Lipophilic macrocyclic ligands, complexes thereof, and uses of same

Abstract

The present invention relates to novel lipophilic macrocyclic ligands, the complexes thereof, in particular radioactive complexes, and the uses of same in medical imaging and/or in therapy, in particular in interventional radiology.

Claims

1. A compound of formula (I): ##STR00070## wherein: R.sub.1 is a methyl or a (C.sub.6-C.sub.10)aryl; R.sub.3, R.sub.4 and R.sub.5 are selected independently of one another from the group consisting of: H, (C.sub.1-C.sub.20)alkyl, (C.sub.2-C.sub.20)alkenyl, (C.sub.2-C.sub.20)alkynyl, (C.sub.6-C.sub.10)aryl, (C.sub.1-C.sub.20)alkylene-(C.sub.6-C.sub.10)aryl, (C.sub.2-C.sub.20)alkenylene-(C.sub.6-C.sub.10)aryl and (C.sub.2-C.sub.20)alkynylene-(C.sub.6-C.sub.10)aryl; said alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene groups of the radicals R.sub.3, R.sub.4 and R.sub.5 may optionally comprise one or more (C.sub.6-C.sub.10)arylene(s) and/or one or more (C.sub.5-C.sub.10)cycloalkylene(s) in their chain; and said alkyl, alkenyl, alkynyl, aryl, alkylene, alkenylene and alkynylene groups of the radicals R.sub.3, R.sub.4 and R.sub.5 optionally being substituted with one or more substituent(s) selected from the group consisting of: halogen, halo(C.sub.1-C.sub.20)alkyl, (C.sub.1-C.sub.20)alkyl, (C.sub.2-C.sub.20)alkenyl, (C.sub.2-C.sub.20)alkynyl; said alkyl, alkenyl and alkynyl groups optionally comprising one or more (C.sub.6-C.sub.10)arylene(s) in their chain; A is a group —(CH.sub.2).sub.n— which may optionally comprise one or more (C.sub.6-C.sub.10)arylene(s) in its chain; n is an integer in the range from 0 to 15; and m is an integer in the range from 1 to 10; or a pharmaceutically acceptable salt thereof or an optical isomer thereof or a geometric isomer thereof or a tautomer thereof or a solvate thereof.

2. The compound of formula (I) as claimed in claim 1, in which when R.sub.1 is a methyl, n is an integer in the range from 4 to 8.

3. The compound as claimed in claim 1, of formula (I-1): ##STR00071## wherein: R.sub.1 is a methyl or a (C.sub.6-C.sub.10)aryl; R.sub.3 and R.sub.5 are selected independently of one another from the group consisting of: H, (C.sub.1-C.sub.20)alkyl, (C.sub.2-C.sub.20)alkenyl, (C.sub.2-C.sub.20)alkynyl, (C.sub.6-C.sub.10)aryl, (C.sub.1-C.sub.20)alkylene-(C.sub.6-C.sub.10)aryl, (C.sub.2-C.sub.20)alkenylene-(C.sub.6-C.sub.10)aryl and (C.sub.2-C.sub.20)alkynylene-(C.sub.6-C.sub.10)aryl; said alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene groups of the radicals R.sub.3, R.sub.4 and R.sub.5 may optionally comprise one or more (C.sub.6-C.sub.10)arylene(s) and/or one or more (C.sub.5-C.sub.10)cycloalkylene(s) in their chain; and said alkyl, alkenyl, alkynyl, aryl, alkylene, alkenylene and alkynylene groups of the radicals R.sub.3, R.sub.4 and R.sub.5 optionally being substituted with one or more substituent(s) selected from the group consisting of: halogen, halo(C.sub.1-C.sub.20)alkyl, (C.sub.1-C.sub.20)alkyl, (C.sub.2-C.sub.20)alkenyl, (C.sub.2-C.sub.20)alkynyl; said alkyl, alkenyl and alkynyl groups optionally comprising one or more (C.sub.6-C.sub.10)arylene(s) in their chain; n is an integer in the range from 0 to 15; m is an integer in the range from 1 to 10; B is a bond, a (C.sub.1-C.sub.20)alkylene, a (C.sub.2-C.sub.20)alkenylene or a (C.sub.2-C.sub.20)alkynylene; and R.sub.6, R.sub.7 and R.sub.8 are selected, independently of one another, from H and (C.sub.1-C.sub.20)alkyl.

