defined above, where R "denotes or not a hydroxymethyl radical) , can be subjected to a subsequent step (d) consisting in functionalizing one or more of the nitrogen atoms of their tetraazacycloalkane ring, whereby a compound is obtained having the following formula (I '):

in which :

• the groups A, B and D have the abovementioned meanings for the compounds of formula (I); and • each of the groups Zi, Z ₂ , Z ₃ and Z ₄ , (identical or different) represents, independently of the other groups:

- a hydrogen atom; or

- an alkyl radical, linear or branched, comprising from 1 to 15 carbon atoms, a [hetero (aryl)] alkyl radical comprising from 7 to 12 carbon atoms; or

- a radical - (CH ₂ ) _W -Y. in which :

• w represents a number greater than zero and less than or equal to 6 and more particularly less than or equal to 3; and "Y represents: a radical [-C (= 0)] _y -V in which:

• y is 0 or 1; and

• V represents an OH radical, or an OR ₃ radical (in which R ₃ represents an alkyl radical containing from 1 to 6 carbon atoms, and more particularly from 1 to

3 carbon atoms, optionally substituted by one or more COOH, SO ₃ H, PO ₃ H ₂ or CO (NH ₂ ) groups or an NH ₂ , NHR ₄ or N (R ₄ ) (R ₅ ) radical (in which R ₄ and R ₅ represent an alkyl radical containing 1 to 4 carbon atoms); or else a radical -P (= O) (OR ₆ ) (OR ₇ ) in which R ₆ and R ₇ each independently represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms; or - a radical -S0 ₃ H.

The functionalization of step (d) can be obtained by an appropriate treatment, within the reach of those skilled in the art.

According to another aspect, the present invention also relates to the process for the preparation of the compounds of formula (I ') comprising the additional step (d) defined above. More particularly, the invention also relates to the compounds capable of being obtained by subjecting the compounds of formula (la) to the abovementioned functionalization step (d), namely the compounds of formula (la ¹ ) below :

in which R "and Zi, Z ₂ , Z ₃ and Z ₄ have the above definitions.

The following examples illustrate the invention without, however, limiting it.

Example A: Synthesis of 1,4,8,1-methyl tetraazacyclotetradecane-6-carboxylate (compound 5).

(a) Preparation of 9a, 9b-dimethyl-octahydro-1,3a, 6a, 9-tetraazaphenalene (compound 1)

A solution of 5.37 g (62.4 mmol) of butanedione in 30 ml of acetonitrile is added by slow dropwise to a solution of 10.00 g (62.4 mmol) of N, N ' -bis (2-aminoethyl) -1, 3-propanediamine commercial in 100 ml of acetonitrile at 0 ° C. The mixture is kept at this temperature for two hours. After evaporation of the solvent, the compound 1 is quantitatively isolated in the form of a yellow solid and used for the rest without further purification. ¹³ C NMR spectrometry (125 MHz, CDCI ₃ , δ in ppm):

10.7; 18.3; 23.3; 39.2; 42.0; 45.6; 46.6; 49.0; 51, 1; 68.1; 73.3. Mass spectrometry: (MALDI-TOF): m / z = 210 M ^{+ *}

(b) Preparation of methyl 10b, 10c-dimethyl-decahvdro-3a, 5a, 8a, 10a-tetraazapyrene-2-carboxylate (compound 3)

A solution of 4.95 g (19.0 mmol) of methyl 3-bromo-2- (bromomethyl) propanoate in 20 ml of acetonitrile is added slowly to a solution of 4.00 g (19.0 mmol) of compound 1 prepared in the preceding stage, and 13.15 g (95.0 mmol) of potassium carbonate (K ₂ CO ₃ ) in 100 ml of acetonitrile at reflux. The solution is stirred vigorously and the reflux is maintained for 48 hours. After filtration on celite and evaporation, compound 3 is obtained in the form of an orange oil (5.58 g; Yield = 95%). ¹³ C NMR spectrometry (125 MHz, CDCI ₃ , δ in ppm):

9.9; 10.6; 17.9; 35.4; 44.7; 46.3; 46,4-; 46.6; 47.9; 48.9; 50.2; 50.4; 52.1; 73.2; 73.8; 174.6.

