WO1996034872A1

WO1996034872A1 - Iodine derivatives of monosaccharides useful as radiopharmaceutical products

Info

Publication number: WO1996034872A1
Application number: PCT/FR1996/000655
Authority: WO
Inventors: Gilles Bignan; Catherine Guezzi; Christel Henry; Françoise KOUMANOV; Christophe Morin; Lionel Ogier; Laurent Mauclaire
Original assignee: Cis Bio International
Priority date: 1995-05-02
Filing date: 1996-04-30
Publication date: 1996-11-07
Also published as: EP0824537A1; FR2733753A1; FR2733753B1

Abstract

Iodine derivatives of monosaccharides of formula (I), useful as a radiopharmaceutical product for determining the importance of glucose membrane transport are described, wherein at least one of R?1, R2 and R3¿ bears a CH¿2?CH2I group or at least one of R?4 and R6¿ is I or an OCH¿2?CH2I group.

Description

IODIC DERIVATIVES OF MONOSACCHARIDES FOR USE AS RADIOPHARMACEUTICALS DESCRIPTION

The present invention relates to new iodinated derivatives of monosaccharides which can be used as radiopharmaceuticals, in particular for determining the importance of the membrane transport of a monosaccharide such as glucose.

Glucose is an energy substrate for all of the body's tissues and the appreciation of its cellular uptake is of great importance in medicine.

Thus, in muscle tissue, fatty acids are the most used energy substrate under normal oxygenation conditions. On the other hand, in the event of ischemia, glucose becomes the predominant substrate. An akinetic myocardial territory with an increased glucose uptake compared to that of neighboring territories can be described as viable and ischemic. In principle, the revascularization of such a territory should lead to its functional recovery.

In the brain, cellular uptake of glucose is disturbed under various pathological conditions: Alzheimer's disease, Parkinson's disease, dementias, etc.

In tumor cells, glucose uptake is increased compared to that of the surrounding healthy tissue. In diabetes, the assessment of the cellular uptake of glucose should make it possible to better adapt the therapies.

Also, radiopharmaceutical products making it possible to assess cellular uptake of glucose are of great interest for diagnosis of all pathologies linked to disturbances in carbohydrate metabolism, these pathologies being characterized by a variation in the number of glucose transporters and / or a variation in its uptake.

Such molecules can be used in an extremely wide field of application since it concerns oncology, degenerative cerebral diseases, epilepsy, diabetes, myocardial ischemia, non-ischemic cardiomyopathies and finally myopathies. ^"

The only molecule currently used to assess cellular uptake of glucose in humans is [ ¹⁸ F] fluorodeoxyglucose (FDG), but it has certain drawbacks. Indeed, it can only be used near the cyclotron producing ¹⁸ F which is a short-lived radioelement (110 min.). In addition, ¹⁸ F being a positron emitter, the camera necessary for its detection is very expensive; therefore there are very few centers with this device and the number of patients likely to be explored is therefore very limited.

Also, a lot of research has been undertaken to use other molecules or other techniques to assess cellular glucose uptake for this purpose.

US-A-5 342 926 describes the use of radionuclide-labeled cytochalasin B analogs to assess the transport of glucose across cell membranes. WO-A-94/14477 describes the use of phloretin analogs, which are halogen-labeled polyphenol-like compounds, to detect and identify tissues with a disturbed glucose metabolism.

For the assessment of cellular uptake of glucose, the use of glucose derivatives labeled with radioactive iodine would be particularly interesting, since iodine is a readily available γ emitter and compatible with a slight change in biological properties.

However, the attempts made so far to obtain such glucose derivatives capable of being used as radiopharmaceuticals have failed.

Thus, as described in J. Neuro Surg., Vol. 44, June 1976, p. 668-676, Wassenaar et al prepared and tested methyl-6-I-deoxy-D-glucoside and 6-I-deoxy-D-glucose as a marker for brain tumors in mice, and found that the contrast obtained between the brain and the tumor was not sufficient for clinical application. More recently, Lutz et al in European J.