4. The compound as claimed in claim 1, of formula (I-2) or (I-3): ##STR00072## wherein: R.sub.3, R.sub.4 and R.sub.5 are selected independently of one another from the group consisting of: H, (C.sub.1-C.sub.20)alkyl, (C.sub.2-C.sub.20)alkenyl, (C.sub.2-C.sub.20)alkynyl, (C.sub.6-C.sub.10)aryl, (C.sub.1-C.sub.20)alkylene-(C.sub.6-C.sub.10)aryl, (C.sub.2-C.sub.20)alkenylene-(C.sub.6-C.sub.10)aryl and (C.sub.2-C.sub.20)alkynylene-(C.sub.6-C.sub.10)aryl; said alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene groups of the radicals R.sub.3, R.sub.4 and R.sub.5 may optionally comprise one or more (C.sub.6-C.sub.10)arylene(s) and/or one or more (C.sub.5-C.sub.10)cycloalkylene(s) in their chain; and said alkyl, alkenyl, alkynyl, aryl, alkylene, alkenylene and alkynylene groups of the radicals R.sub.3, R.sub.4 and R.sub.5 optionally being substituted with one or more substituent(s) selected from the group consisting of: halogen, halo(C.sub.1-C.sub.20)alkyl, (C.sub.1-C.sub.20)alkyl, (C.sub.2-C.sub.20)alkenyl, (C.sub.2-C.sub.20)alkynyl; said alkyl, alkenyl and alkynyl groups optionally comprising one or more (C.sub.6-C.sub.10)arylene(s) in their chain; and m is an integer in the range from 1 to 10.

5. The compound of formula (I) as claimed in claim 1, selected from the group consisting of the following compounds: ##STR00073## ##STR00074## ##STR00075## ##STR00076## or their pharmaceutically acceptable salts.

6. A complex of a compound of formula (I) or of a salt thereof as claimed in claim 1, with M; M being a chemical element.

7. A method for treating cancer comprising administering to a mammal in need thereof a therapeutically effective amount of the complex as claimed in claim 6.

8. A pharmaceutical composition comprising the compound as claimed in claim 1 and optionally one or more pharmaceutically acceptable excipients.

9. The pharmaceutical composition as claimed in claim 8, further comprising an iodinated oil.

10. The compound as claimed in claim 3, wherein n is equal to 6 or is equal to 8.

11. The complex as claimed in claim 6, wherein M is a radioelement.

12. The method for treating cancer as claimed in claim 7, wherein the cancer is liver cancer.

13. The pharmaceutical composition as claimed in claim 9, wherein the iodinated oil is an iodinated oil comprising iodinated ethyl esters of fatty acids of poppyseed oil.

14. A pharmaceutical composition comprising the complex as claimed in claim 6 and optionally one or more pharmaceutically acceptable excipients.

15. The pharmaceutical composition as claimed in claim 14, further comprising an iodinated oil.

16. The pharmaceutical composition as claimed in claim 15, wherein the iodinated oil is an iodinated oil comprising iodinated ethyl esters of fatty acids of poppyseed oil.

Description

DESCRIPTION OF THE FIGURES

(1) FIG. 1 shows the radiolabeling yield as a percentage for ligands according to the invention.

(2) FIG. 2 shows the degree of extraction in the oily phase as a percentage for complexes according to the invention.

(3) FIG. 3 shows the stability test in normal saline solution, giving the percentage level of loss as a function of radioactive tracers according to the invention.

(4) FIG. 4 shows the percentage level of loss in normal saline solution of the radioactive tracers H5 (a) and H6 (b) according to the invention.

(5) FIG. 5 shows the percentage level of loss in normal saline solution of the radioactive tracers H5 (a) and H6 (b) according to the invention.

EXAMPLES

(6) I. General Experimental Conditions:

(7) The commercial products as well as the solvents used for these syntheses are obtained essentially from the companies Sigma-Aldrich®, Merck®, Interchim® and VWR®.

(8) The ambient temperature of the room generally varies between 20° C. and 25° C. Solvent evaporation is carried out at reduced pressure, using a Buchi R-210 evaporator, at temperatures of about 40° C. The reactions and purifications are monitored by thin-layer chromatography (TLC) using silica glass plates (silica gel 60 F254), developed under UV and with iodine. The purifications are carried out on flash chromatography apparatus GRACE Reveleris® or CombiFlash® Rf obtained from Teledyne Isco®. The cartridges used for the purifications on silica are essentially GRACE Reveleris® cartridges (40 μm, 4 or 12 g). The microwave-activated reactions were carried out in the Monowave Series Anton Paar® reactor.

(9) The purifications by preparative HPLC are carried out on PuriFlash® 4250 with Symmetry column (150×30 mm; 5 μm).