Mass spectrometry: (MALDI-TOF): m / z = 308 M ^{+ *}

(c) Preparation of methyl 1, 4,8,11-tetraazacyclotetradecane-6-carboxylate (compound 5)

A solution of 5.00 g (16.2 mmol) of compound 3 prepared in the preceding stage in 50 ml of absolute methanol is brought to reflux. 30 ml of a 35% aqueous hydrochloric acid solution are added in small quantities. The reflux is maintained for 48 hours. The mixture is cooled to 0 ° C. and the precipitate formed is filtered and then washed with ice-cold methanol. The filtrate is evaporated and then taken up in a minimum of methanol. The precipitate formed is filtered and washed with ice-cold methanol. Compound (5), (4HCI) is isolated in the form of a white powder (4.55 g; Yield = 76%). Overall yield from tetraamine: 72%. ¹ H NMR spectrometry (500 MHz. D? O; 'δ in ppm): 2.22 (qt, 2H); 3.10-3.80 (m, 17H); 3.78 (s, 3H). ¹³ C NMR spectrometry (125 MHz, D? O, δ in ppm): 21.9; 38.3; 41, 7; 42.4; 44.5; 46.9; 56.5; 173.5. Mass spectrometry: (MALDI-TOF): m / z = 259 (M + H) ^{+ #}

Example B: Synthesis of 1, 4,8,11 -tetraazacyclotetradecane-6-carboxylic acid (compound 6).

A solution of 0.50 g (1.62 mmol) of compound 3, prepared in Example A, stage (b), in 20 ml of absolute ethanol is brought to reflux. 3 ml of a 35% aqueous hydrochloric acid solution are added in small quantities. The reflux is maintained for 48 hours. The mixture is cooled to 0 ° C. and the precipitate formed is filtered and then washed with ice-cold ethanol. The filtrate is evaporated and then taken up in a minimum of ethanol. The precipitate formed is filtered and washed with ice-cold ethanol. Compound 6 (3HCI), is isolated in the form of a white powder (0.57 g; Yield = 92%).

Overall yield from tetraamine: 87%. ¹ H NMR spectrometry (500 MHz. D? Q; δ in ppm): 1.55 (qt, 2H); 2.64 (qt, 1H); 2.70-3.00 (m, 16H). ¹³ C NMR spectrometry (125 MHz. DO, δ in ppm): 22.3; 38.6; 42.3; 42.7; 44.8; 46.9; 175.7. Elementary analysis for C- | 1 H24N4O2. 3HCI, 3H2O

Calculated: C 32.40%; H 8.16%; N 13.74% Found: C 32.66%; H 8.03%; N 13.81%

Example C: Synthesis of. 1,4,8,11-tetraazacvclodecan-6-ol (compound 7)

(a) Preparation of 10b, 10c-dimethyl-decahydro-3a, 5a, 8a, 10a-tetraazapyren-2- ol (compound 4)

This product is obtained according to a procedure identical to that described in Example A stage (b) from 8.00 g (38.1 mmol) of compound 1, 8.36 g (38.1 mmol) of 1 , 3-dibromopropan-2-ol, and 26.32 g (190.5 mmol) of K2CO3. Compound 4 is isolated in the form of an orange oil (9.00 g; Yield = 90%), consisting of two isomers. Mass spectrometry: (MALDI-TOF): m / z = 267 (M + H) ^{+ #}

(b) Preparation of 1, 4,8,11-tetraazacyclodecan-6-ol (compound 7)

This product is obtained according to a procedure identical to that described in Example B from 1.15 g (4.31 mmol) of compound 4 prepared in the preceding stage. Compound 7 (4HCI) is isolated in the form of a whitish powder (1.23 g; Yield = 79%).