Nucl. Med., 21 (B), 1994, p. 785 No. 243, described the preparation of a glucose derivative consisting of 2-iodo-2-deoxy-1,5, anhydro-D-glucitol, but the biodistributions of this derivative are not very high. The present invention specifically relates to other derivatives of monosaccharides, labeled with iodine, which precisely allow to appreciate the importance of the membrane transport of an onosaccharide such as glucose. According to the invention, the iodized monosaccharide derivative corresponds to the formula:

in which - R ¹ represents a hydrogen atom, an alkyl group, a group of formula -C (O) R ⁷ with R ⁷ being an alkyl group, or a group of formula

- (CH) ₂ - (OCH ₂ CH ₂ ) _m I with m equal to 0 or 1;

- R ² and R ³ which may be the same or different, represent a hydrogen atom, a group of formula -C (O) R ⁷ or C (0) OR ⁷ with R ⁷ being an alkyl group, or a group of formula

- (CH ₂ ) ₂ - (OCH ₂ CH ₂ ) _m I with m equal to 0 or 1;

- R ⁴ and R ⁶ which may be identical or different, represent I, OH, an alkyl group, a group of formula OR ⁷ , -OC (0) R ⁷ , or -OC (0) OR ⁷ with R ⁷ being a alkyl group, or a group of formula - (OCH ₂ CH ₂ ) _n I with n equal to 1 or 2; at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁶ representing I or a group comprising I.

Preferably, only one of R ¹ , R ² , R ³ , R ⁴ and R ⁶ represents I or a group comprising I.

Advantageously, the monosaccharide is glucose, and the derivative corresponds to the formula:

in which R ¹ , R ² , R ³ , R ⁴ and R ⁶ have the meanings given above.

In the formulas I and II given above, the alkyl groups used for R ¹ , R ¹ and R ⁷ may be linear or branched, and preferably have 1 to 18 carbon atoms.

As examples of such groups, mention may be made of methyl and tert-butyl groups. In the monosaccharide derivative of formula

(I), the iodine can occupy different positions, and it is preferably introduced in the form of the group

(CH ₂ ) 2 (OCH2CH2) _n ¹ / ^{with n é (} ? ^Al at 0 or at 1.

Indeed, the introduction of iodine in the form of the β-iodoethoxy group is advantageous because of the high stability of this group and its small steric bulk.

The iodinated monosaccharide derivatives according to the invention can be prepared by conventional methods, chosen as a function of the position occupied by the iodine on the monosaccharide molecule.

Preferably, according to the invention, the Helferich method is used starting from the pentacetylated derivative of the monosaccharide, for example glucose. When the iodine is introduced in position 4 in form I, it is possible to start from a galactose derivative in which the hydroxyl in position 1 is protected by a tert-butyl group, and the hydroxyls in positions 2, 3 and 6 are protected by the silyl, benzoyl or acetyl group, introduce a triflyle group CF3-SO2 on the hydroxyl in position 4 of the galactose derivative, then carry out a nucleophilic substitution with inversion of configuration by the action of sodium iodide. When the iodine is introduced in position 6 in form I, the technique described by Wassenaar et al. in J. Neurosurg, vol. 44, June 1976, p. 668-676.

The subject of the invention is also a radiopharmaceutical product comprising an iodized monosaccharide derivative corresponding to one of the formulas I and II given above, in which the iodine is in the form of radioactive iodine, in particular ¹²³ i, 125 _or ^• * -31d [, which have respective periods of 13 h, 60 days and 8.05 days and energies suitable for use in nuclear medicine for diagnosis or therapy.

Preferably, one uses 123j_ q _U __ _{is a} gamma emitter with a period of thirteen hours with a main emission γ of 159.5 keV.

The radioactive iodine can be introduced into the iodized derivative by conventional methods, for example by isotopic exchange, by nucleophilic substitution, electrophilic halogenation or iodo metallation. Preferably, the isotopic exchange technique is used, which consists in bringing a radioactive sodium iodide solution in acetone containing the iodized derivative of formula I at a temperature of 100 to 130 ° C for about 30 minutes, then cooling the solution and purifying it by passage over an anionic resin in order to eliminate iodides and negatively charged species such as I ^~ , I ~ 3, IO ~ and IO ~ 3. After evaporation under vacuum at room temperature, the pure radioactive iodine derivative can be recovered in physiological saline for its use as a radiopharmaceutical, in particular for assessing cellular uptake of glucose in vivo.