(10) The HPLC chromatograms are recorded on an Agilent Technologies® instrument of series 1200. Detection is generally performed at 201 nm and 270 nm. In certain cases, a Corona or ELSD detector is required. The columns used are obtained from various suppliers: Waters® (Symmetry C18), Phenomenex® (Luna C8) and ACE® (C4 ACE). The mass spectrometry analyses were performed by liquid chromatography coupled to an amaZon X mass spectrometer from Bruker®.

(11) II. Synthesis of the Ligands:

(12) Note: in the following examples, the term “Ar” denotes a phenyl substituted with the radicals R.sub.3, R.sub.4 and R.sub.5 such as according to the invention.

Example 1: Preparation of Alkylating Agents

(13) 1—General Procedure for Transformation of the Alcohol Derivatives

(14) ##STR00021##

(15) Bromination:

(16) The alcohol derivative is diluted in dichloromethane, and then PBr.sub.3 (dissolved in dichloromethane) is added dropwise to the solution previously cooled in an ice/acetone bath. The reaction mixture is stirred at room temperature for 2 hours and then treated with 10 mL of water. The organic phase is recovered, purified on a silica plug (Heptane/DCM (1:1)), dried over Na.sub.2SO.sub.4 and concentrated to dryness.

(17) Mesylation:

(18) A three-necked flask is charged with the alcohol (3.64 mmol, 1 equivalent) diluted in 15 mL of DCM (4 mL/mmol). The solution is cooled in a water/ice bath, and Et.sub.3N (2 equiv) and mesyl chloride (1.2 equivalent) are added dropwise through a septum. The reaction mixture is stirred for 10 minutes and then 15 mL of water is added. The organic phase is recovered, dried over Na.sub.2SO.sub.4 and concentrated to dryness. A yellow solid is obtained, which will be purified on a silica plug with the Heptane/DCM mixture (4:6).

(19) TABLE-US-00003 TABLE 1 Preparation of certain alkylating agents B Molecular Alkylating weight agent B Expected product Type Yield (g/mol) 1-bromo-8- phenyloctane Bromination   31% 331.30 4-(2- Bromoethyl)- 4′-octyl-1,1′- biphenyl Bromination 33.3% 372.15 4-(2- Bromoethyl)- 4′-pentyl- 1,1′-biphenyl Mesylation   43% 352.11

Example 2: Alkylation of Cyclen-Glyoxal A

(20) ##STR00025##
Cyclen-glyoxal A (1.2 eq, 5.6 mmol) is dissolved in 4 mL of toluene, and the alkylating agent B where X is a halogen or a mesyl (1 eq, 2.16 mmol) is added. The reaction mixture is then stirred under argon at 60° C. for 5 hours to 5 days (depending on the nature of the alkylating agent B). At the end of the reaction, the solid that has precipitated is filtered and washed abundantly with toluene. After drying in a desiccator, the product C obtained is used without further purification.

(21) TABLE-US-00004 TABLE 2 alkylation of cyclen-glyoxal A HPLC Reaction (retention Alkylating agent B Expected product C time Yield M**** MS (ES+)*** time tr) (Bromomethyl)-1- di-tert-butyl-3.5- benzene  5 hours 97% 374.6  C.sub.23H.sub.42N.sub.4 397.2  [M + Na].sup.+ 6.16 min* (Bromomethyl)-1- di(triftuoromethyl)- 3,5-benzene 4 days 90% 421.2  C.sub.19H.sub.23F.sub.6N.sub.4Br 421.1  5.23 min* Chloromethyl-1-n- octyl-4-benzene 18 hours 57% 397.3  C.sub.25H.sub.41N.sub.4 397.2   5.4 min* (Chloromethyl)-4- diphenyl-1,2-ethane 24 hours 74% 389.6  C.sub.25H.sub.33N.sub.4 389.5   5.8 min* Chloro-4- Phenylbenzyle 0  3 hours 80% 361.5  C.sub.23H.sub.29N.sub.4 361.1  7.39 min* (Bromo-2-ethyl)- methyl-3-benzene 48 hours 70-90% 313.47 C.sub.19H.sub.29N.sub.4 313   4.77 min* (Bromo-3-propyl)- benzene 48 hours 98% 313.47 C.sub.19H.sub.29N.sub.4 313   4.64 min* 1-bromo-8- phenyloctane 60 hours 79% 383.6  C.sub.24H.sub.39N.sub.4 383.35 [M + H].sup.+  6.96 min** 4-(2-Bromoethyl- 4′-octyl-1,1′- biphenyl 48 hours 56% 487.76 C.sub.32H.sub.47N.sub.4  9.36 min** 4-(2-Bromoethyl)- 4′-pentyl-1,1′- biphenyl 60 hours 76% 445.68 C.sub.29H.sub.41N.sub.4 445.38 [M + H].sup.+  8.1 min** 4-(2-mesylethyl)- 1,1′:3′,1″- terphenyl 24 hours 90% 466.66 C.sub.30H.sub.35N.sub.4 10.65 min** *Sunfire ™ C-18 column (Waters ®), 3.5 μm, 150 × 4.6 mm, 98/2 Water (0.05% HCOOH)/CH.sub.3CN in 10 min 100% CH.sub.3CN **Symmetry C-18 column, Waters, 3.5 μm, 150 × 4.6 mm; 98/2 Water (0.05% TFA)/CH.sub.3CN in 12 min 100% CH.sub.3CN and 8 min at 100%. ***MS (ES+) corresponds to the results of mass spectrometry with an electrospray ionization modality in positive mode. M****: Molecular weight (g/mol)