Overall yield from tetraamine: 71%.

¹ H NMR spectrometry (200 MHz, D? O; δ in ppm): 2.11 (qt, 2H); 2.8-3.8 (m, 17H).

¹³ C NMR spectrometry (50 MHz, D? O, δ in ppm):

23.8; 43.8; 45.3 (x2); 46.1 (x2); 46.7; 50.3; 59.5; 61, 7.

Mass spectrometry: (MALDI-TOF): m / z = 217 (M + H) ^{+ *}

Example D: Synthesis of 1, 4,7,10-tetraazacyclotridéc-5-yl-methanol (compound 9)

(a) Preparation of 9b, 9c-dimethyl-decahvdro-2a, 4a, 7a, 9a- tetraazacyclopentarccπphenalèn-1-yl-methanol (compound 8)

This product is obtained according to a procedure identical to that described in Example A stage (b) from 1.00 g (4.73 mmol) of compound 1, 1.05 g (4.73 mmol) of 2 , 3-dibromopropan-1-ol and 3.27 g (23.65 mmol) of K2CO3. The compound

8 is isolated in the form of an orange oil (1.20 g; Yield = 95%), consisting of several isomers. Mass spectrometry: (MALDI-TOF): m / z = 267 (M + H) ^{+ *}

(b) Preparation of 1, 4,7,10-tetraazacvclotridéc-5-yl-methanol (compound 9)

This product is obtained according to a procedure identical to that described in Example B from 1.20 g (4.51 mmol) of compound 8 prepared in the preceding stage. Compound 9 is isolated in the form of a whitish powder (0.93 g; Yield = 54%).

Overall yield from tetraamine: 52%. ¹³ C NMR spectrometry (125 MHz. D? O, δ in ppm): 29.0; 46.4; 47.9; 49.1; 49.3; 50.1; 50.1; 50.4; 58.5; 63.4. Mass spectrometry: (MALDI-TOF): m / z = 217 (M + H)

Example E: Synthesis of 1, 4,7,10-tetraazacvclododec-2-yl-methanol (compound 11)

(a) Preparation of 5a, 8b-dimethyl-octahydro-2a, 5,6,8a- tetraazaacenaphthylene (compound 2)

This product is obtained according to a procedure identical to that described in Example A, stage (a) from 10.00 g (68.4 mmol) of triethylenetetraamine and 5.88 g (68.4 mmol) of butanedione . Compound 2 is quantitatively isolated in the form of an amber solid and used later without further purification. Mass spectrometry: (MALDI-TOF): m / z = 97 (M + H) ⁺ '

M. Preparation of (8b, 8c-dimethyl-decahydro-2a, 4a, 6a, 8a- tetraazacyclopentaffg1acenaphthylen-1yl-methanol (compound O)

A solution of 5.58 g (25.5 mmol) of 2,3-dibromopropan-1-ol in 20 ml of acetonitrile is added by slow dropwise to a solution of 5.00 g (25, 5 mmol) of compound 2 prepared in the preceding stage and 17.54 g (127 mmol) of l < ₂ CO ₃ in 125 ml of acetonitrile at reflux. The solution is stirred vigorously and the reflux is maintained for 48 hours. After filtration on celite, evaporation, and chromatography of the oil obtained on an alumina column (eluent CH3OH

/ CH2CI2; 3/100), compound 10 is obtained in the form of an orange oil (3.10 g; Yield = 48%) consisting of several isomers. Mass spectrometry: (MALDI-TOF): m / z = 253 (M + H) ^{+ *}

(c) Preparation of 1,4,7,10-tetraazacvclododec-2-yl-methanol (compound 11)