In this case, the radiopharmaceutical is administered to a patient in an amount sufficient for its subsequent detection, then after having waited the time necessary for the glucose derivative to reach the tissues to be studied, the retention of the latter is observed by means of of a gamma camera. The radiopharmaceutical can be in the form of an aqueous solution, in particular of a solution in physiological saline optionally comprising other additives.

Product concentrations and doses administered may vary depending on the mode of administration, age, weight and condition of the patient. Administration can be carried out parenterally, for example by intravenous injection.

The dose administered is generally in the range of 70 to 100 μCi per kg of body weight. The gamma camera examination is generally performed upon administration of the radiopharmaceutical.

Other characteristics and advantages of the invention will appear better on reading the following examples, given of course by way of illustration and not limitation, with reference to the appended drawings.

Figures 1 and 2 are diagrams illustrating the results of in vivo study in dogs of ^' two glucose derivatives labeled with iodine 123. In these figures, curves 1, 2, 3 and 4 illustrate the evolution of radioactivity (in counts / min.mCi.pixel) as a function of time (in min.) in the heart, liver, background noise and lungs.

Example 1: Preparation of 2,3, 6-tetra-O-acetyl- -D- 2'-iodoethyl glucopyranoside (compound 1) a) Preparation of 2, 3, 4, 6-tetra-0-acetyl- jθ- 2'bromoethyl D-glucopyranoside.

the lb

At 1, 2, 3, 4, 6-penta-O-acetyl-β-D-glucose

(0.39 g-1 mmol), anhydrous dichloromethane (2 ml) and 2-bromo-ethanol are successively added

(0.15 g - 1.2 mmol), then with stirring, under argon and at -20 ° C, boron trifluoride etherate in solution in dichloromethane (1 ml) (0.36 g - 2, 5 mmol), drop by drop for 15 min. After 7 hours of stirring at room temperature, the reaction mixture is hydrolyzed with ice. The aqueous phase is extracted with dichloromethane (3 x 5 ml), the organic phases are combined to wash them with a 5% NaHCO 3 solution, then neutralize them with water and dry them. After evaporation under reduced pressure, crystals of 2,3, 6-tetra-O-acetyl-β-D-glucopyranoside of 2'-bromoethyl are obtained. Cold recrystallization from ethyl acetate and pentane gives 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside of pure 2'-bromoethyl (363 mg, 80% °). Mp 115 ° C.

1 H NMR, 200 MHz, (CDCI3): 5.25-4.8 (m, 3H, H-4, H-3 and H-2); 4.5 (d, J = 7.8, Hl); 4.2-3.9 (m, 3H, H-6, H- 6 'and -OCH ₂ CH ₂ Br); 3.8-3.55 (m, 2H, H-5 and -OCH ₂ CH ₂ Br); 3.2-3.05 (m, 2H, -OCH ₂ CH ₂ Br); 2.0-1.9 (m, 12H, - CHCH3).

¹³ C NMR, 50 MHz, (CDCI3): 170.5-170.1-169.3 (CO); 100.8 (Cl); 72.5-71.9-70.9-68.1 (C-2, C-5, C-3 and C- 4); 69.7 (C-1); 61.7 (C-6); 29.8 (C-2 *); 20.7-20.6-20.4 (COÇH3). b) Preparation of compound 1

To 2,3,4,6-tetra-O-acetyl-β-D-2'-bromoethyl glucopyranoside (0.91 g - 2 mmol), 3 ^ obtained in a), acetone is added (10 ml), sodium iodide (0.6 g - 4 mmol), then heated to 60 ° C with stirring for one hour. After having cooled the reaction mixture in ice, the NaBr salt is separated by filtration, it is washed with acetone and the filtrate is recovered which is evaporated under reduced pressure to give the compound 1_ in the form of precipitate: the latter is taken up in dichloromethane. After separation of the NaBr salt by filtration, the filtrate is evaporated under reduced pressure to give 2, 3, 4, 6, -tetra-O-acetyl-β-D- pure 2'odoethyl glucopyranoside (0.5 g, 50%).

Mp 97 ° C.