Example 3: Deprotection of the Monoalkylated Cyclen-Glyoxal C

(22) ##STR00037##

(23) The monoalkylated cyclen-glyoxal C (1 eq, 1.5 mmol) is dissolved in aqueous potash (20%, 10 mL) or in hydrazine monohydrate (NH.sub.2—NH.sub.2—H.sub.2O, 3 mL). The reaction mixture is then heated and stirred under argon.

(24) With Microwave Heating:

(25) The product is put in a glass tube with 2M potash solution and it is placed in the cavity of the Anton Paar reactor. The heating cycle is carried out, programming a temperature ramp of 10 minutes and then heating at constant temperature (180° C.) for 1 hour.

(26) Treatment:

(27) Reaction with Potash:

(28) The mixture is extracted with chloroform (×3). The organic phases are combined, dried, filtered and then evaporated. The desired product D is obtained in the form of an oil or a solid. In certain cases, purification on a basic alumina column is necessary.

(29) Reaction with Hydrazine:

(30) The reaction mixture is cooled. The solid obtained is filtered and then taken up in ethanol. The mixture is concentrated at reduced pressure. The desired product D is obtained in the form of an oil or a solid. In certain cases, purification on a basic alumina column is necessary.

(31) TABLE-US-00005 TABLE 3 Deprotection of the monoalkylated cyclen-glyoxal C HPLC Reaction (retention Product D Base time Yield M**** MS (ES+) time tr) Potash Hydrazine 5 days 4 hours 81% 374.6  C.sub.23H.sub.42N.sub.4 397.25 [M + Na].sup.+ 3.3 min* Potash Hydrazine 5 days 18 hours 84% 398.4  C.sub.17N.sub.24F.sub.6N.sub.4 421.10 [M + H].sup.+ 1.8 min* 0 Hydrazine 18 hours then 2 days at 20° C. 32% 374.6  C.sub.23H.sub.42N.sub.4 375.25 [M + H].sup.+ 3.5 min* Hydrazine 18 hours 91% 366.6  C.sub.23H.sub.34N.sub.4 367.19 [M + H].sup.+ 1.8 min* Potash 6 days at 60° C. 83% 338.5  C.sub.21H.sub.30N.sub.4 339.16 [M + H].sup.+ 7.63 min*  Hydrazine 2 hours at 100° C. 92% 290.46 C17H30N4 291   [M + H].sup.+ 4.59 min*  Hydrazine 2 hours at 100° C. 90% 290.46 C17H30N4 291   [M + H].sup.+ 4.84 min*  Hydrazine 2 hours 76% 360.59 C22H40N4 361.25 [M + H].sup.+ 7.12 min** Hydrazine 4 hours 85% 464.74 C.sub.30H.sub.48N.sub.4  9.0 min** Hydrazine 2 hours 56% 422.66 C.sub.27H.sub.42N.sub.4 423.4  [M + H].sup.+ 8.03 min** *Sunfire ™ C-18 column (Waters ®), 3.5 μm, 150 × 4.6 mm, 98/2 Water (0.05% HCOOH)/CH.sub.3CN in 10 min 100% CH.sub.3CN **Symmetry C-18 column, Waters, 3.5 μm, 100 × 4.6 mm 98/2 Water (0.05% TFA)/CH.sub.3CN in 12 min 100% CH.sub.3CN and 8 min at 100% M****: Molecular weight (g/mol)

Example 4: Alkylation of the Monoalkylated Cyclen D

(32) ##STR00048##

(33) TABLE-US-00006 TABLE 4 Alkylating agents E Empirical formulas, Structures of E Names RN, MW (g/mol) Ethyl ester of bromo-2- dodecanoic acid racemic E1 C.sub.14H.sub.27BrO.sub.2, 6974- 87-4, 307.27 0 Ethyl ester of bromo-2- decanoic acid racemic E2 C.sub.12H.sub.23BrO.sub.2, 6974- 85-2, 279.22 Ethyl ester of bromo-2- octanoic acid racemic E3 C.sub.10H.sub.19BrO.sub.2 5445-29-4 251.16