A solution of 1.00 g (3.99 mmol) of the compound (10) obtained in the preceding stage, in 50 ml of absolute ethanol is brought to reflux. 10 ml of a 35% aqueous hydrochloric acid solution are added in small quantities. The reflux is maintained for 48 hours. After evaporation of the solvents, the residue is taken up in a minimum of ice-cold ethanol. The precipitate formed is filtered and washed with ice-cold methanol. The filtrate is evaporated and then taken up in a minimum of methanol. The precipitate formed is filtered and washed with ice-cold methanol. Compound 11 (4HCI) is isolated in the form of a white powder (0.80 g; Yield = 57%). Overall yield from tetraamine: 27%. ¹³ C NMR spectrometry (125 MHz. DgO. Δ in ppm): 42.1; 43.3; 43.9; 44.0; 44.5; 44.9; 46.9; 56.0; 59.5. Mass spectrometry: (MALDI-TOF): m / z = 203 (M + H) ^{+ *} Example F: Synthesis of decahydro-3a, 5a, 8a, 10a-methyl tetraazapyrene-2-carboxylate (compound 13)

(a) Preparation of roctahvdro-1,3a, 6a, 9-tetraazaphenalene (compound 12)

9.04 g (62.4 mmol) of a 40% by weight aqueous solution of glyoxal are added by slow dropwise to a solution of 10.00 g (62.4 mmol) of N, N '-bis- (2-aminoethyl) -1, 3-propanediamine in 30 ml of water at 0 ° C. The mixture is maintained at this temperature for one hour and then stirred for 10 hours at room temperature. After evaporation of the water, compound 12 is quantitatively isolated in the form of a pale yellow solid and used subsequently without further purification.

¹³ C NMR spectrometry (50 MHz, CDC δ in ppm): 19.8; 54.0-55.5 (wide); 67.3; 77.3.

(b) Preparation of methyl decahvdro-3a, 5a, 8a, 10a-tetraazapyrene-2-carboxylate (compound 13)

This product is obtained according to a procedure identical to that described in Example A stage (b), from 1 g (5.48 mmol) of compound 12 prepared in the preceding stage, 1.42 g (5.48 mmol ) of 3-bromo-2- (bromomethyl) propanoate methyl, and 3.80 g (27.45 mmol) of K2CO3. Compound 13 is isolated in the form of an orange oil (1.46 g; Yield = 95%) consisting of two isomers.

Example G: Synthesis of decahvdro-2a, 4a, 6a, 8a-tetraazacyclopentaffq1acé-naphthylèn-1-yl-methanol (compound 15)

(a) Preparation of roctahydro-2a, 5,6,8a-tetrazaacenaphthylene (compound 14)

This product is obtained according to a procedure identical to that described in Example F stage (a), from 5.00 g (34.2 mmol) of triethylenetetraamine and

4.95 g (34.2 mmol) of a glyoxal solution (40% in H ₂ 0). Compound 14 (4 isomers) is quantitatively isolated in the form of a yellow oil and used subsequently without further purification.

Mass spectrometry: (MALDI-TOF): m / z = 169 (M + H) ^{+ *}

(b) Preparation of decahydro-2a, 4a, 6a, 8a-tetraazacyclopentarfty1acé-naphthylèn-1-yl-methanol (15)

This product is obtained according to a procedure identical to that described in Example A stage (b), from 3.00 g (17.87 mmol) of compound 14 prepared in the preceding stage, 3.92 g (17, 87 mmol) of 2,3-dibromo propan-1-ol, and 12.34 g (89.3 mmol) of K2CO3. Compound 15 is isolated in the form of a red oil

(3.95 g). Example H: Synthesis of 1 - (1,4,7,10-tetraazacyclotridéc-5-yl) - allyloxymethane (compound 18)

(a) Preparation of 3-aHyloxy-1,2-propanediol ditosylate (compound 16)

A solution of 216.7 g of p-TsCI (1.13 mol) in 300 ml of pyridine is cooled to -5 ° C. A solution of 50 g of 3-allyloxy-1,2-propanediol (0.38 mol) is added slowly. At the end of the addition, the mixture is kept at room temperature and stirred for 12 h. The precipitate formed is then filtered and the filtrate is evaporated. The oil obtained is taken up in 50 ml of chloroform and washed with 200 ml of a 0.5 M HCl solution and then with 200 ml of a 1 M Na ₂ CO _{3 solution} . After evaporation of the organic phase, the compound 16 is isolated in the form of a yellow oil (142.39 g, yield = 85%).