[α] "= - 12, l ° (c = l; CH ₂ Cl ₂ )

IR (film): 1750 cm ^-1 (CO)

¹ H NMR, 200 MHz, (CDCI3): 5.2-4.8 (m, 3H, H-4, H-3 and

H-2); 4.5 (d, 1H, J = 7.8, H-1); 4.2-3.9 (m, 3H, H-6,

H-6 'and -OCH ₂ CH ₂ I); 3.8-3.55 (m, 2H, H-5 and -OÇH ₂ CH ₂ I)

3.2-3.0 (m, 2H, -OCH ₂ CH ₂ ÇH I_); 2.05-1.9 (m, 12H, -

COCH3).

¹³ C NMR, 50 MHz, (CDCI3): 170.5-170.1-169.3 (-COCH3);

100.6 (C-1); 72.5-71.8-70.9-68.2 (C-5, C-4, C-3 and C-

2); 69.6 (C-1 *); 61.7 (C-6); 20.8-20.7-20.5 5 (-

COÇH3); 2.0 (C-2 ').

Example 2: Preparation of {3-D-glucopyranoside 2 '- iodoethyl (compound 2)

compound 1 compound 2

To 2,3,4,6,6 -tetra-O-acetyl-β-D-glucopyranoside of 2 'iodoethyl (0.25 g - 0.55 mmol) obtained in Example 1, chloroform (2) is successively added ml) and methanol (2 ml), then with stirring and at -20 ° C, sodium methylate in small quantities (0.108 g - 2 mmol). After stirring for 2 h 30 min, the reaction mixture is neutralized with a 5% aqueous solution of sulfuric acid. After filtration and washing with methanol, the filtrate is evaporated to dryness to give the crude iodoethyl glucoside. The residue is then purified using chromatography on silica gel washed beforehand with methanol and dried using methanol / dichloromethane (5/96) as eluent. After evaporation of the solvent under reduced pressure, the β- D (pure 2'-iodoethyl glucopyranoside is obtained (132 mg, 72%).

F = 1190 ° C

[α] "= - 21.2 ° (c = 1; acetone) ¹ U NMR, 300 MHz, (D ₂ 0): 4.62, (d, 1H, J =

7.14, Hl); 4.3 to 4.02 (2m, 2H, -OCH ₂ CH ₂ l); 4.0-3.75 (2m, 2H, H-6 and H-6 '); 3.65-3.55 (m7 3H, H-3, H-4 and

H-5); 3.5 (t, J = 7.2H, -OCH ₂ CH ₂ I); 3.4 (m, 1H, H-

2). ¹³ C NMR, 75 MHz, (D ₂ 0): 104.1 (Cl);

77.83 (C-5); 77.6 (C-3); 71.80 (C-1 '); 69.4 (C-4);

62.53 (C-6); 2.7 (C-2 *).

The ¹ H and ¹³ C assignments were made using COSYDQF 2D and COZY ^ - ^ C.

Example 3: Preparation of 2,3,4,6, tetra-O-acetyl-jî-D-glycopyranoside of (2 "-iodoethoxy) -2'-ethyl (compound 3). A) Preparation of 2,3,4 , 6-tetra-0-acetyl-j3-D-glycopyranoside of (2 "-iodotosyloxyethoxy) -2'-ethyl 3b.

RHCH) OCCH) <"^" »

3b la 3a

To a solution of 1,2,3,4,6-penta-0-acetyl- β-D-glucose (1.95 g - 5mmol) in anhydrous acetonitrile (20 ml), successively added under argon 2- (2'-tosyloxy ethoxy) - ethanol (1.3 g - 4.99 mmol), then with stirring and at -20 ° C, tin tetrachloride (3.26 g - 12.5 mmol ) dissolved in dichloromethane (1.50 ml) dropwise for 20 min. After stirring for 2 hours at room temperature, it is hydrolyzed with an aqueous solution of sodium hydrogencarbonate 5% (20 ml). The aqueous phase is extracted with dichloromethane (3 x 10 ml), the organic phases are combined to wash them with water and then dry them. After evaporation under reduced pressure, the crude compound is obtained. The latter is then purified by medium performance liquid chromatography CLMP on silica gel with ether as eluent, then a second time by means of a chromatographic column on silica gel with ether to give pure 3b in the form of an oil (0.7 g,

24%).