(34) The monoalkylated cyclen D (1 eq, 1.5 mmol) is dissolved in anhydrous acetonitrile (5 mL), and K.sub.2CO.sub.3 (3.2 eq, 4.8 mmol) is added. The alkylating agent E (3.5 eq, 5.25 mmol), previously dissolved in acetonitrile (3 mL), is added dropwise to the mixture. The reaction mixture is then heated under reflux for 18 hours under argon. At the end of the reaction, the salts are filtered and the filtrate is evaporated. The oil obtained containing F is then purified by silica column flash chromatography: 100% of dichloromethane and then progressive addition of methanol up to proportions 80/20.

(35) TABLE-US-00007 TABLE 5 Alkylation of the monoalkylated cyclen D Molecular HPLC weights (retention Types Codes Substituents Yields (g/mol) MS (ES+) time (tr) C12 F1 -N-(3,5-di-tert- 31% 1053.70 C.sub.65H.sub.120N.sub.4O.sub.6 * butyl)benzyle F2 -N-(4-n-octyl)benzyle 29% 1053.70 C.sub.65H.sub.120N.sub.4O.sub.6 10.6 min*  1053.9 [M + H].sup.+ C10 F3 -N-(3,5-di-tert- 46% 969.5 C.sub.59H.sub.108N.sub.4O.sub.6 9.9 min* butyl)benzyle 969.98 [M + H].sup.+ F4 -N-[3,5- 36% 992.7 C.sub.53H.sub.90F.sub.6N.sub.4O.sub.6 9.9 min* Bis(trifluomethyl]benzyle 993.71 [M + H].sup.+ F5 N-[4-(2-PhenylEthyl)- 23% 961.48 C.sub.59H.sub.100N.sub.4O.sub.6 8.9 min* benzyl] 961.92 F6 -N-(4-phenyl)benzyle 17.5%   933.46 C.sub.67H.sub.96N.sub.4O.sub.6 8.5 min* 933.78 F7 N-(4-n-octyl)benzyle 55% 969.54 C.sub.59H.sub.108N.sub.4O.sub.6 9.6 min* F11 N-(2-(4′-pentyl-[1,1′- 21% 1017.58 C.sub.63H.sub.108N.sub.4O.sub.6 10.9 min** biphenyl]-4-yl)ethy) 1017.90 [M + H].sup.+ F12 N-(2-(4′-octyl-[1,1′- 30% 1059.66 C.sub.66H.sub.114N.sub.4O.sub.6 11.23 min, biphenyl]-4-yl)ethyl) 1017.85 11.81 min** [M + H].sup.+ (methyl triester)**** C8 F8 -N-(4-n-octyl)benzyle 33% 884.7 C.sub.52H.sub.94N.sub.4O.sub.6 8.5 min* 885.85 [M + H].sup.+ F9 -N-[4-(2-PhenylEthyl)- 56% 877.3 C.sub.53H.sub.88N.sub.4O.sub.6 8.0 min* benzyl] 877.82 [M + H].sup.+ *Sunfire ™ C-18 column (Waters ®), 3.5 μm, 150 × 4.6 mm, 98/2 Water (0.05% HCOOH)/CH.sub.3CN in 10 min 100% CH.sub.3CN **Symmetry C-18 column, Waters, 3.5 μm, 100 × 4.6 mm 98/2 Water (0.05% TFA)/CH.sub.3CN in 8 min 100% CH.sub.3CN and 5 min at 100% ***Transesterification in the course of reaction.

Example 5: Alkylation of the Monoalkylated Cyclen D, Stereospecific Alkylation

(36) ##STR00052##

(37) TABLE-US-00008 TABLE 6 Alkylating agent E Empirical formula, RN, Structure of E Name MW (g/mol) Ethyl ester of phenyl-4- butanoic acid of configuration R E4 C.sub.13H.sub.15F.sub.3O.sub.5S, 88767-98-0 340.32

(38) Procedure for Preparing the Triflate Alkylating Agent E4:

(39) ##STR00054##

(40) A solution of triflic anhydride in 5 ml of CH.sub.2Cl.sub.2 is added dropwise, at 0° C., under argon, to a solution of 15 mmol of ethyl ester of R—(−) hydroxy-2-phenyl-4-butyric acid in 10 ml of CH.sub.2Cl.sub.2 and 1.2 ml of pyridine.