¹ H NMR (200 MHz, CDCh):

2.33 (s, 6H); 3.44 (d, 2H); 3.72 (m, 2H); 4.07 (m, 2H); 4.61 (m, 1H); 4.99-5.10 (m, 2H); 5.52-5.71 (m, 1H); 7.20 (m, 4H); 7.55-7.70 (m, 4H).

¹³ C NMR (50 MHz, CDCI ₃ ):

21.7 (x2); 67.5; 67.7; 72.3; 77.0; 117.5; 127.9 (x3); 129.9 (x2); 133.8 (x2);

145.3 (x2). (b) Preparation of 1- (9b, 9c-dimethyldecahydro-2a, 4a, 7a, 9a- tetraazacyclopenta-rccflphenalèn-1 -vD-allyloxymethane (compound 17)

This product is obtained according to a procedure identical to that described in Example A stage (b) from 26.2 g (0.12 mol) of compound 1.54.9 g (0.12 mol) of compound 16 and 86 g (0.62 mol) of K ₂ C0 ₃ . The red oil obtained is purified by chromatography on an alumina column (eluent CH ₂ CI ₂ ). Compound 17 is obtained in the form of a yellow oil (8.6 g, yield = 22%) consisting of two isomers.

Mass spectrometry: (MALDI-TOF) m / z = 306 (M ⁺ )

(c) Preparation of 1 - (1, 4,7,10-tetraazacvclotridéc-5-yl) -allyloxymethane (compound 18)

This product is obtained according to a procedure identical to that described in Example B from 0.8 g (2.61 mmol) of compound 17. Compound 18 (4HCI) is isolated in the form of a whitish powder. This powder is dissolved in a minimum of water and the solution is brought to basic pH by adding NaOH tablets. After extraction with 3 × 100 ml of chloroform, and drying over MgSO ₄ , the solvents are evaporated. Compound 18 is obtained in the form of a yellow oil (0.5 g, Yield = 75%).

¹ H NMR (500 MHz. CDCI.:

1.34 (m, 2H); 1.96 (s, 4H); 2.16 (m, 1H); 2.25-2.55 (m, 14H); 3.01 (m, 1H); 3.10 (m, 1H); 3.63 (m, 2H); 4.81 (dd, 1 H, J = 1, θ Hz, 10.5 Hz); 4.91 (dd, 1 H, J = 1.5 Hz, 15.5 Hz); 5.55 (m, 1 H, J = 5.5 Hz, 10.5 Hz, 15.5 Hz).

¹³ C NMR (125 MHz, CDCI ₃ ):

(CH ₂ -β) 29.1; (CH ₂ -α) 46.2; 47.8; 48.9; 49.2; 49.9; 49.8; 50.4; (CH-) 56.8;

(CH ₂ -O) 72.1; 72.4; (C ₂ = C) 116.8; (CH =) 134.8.

Mass spectrometry: (MALDI-TOF): m / z = 256.89 (M ^{+ #} )

Calculated: C 56.89; H 11.03; N 20.42 Found: C 57.39; H 10.98; N 19.94

Example I: Preparation of 1, 4,8,11-tetraethoxycarbonylmethyl-1,4,8,11-methyl tetraazacyclotetradecane-6-carboχylate (compound 19)

A solution of 1 g (2.5 mmol) of compound 5, (4HCI) prepared in Example A, stage (c) and 6.8 g (0.50 mol) of " ₂ C0 ₃ in 500 ml of acetonitrile is brought to reflux. 1.65 g (9.9 mmol) of ethyl 2-bromoacetate are then added. The reflux is maintained for 6 days. After filtration and evaporation of the solvents, the red oil obtained is purified by chromatography on an alumina column (eluent CH ₂ CI ₂ ). Compound 19 is obtained in the form of a yellow oil (0.9 g, Yield = 60%).