[a ¹ = - 12.6 ° (c = 0.9; CH ₂ Cl ₂ )

IR (film): 1750 cm ^-1 (CO); 1580 cπT ¹ (Ar)

¹ H NMR, 200MHz, (CDCI3): 7.6 and 7.2

(system AB, 4H, J _j ^ ≈lO, H Ar); 5.1-5.0 (m, 1H, H-3);

4.9-4.8 (m, 1H, H-2); 4.5 (d, 1H, H = 7.8, H-1); 4.2-

3.9 (m, 4H, H-6 and H-6 ', -CH ₂ OTs); 3.8-3.7 (M, 1H, H-5); 3.7-3.4 (M, 6H, OCH ₂ CH ₂ ~ ÔCH ₂ _); 2.3 (s, 3H, H3C-

Ar); 2.02-1.96, -1.94 ^' (4s, 12 ^~ H, COCH3).

¹³ C NMR, 50 MHz, (CDCI3) ~ 170.4-170.0-169.2

(CO); 144.7 (C ipso); 132.0 (C para); 129.7 (C ortho); 127.7 (C meta); 100.5 (C-1); 72.6-71.5-71.0-70.1 (C-2, C-3, C-4, C-5); 69.0-68.8-68.5-68.1 (C-1 *,

C-2 *, C-3 *, C-4 '); 61.7 (C-6); 21.4-20.5-20.4 (ÇH ₃ -Ar and CH3CO).

MS (D / CI; NH ₃ -isobutane): 608 (M + NH ₄ ) ⁺ (100); 331 (590-O (CH ₂ ⁾ ₂ O (CH ₂ ) ₂ OTs) ⁺ ; 271 (331-AcOH) +; 211 (271-AcOH) ⁺ ; 169 (211-ÇH ₂ CO) ⁺ . b) Preparation of compound 3.

R = - <CH ₂ ) ₂ θ (CH ₂ ) OTs R = CH ₂ ) ₂ θ (CH ₂ ) ₂ I

3b compound 3

To derivative 3b (0.5 g-0.85 mmol), dissolved in acetone (30 ml), iodide is added sodium (0.63 g - 4.2 mmol) then heated to 60 ° C with stirring overnight. After cooling the reaction mixture to room temperature, the salts obtained are separated by filtration, washed with acetone and the filtrate is recovered which is evaporated under reduced pressure to give a precipitate of compound 3_. The latter is then purified by CLMP on silica gel with methanol / dichloromethane (5/95) as eluent and then purified a second time by means of column chromatography on silica gel with methanol / dichloromethane (2/98) as eluent to give the pure compound 3 (0.436 g, 94%). F = 53 ° C [αj ⁵ = - 17.9 ° (c = l; CH ₂ Cl ₂ ) IR (film): 1750 cm ^-1 (CO)

RMH -TH, 200MHz, (CDCI3): 5.2-5.1 (m, 1H, H-4); 5.1-5.0 (m, 1H, H-3); 5.0-4.9 (m, 1H, H-2); 4.6 (d, 1H, J = 7.8, H1); 4.3-4.0 (M, 2H, H-6 and H- 6 '); 4.0-3.8 (M, 1H, H-5); 3.8-3.55 (M, 6H, - OCH ₂ CH ₂ OCH ₂ CH ₂ ); 3.2 (t, J = 6.7.2H, -CH ₂ I); . 2.02-2.0- 1.95-1.90 74 sec, 12 H, -COCH3).

¹³ C NMR, 50 MHz, (CDCI3): 170.5-170.0-169.3-169.2 (CO); 100.6 (Cl); 72.6-71.7-71.1-68.2 (C-2, C-3, C-4, C-5); 71.8-68.8-68.25 (C-1 ', C-2', C-3 '); 61.7 (C-6); 20.6-20.4 (H3ÇCO-); 2.8 (-ÇH ₂ I). Elemental analysis: calculated C (39.57), H, 4.98; I (23.22), 0 (32.21)

Obtained C (39.86), H (5.07); I (22.95), O (32.00) Example 4 Preparation of the fi-D-glucopyranoside of (2 ^π - iodoethoxy) -2 '-ethyl (compound 4)