(41) The mixture obtained is kept at this same temperature for 1 h, then for 1 h at 15° C., and overnight at room temperature. After filtration to remove the pyridinium salts, the filtrate is concentrated and then chromatographed on SiO.sub.2 with an eluent of composition cyclohexane 5/EtOAc 5. The fractions selected and then evaporated give a translucent oil with a yield of 53%, which will quickly be used in the next step. TLC: Rf=0.5 with eluent EtOAc 5/Cyclohexane 5.

(42) Procedure for Alkylation with the Triflate Alkylating Agent E4:

(43) A solution of the triflate reagent E4 prepared beforehand (1.3 mmol in 10 ml of CH.sub.3CN) is added dropwise, under argon and at room temperature, to a solution of 3.8 mmol of monofunctionalized cyclen D in 10 ml of CH.sub.3CN and 0.54 ml of diisopropylethylamine. After reaction for 18 h at room temperature, the reaction mixture is filtered and then concentrated before being chromatographed on SiO.sub.2 with an eluent of composition CH.sub.2Cl.sub.2/MeOH. The fractions are mixed and evaporated, giving an amber-colored oil (yield 41%).

(44) TABLE-US-00009 TABLE 7 Alkylation of the monoalkylated cyclen D, Stereospecific alkylation HPLC Molecular weight (retention Type Code Substituent Yield (g/mol) MS (ES+) time (tr) PheEth F10 N-(4-phenyl)benzyl 41% 909.23 C.sub.57H.sub.72N.sub.4O.sub.6 tr = 8.52 909.7 [M + H].sup.+ 455.38 [M + 2H].sup.2+ * Sunfire ™ C-18 column (Waters ®), 3.5 μm, 150 × 4.6 mm

Example 6: General Procedure for Saponification of F

(45) ##STR00055##

(46) The ligand in the form of ethyl ester F (1 eq, 0.5 mmol) is dissolved in ethanol (5 mL), and an alcoholic potash solution (2 mol/L, 10 mL) is added. The reaction mixture is then stirred under reflux for 18 hours. On return to room temperature, the ethanol is evaporated. Addition of hydrochloric acid (1 mol/L) to pH=1 leads to precipitation of a solid. The latter is filtered and washed abundantly with water to remove the salts and give the ligand G.

(47) For the ligand G1, it was possible, at the ester stage, to separate four fractions during purification by silica chromatography. These four fractions were saponified separately to give 4 ligand fractions (G1-Iso1 to G1-Iso4).

(48) TABLE-US-00010 TABLE 8 Saponification Ligands G according to the invention Molecular HPLC weights (retention Types Codes Products Yields (g/mol) MS (ES+) time (tr) C12 G1 81% 969.54 C.sub.59H.sub.108N.sub.4O.sub.6 969.8  [M + H].sup.+ — G2 94% 969.54 C.sub.59H.sub.108N.sub.4O.sub.6 969.8  [M + H].sup.+ 9.9 min* C10 G3 19% (purity: 93%) 884.7  C.sub.53H.sub.96N.sub.4O.sub.6 885.72 [M + H].sup.+ — G4 30% 908.6  CH.sub.47H.sub.78F.sub.6N.sub.4O.sub.6 909.59 [M + H].sup.+ — G5 0 61% 877.32 C.sub.53H.sub.88N.sub.4O.sub.6 877.73 [M + H].sup.+ 7.8 min* G6 90% 849.26 C.sub.51H.sub.84N.sub.4O.sub.6 849.72 [M + H].sup.+ 7.5 min* G7 86% 885.38 C.sub.53H.sub.96N.sub.4O.sub.6 885.7  [M + H].sup.+ 8.4 min* C8 G8 25% 801.6  C.sub.47H.sub.84N.sub.4O.sub.6 801.6  [M + H].sup.+ — G9 70% 793.2  C.sub.47H.sub.76N.sub.4O.sub.6 793.59 [M + H].sup.+ 6.4 min* PheEth. G10 20% 825.07 826   [M + H].sup.+ 413   [M + 2H].sup.2+ 8.08 min*  C10 G11 90% 933.42 C57H96N4O6 [M + H]+ 933.8  9.8 min  10.0 min** G12 33% 975.50 C60H102N4O6 [M + H]+ 975.8  10.3 min** *Sunfire ™ C-18 column (Waters ®), 3.5 μm, 150 × 4.6 mm, 98/2 Water (0.05% HCOOH)/CH.sub.3CN in 10 min 100% CH.sub.3CN **Symmetry C-18 column, Waters, 3.5 μm, 100 × 4.6 mm 98/2 Water (0.05% HCOOH)/CH.sub.3CN in 12 min 100% CH.sub.3CN and 8 min at 100%*

(49) III. Synthesis of the Complexes:

Example 7: General Procedure for Complexation of G with Yttrium 89

(50) ##STR00068##

(51) The ligand G (1 eq, 0.07 mmol) is dissolved in 3 mL of methanol (pH=6). Yttrium chloride hexahydrate (1.5 eq, 0.1 mmol) is then added (pH=4). This is followed by controlled addition of a solution of sodium methoxide to obtain neutral pH. The mixture is stirred and heated at 65° C. overnight. At the end of the reaction, the solvent is evaporated and the solid obtained is washed abundantly with water to give the complex H.