¹³ C NMR (125 MHz, CDCl ₃ ): 14.8 (x4); 25.7; 45.2; 51.5 (x2); 52.1 (x2); 52.2; 55.6 (x2); 55.7 (x2); 56.0 (x2); 56.7 (x2); 60.7 (x4); 172.2 (x4); 176.1.

Example J: preparation of (1, 4,7,1 Q-tetra- (N, N-dimethylcarbamoylmethyl) - 1, 4,7,10-tetraazacyclotridéc-5-yl) -methanol (compound 20)

This product is obtained according to a procedure identical to that described in Example I from 7.7 g (35.6 mmol) of compound 9 and 21, 66 g (176.2 mmol) of 2-chloro-N , N-dimethylacetamide. The red oil obtained is purified by chromatography on an alumina column (eluent CH ₂ CI ₂ / MeOH-98/2). Compound 20 is obtained in the form of a yellow oil (5.5 g, yield = 28%).

¹ H NMR (500 MHz. CDCI.):

1.56 (m, 2H, J = 6.3 Hz); 2.39 (m, 1H); 2.45-3.10 (m, 14H); 2.85 (s, 3H); 2.87 (s,

9H); 2.93 (s, 3H); 2.97 (s, 3H); 3.01 (s, 3H); 3.02 (s, 3H); 3.15-3.6 (m, 1 1 H). ¹³ C NMR (125 MHz, CDCTQ:

(CH ₂ -β) 24.2; (CH ₃ -N) 35.8 (x3); 36.1; 36.8; 37.1; 37.4 (x2); (CH ₂ -α, CH-) 50.8 (x2); 50.9; 51, 5; 52.1 (x2); 54.7; 54.8; (CH ₂ -CO) 57.4 (x2); 58.0; 60.2; (CH ₂ -OH) 62.5; (C = 0) 170.9; 171.0; 171, 1; 172.8.

Mass spectrometry: (MALDI-TOF): m / z = 557.71 (M ⁺ ')

Example K: preparation of (1, 4,7,10-tetra- (N, N-dimethylcarbamoylmethyl) -1 • (1, 4,7,10-tetraazacvclotridéc-5-yl) -allyloxymethane (compound 21)

This product is obtained according to a procedure identical to that described in Example I from 4.9 g (19.1 mmol) of compound 18 and 9.3 g (76.6 mmol) of

2-chloro-N, N-dimethylacetamide. The red oil obtained is purified by chromatography on an alumina column (eluent CH2C.2 / MeOH-99/1). Compound 21 is obtained in the form of a yellow oil (4.15 g, Yield = 36%).

¹ H NMR (500 MHz. CDCI: 1.40 (m, 2H); 2.3-3.5 (m, 49H); 3.72 (m, 2H); 4.93 (d, 1 H, J = 10.3 Hz); 5.05 (dd, 1 H, J = 1.8 Hz, 17 Hz); 5.60 (m, 1 H). ¹³ C NMR (125 MHz, CDCI ₃ ):

(CH ₂ -β) 23.4; (CH ₃ -N) 35.6 (x2); 35.7; 35.9; 37.1; 37.2; 37.3; 37.5; (CH ₂ -, CH-α) 49.8; 50.9; 51, 9; 52.2 (x2); 53.2; (x2); 55.4; (CH ₂ -CO) 57.3; 57.6; 57.5; 58.2; (CH ₂ -0) 69.7; 72.2; (CH ₂ =) 116.5; (CH =) 135.2; (C = 0) 170.5; 170.8; (x2); 171, 1.