(52) TABLE-US-00011 TABLE 9 Complexation of G with yttrium 89 Complexes of yttrium 89 H Molecular weights Types Codes Products Yields (g/mol) MS (ES+) C12 H2 -N-(4-n- 70% 1055.42 C.sub.59H.sub.105N.sub.4O.sub.6Y octyl)benzyle 1055.7 [M + H].sup.+ C10 H3 -N-(3,5-di-tert- 85% 971.3 C.sub.53H.sub.93N.sub.4O.sub.6Y butyl)benzyle  971.6 [M + H].sup.+ H4 -N-[3,5- 80% 994.5 C.sub.47H.sub.75F.sub.6N.sub.4O.sub.6Y Bis(trifluométhyl) 995.46 [M + H].sup.+ benzyle H5 -N-[4-(2- — 963.20 C.sub.53H85N4O6Y PhenylEthyl)-  963.6 [M + H].sup.+ benzyl H7 -N-(4-n- 82% 971.26 C.sub.53H.sub.93N.sub.4O.sub.6Y octyl)benzyle  971.6 [M + H].sup.+ C8  H8 -N-(4-n- 93% 887.1 C.sub.47H.sub.81N.sub.4O.sub.6Y octyl)benzyle  887.5 [M + H].sup.+ H9 -N-[4-(2- 64% 879.0 C.sub.47H.sub.73N.sub.4O.sub.6Y PhenylEthyl)- 879.42 [M + H].sup.+ benzyl Symmetry Sunfire ™ C-18 column, 3.5 μm, 150 × 4.6 mm

(53) IV. Radiochemistry:

(54) The following equipment was used for radiolabeling (Table 9):

(55) TABLE-US-00012 Bottles 12 mL, borosilicate glass, IBA crimped Elu-lll Incubator Fisherbrand 15 L Fisher Tubes 5 mL made of PP with VWR screwed stopper white Syringes 1 mL BD Plastipak ® Becton-Dickinson Needles BD Microlance 21G 2″ Becton-Dickinson Activity meter CRC-127R Capintec Counter Cobra II Auto-gamma Packard

(56) The experiments were carried out in crimped borosilicate glass bottles. The bottles were heated in a Bioblock heating block suitable for heating up to 6 bottles. When stirring was necessary, a Lab Dancer S40 vortex (VWR) was used. The centrifugations were carried out with an MF 20-R centrifuge (Awel).

(57) The activities were measured in a CRC-127R activity meter (Capintec), which was calibrated each morning.

(58) Quality controls were performed by TLC on Whatman 1 paper, with MeOH/NEt.sub.3 0.1% mixture as eluent. The RadioChemical Purity (RCP) is determined using a Cyclone phosphoimager (Perkin Elmer), and processed with Optiquant software.

Example 8: General Procedure for Complexation of G with Yttrium 90

(59) ##STR00069##

(60) 1 mL of yttrium-90 chloride in solution in an acetate buffer pH=7 is added to 1 mL of ligand G in solution in ethanol at a concentration of 10.sup.−3 mol/L. The solution is heated at 90° C. for 30 min. The yttrium 90 complex J is thus obtained.

(61) TABLE-US-00013 TABLE 11 Radiolabeling yield Radiolabeling yield, % Ligands G1iso1 G1iso2 G1iso3 G1iso4 G2 G3 G4 G5 G6 G7 G8 G9 G10 G11 G12 Complexes 89 94.4 81.5 95.5 14.1 97.4 96 98.7 97.9 36.3 78.8 82.3 90 76.5 35.7 .sup.90Y J
The results are also presented in FIG. 1.

(62) It can be seen that the ligands according to the invention have a radiolabeling yield that is satisfactory, or even very good, and notably greater than 75%.

Example 9: General Procedure for Extraction in Iodinated Poppyseed Oil

(63) 2 mL of Lipiodol® is added to the complex J prepared in example 8 and the mixture is stirred vigorously. The phases are then separated by centrifugation (3500 rev/min, 15 min) and the oily phase is collected to give the expected radioactive tracer H. The activity of the oily phase H is then measured to evaluate the degree of extraction of the radiolabeled complex J.