Mass spectrometry: (MALDI-TOF): m / z = 597.41 (M ^{+ Φ} )

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Claims

1. Process for the preparation of a compound of formula (I)

in which: one of the groups A or B represents a radical - (CH ₂ ) - and the other group represents, or else a radical -CH (R ') - CH ₂ - in which R' represents either an aliphatic radical saturated or unsaturated containing from 1 to 12 carbon atoms, ie a radical - (CH ₂ ) _n -O-Rι ', in which n represents an integer between 0 and 4 and Ri' represents a hydrogen atom or a saturated or unsaturated aliphatic radical containing from 1 to 8 carbon atoms, either a radical (CH ₂ ) _n -C (= 0) -0- Ri 'in which n and RT are as defined "above, or a radical - ( CH ₂ ) n- ₂ \ in which R ₂ 'represents an unsubstituted phenyl radical or a phenyl radical substituted by one or more radicals chosen from amino, nitro, chloro, bromo, iodo or methoxy or hydroxy radicals, or alternatively a radical -CH (R ") - in which R" represents either a saturated or unsaturated aliphatic radical containing from 1 to 12 carbon atoms, or a radical - (CH ₂ ) _n -0-Rι "in which n represents an integer between 0 and 4 and R- _t " represents a hydrogen atom or a saturated or unsaturated aliphatic radical containing from 1 to 8 carbon atoms, ie a radical ( CH ₂ ) _n -C (= 0) -0-R ₁ "in which n and Ri" are as defined above, ie a radical - (CH ₂ ) _n -R ₂ "in which R ₂ " represents a phenyl radical unsubstituted or a phenyl radical substituted by one or more radicals chosen from amino, nitro, chloro, bromo, iodo or methoxy or hydroxy radicals, and the group D represents a radical - (CH ₂ ) _m - _> in which m is equal at 0, or at 1, comprising the following successive reaction stages:

- a step (a) during which the compound of formula (II):

in which R and R1, identical or different, represent, independently of one another, a hydrogen atom or a radical chosen from methyl, ethyl, propyl, linear or branched or butyl, linear or branched and preferably represent a hydrogen atom or a methyl radical, to form a compound of formula (IV):

in which D, R and R1 are as defined above;

in which A and B are as defined above and X represents a radi cal chosen from the bromo, iodo, chloro or tosylate radicals, to form the compound of formula (VI): in which A, B, D, R and R1 are as defined above; and

2. Compound of formula (VI)

in which: one of the groups A or B represents a radical - (CH ₂ ) - and the other group represents, or else a radical -CH (R ') - CH ₂ - in which R' represents an aliphatic radical saturated or unsaturated containing from 1 to 12 carbon atoms, ie a radical - (CH ₂ ) _n -O-Rι ', in which n represents an integer between 0 and 4 and Ri' represents a hydrogen atom or a saturated or unsaturated aliphatic radical containing from 1 to 8 carbon atoms, either a (CH) _n -C (= 0) -O- Ri 'radical in which n and RT are as defined above, or a - (CH ₂₎ radical ) nR ₂ ', in which R ₂ ' represents an unsubstituted phenyl radical or a phenyl radical substituted by one or more radicals chosen from amino, nitro, chloro, bromo, iodo or methoxy or hydroxy radicals, or else a -CH radical (R ") - in which R" represents, leaves a saturated or unsaturated aliphatic radical containing from 1 to 12 carbon atoms, ie a radical - (CH ₂ ) _n -O-Rι "in which n represents an integer between 0 and 4 and Ri" represents a hydrogen atom or a saturated or unsaturated aliphatic radical having from 1 to 8 carbon atoms, sojt is a radical (CH ₂ ) _n -C (= 0) -OR ₁ "in which n and R- _t " are as defined above, ie a radical - (CH ₂ ) _n -R ₂ "in which R" represents an unsubstituted phenyl radical or a phenyl radical substituted by one or more radicals chosen from amino, nitro, chloro, bromo, iodo or methoxy or hydroxy radicals, and group D represents a radical - (CH2) m-. where m is 0, or 1, and

R and R1, identical or different, independently of one another represent a hydrogen atom or a radical chosen from methyl, ethyl, linear or branched propyl or butyl, linear or branched radicals and preferably represent a d atom 'hydrogen or a methyl radical.