(64) TABLE-US-00014 TABLE 12 Extraction yield of the radiolabeled complex J % Extraction yield of the radiolabeled complex J, % Complexes .sup.90Y J J1iso1 J1iso2 J1iso3 J1iso4 J2 J3 J4 J5 J6 J7 J8 J9 J10 J11 J12 Radioactive 96.8 99.2 41.1 75.7 41.8 96.7 99.0 97.7 96.9 64.3 87.4 88.4 76.2 75.9 52.2 tracer .sup.90Y H
The results are also presented in FIG. 2.

(65) It can be seen that the extraction yields of the complexes according to the invention in Lipiodol® are satisfactory, or even above 75%: they are therefore easily extractable in an oily phase.

Example 10: General Procedure for Evaluating the Stability of the Radioactive Tracer H

(66) Assay of the yttrium-90 salted-out in the aqueous solution (normal saline solution or human serum) over time is carried out by counting with the gamma counter. The latter is calibrated beforehand for measuring yttrium-90 (calculation of the counting yield of the apparatus for this isotope).

(67) At different time points, an aliquot of 100 μL is taken from each sample and deposited in a previously weighed 5-mL tube. The tubes are weighed and then counted with the gamma counter. The measurements obtained are corrected for the counting yield and the decrease of yttrium-90 to determine the percentage of yttrium-90 salted-out in the aqueous phase, relative to the initial activity present in the solution. The weight of liquid taken was also taken into account.

(68) 1 mL of freshly prepared radioactive tracer H is taken and then deposited in a 12-mL flat-bottomed glass bottle. The activity is measured with the activity meter, and the time is noted. 10 mL of 0.9% saline solution (normal saline solution) is added and the mixture is stirred. The bottle is then put in the incubator set at 37° C., equipped with a stirrer set at 30 rpm.

(69) It is stirred for several days. Samples are taken from the aqueous phase at different times for assay of the yttrium-90 salted-out.

(70) TABLE-US-00015 TABLE 13 Stability at 7 or 8 days in normal saline solution 7 d stability test. Normal saline solution Radioactive tracer H1iso1 H1iso2 H1iso3 H1iso4 H3 H5 H6 H7 H8 H9 H10 % 7 d 6.8 4.15 14.7 15.7 9.8 3 0.5 4.4 2.4 9.5 9 Radioactive tracer H11 H12 % 8 d 19.7 8.6
The results are also presented in FIG. 3.

Example 11: Stability Test in Normal Saline Solution at 15 Days

(71) 1 mL of freshly prepared radioactive tracer H is taken and then deposited in a 12-mL flat-bottomed glass bottle. The activity is measured with the activity meter, and the time is noted. 10 mL of 0.9% saline solution (normal saline solution) is added and the mixture is stirred. The bottle is then put in the incubator set at 37° C., equipped with a stirrer set at 30 rpm.

(72) It is stirred for 15 days. Samples of the aqueous phase are taken at different times for assay of the yttrium-90 salted-out.

(73) The results are presented in Table 14 below as well as in FIG. 4.

(74) TABLE-US-00016 TABLE 14 Stability at 15 d in normal saline solution [Time (h)] H5 % H6 % 1 0.5 1.56 24 0.27 1.52 48 1.5 1.23 72 1.06 0.57 138 0.71 0.71 168 1.07 0.61 216 2.03 0.74 240 3.32 0.96 360 17.67 4.9

Example 12: Stability Test in Human Serum at 15 Days

(75) 1 mL of freshly prepared radioactive tracer H is taken and then deposited in a 12-mL flat-bottomed glass bottle. The activity is measured with the activity meter, and the time is noted. 10 mL of human serum is added and the mixture is stirred. The bottle is then put in the incubator set at 37° C., equipped with a stirrer set at 30 rpm. It is stirred for 15 days. Samples of the aqueous phase are taken at different times for assay of the yttrium-90 salted-out.

(76) The results are presented in Table 15 below as well as in FIG. 5.

(77) TABLE-US-00017 TABLE 15 Stability at 15 d in human serum [Time (h)] H5 % H6 % 1 14.18 7.73 24 2.4 7.7 48 1.41 3.17 72 1 2.1 138 4.18 7.98 168 6.69 10.15 216 8.83 12.95 240 9.64 14.26 360 19.44 18.5

(78) It can be concluded from the stability tests that the complexes according to the invention are stable in an oily phase and are not lost into an aqueous phase such as normal saline solution. This stability notably allows excellent vectoring of the complexes when administered to patients in an oily phase such as Lipiodol®.