3. Compound of formula (VII)

in which: one of the groups A or B represents a radical - (CH ₂ ) - and the other group represents, or else a radical -CH (R ') - CH ₂ - in which R' represents either an aliphatic radical saturated or unsaturated comprising from 1 to 12 carbon atoms, leaves a radical - (CH ₂ ) nO-Rι ', in which n represents an integer between 0 and 4 and Ri' represents a hydrogen atom or an aliphatic radical saturated or unsaturated containing from 1 to 8 carbon atoms, leaves a radical (CH ₂ ) nC (= 0) -O- Ri 'in which n and Ri' are as defined above, i.e. a radical - (CH ₂ ) nR ₂ '. in which R ₂ 'represents an unsubstituted phenyl radical or a phenyl radical substituted by one or more radicals chosen from amino, nitro, chloro, bromo, iodo or methoxy or hydroxy radicals, or else a radical -CH (R ") - in which R "represents either a saturated or unsaturated aliphatic radical containing from 1 to 12 carbon atoms, or a radical - (CH ₂ ) _n -0-Rι "in which n represents an integer between 0 and 4 and Ri" represents a hydrogen atom or a saturated or unsaturated aliphatic radical containing from 1 to 8 carbon atoms, ie a radical (CH ₂ ) _n -C (= 0) -O-Rι "in which n and Ri" are as defined above, ie a radical - (CH ₂ ) _n -R ₂ "in which R ₂ " represents a phenyl radical unsubstituted or a phenyl radical substituted by one or more radicals chosen from amino, nitro, chloro, bromo, iodo or methoxy or hydroxy radicals, and the group D represents a radical - (CH2) _m -. in which m is equal to 0, or to 1, and R and R1, which are identical or different, independently of one another represent a hydrogen atom or a radical chosen from methyl, ethyl, linear or branched propyl radicals or butyl, linear or branched and preferably represent a hydrogen atom or a methyl radical.

4. Compound of formula (la):

corresponding to formula (I) as defined in claim 1 in which A represents a group -CH ₂ -, B represents a group -CH (R ") - and for which in the definition of D, m is equal to 0 , it being understood that in formula (la), R "does not represent the hydroxymethyl radical.

5. Process for the preparation of a compound corresponding to the following formula (I ′):

in which :

• groups A, B and D are as defined in claim 1; and • each of the groups Zi, Z, Z ₃ and Z, (identical or different) represents, independently of the other groups:

- a hydrogen atom; or

- a radical - (CH ₂ ) -Y, in which:

^» W represents a number greater than zero and less than or equal to 6 and more particularly less than or equal to 3; and • Y represents: - a radical [-C (= O)] _y -V in which:

• y is 0 or 1; and

• V represents an OH radical, or an OR ₃ radical (in which R ₃ represents an alkyl radical containing from 1 to 6 carbon atoms, and more particularly from 1 to 3 carbon atoms, optionally substituted by one or more COOH groups , SO ₃ H, P0 ₃ H ₂ or CO (NH ₂ ) or a radical NH ₂ , NHR or N (R ₄ ) (R ₅ ) (in which R ₄ and R ₅ represent an alkyl radical containing from 1 to 4 atoms carbon); or - a radical -P (= O) (OR ₆ ) (OR ₇ ) in which Rβ and R ₇ each independently represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms ; or - a radical -S0 ₃ H, said method comprising a step (d) consisting in functionalizing one or more of the nitrogen atoms of the tetraazacycloalkane ring of a compound of formula (I) as defined in claim 1.

6. Compound of formula (la '):

in which R is such qμe, defined in claim 1, and in which Zi, Z ₂ , Z ₃ and Z ₄ are as defined in claim 5.