R = -CH ₂ ) ₂ 0 (CH ₂ ) ₂ L R- CH ₂ ) ₂ θ (CH ₂ ) ₂ I

compound 3 compound 4

To compound 3 of Example 3 (105 mg - 0.20 mmol), chloroform (3 ml) and methanol (3 ml) are successively added, then with stirring and at -20 ° C., sodium methylate ( 42 mg - 0.78 mmol). After stirring 45 min at -20 ° C, then 5 hours at room temperature, the reaction mixture is neutralized with an aqueous solution of 5% sulfuric acid. After filtration and washing with methanol of the precipitate, the filtrate is evaporated to dryness to give the crude compound. The residue is then purified using chromatography on silica gel, previously washed with methanol and dried, using methanol / dichloromethane (25/75) as eluent. After evaporation under reduced pressure, pure compound _4 is obtained (68 mg, 90%). F = 94 ° C

^Λ E NMR, 200MHz, (CD3OD): 4.25 (d, 1H, J = 7.1, Hl); 4.0-3.5 (M, 6H, H-6, H-6 *, H-5, H-4, H-3, H-2); 3.4-3.0 (M, 8H, -OCH ₂ CH ₂ OCH ₂ CH ₂ I). ¹³ C NMR, 50 MHz, (CD3OD): 104.3 (Cl); 77.8-74.9-71.5 (C-2, C-3, ^' C-4, C-5); 72.9-71.0-69.6 (OCH ₂ CH ₂ OCH ₂ ); 62.6 (C-6); 3.1 (-CH ₂ I). Elementary analysis: Calculated C (31.76), H (5.06), 1 (33.56)

Obtained C (32.54), H (4.90), 1 (32.39) Example 5: Preparation of 3-0- (2'-iodoethyl) -α and β-D- glucopyranoses (compound 5) a) Preparation of 1,2,5,6-diisopropylidene 3-0- (2'-hydroxyethyl) -α-D-glucofuranose

R-CH ₂ Cθ ₂ e R = -CH ₂ CH ₂ 0H

5a 5b

To a solution of anhydrous ether, containing LiAlH (1.44 g - 38.0 mmol), is added dropwise, under argon, with stirring and at 4 ° C., the

1,2: 5, 6-di-0-isopropylidene-3-0- (methyl acetate) -α

-D-glucofuranose (5.0 g - 15.06 mmol) in 15 min. After stirring for 30 min at 4 ° C and 60 min at room temperature, the excess hydride is removed with ethyl acetate, then with water (the addition of water must be stopped before formation of the aqueous phase). The filtration of the residue obtained on celite and

Evaporation under reduced pressure of the solvent gives pure 5b (4.0 g - 87%) in the form of a colorless oil.

[α] "= - 42.5 ° (c = 1.12; CH ₂ Cl ₂ )

IR (film): 3500 cm ^-1 (OH) 1H NMR, 200MHz, (CDCl3): 5.95 (d, 1H, J _1/2 = 3.7, Hl); 4.5 (d, 1H, J _1/2 = 3.7, H-2); 4.35-4.2 (m, 1H, H5); 4.15-3.45 (2 M, 9H, H-3, H-4, H-6 and H- 6 ', -OCH ₂ CH ₂ OH); 1.35-1.30-30.20-1.15 (4 s, 12H, - C ⁽ CH3 ⁾ ₂ ⁾ . ^~

The exchangeable proton is not visible on the spectrum. ¹³ C NMR, 50 MHz, (CDCl3): 111.9-109.3 (-Ç (CH ₃ ) ₂ ); 105.6 (Cl); 82.6-82.2-81.2 (C-2, C-3, C- 4); 81.2 (C4); 72.8 (C-5); 71.5 (C-1); 67.7 (C-6); 60.9 (C-2 '); 26.8-26.7-26.1-25.0 (-C (CH3) ₂ ). b) Preparation of 1,2: 5,6-diisopropylidene-3-0-2'-iodoethyl) -α-D-glucofuranose 5c

= -CH ₂ CH ₂ θH R-CH ₂ CH ₂ I

5b 5c

To compound 5b obtained in a) (900 mg - 2.96 mmol) in solution in anhydrous toluene (80 ml), triphenylphosphine (1.18 g - 4.5 mmol) is added successively with argon and with stirring. triiodoimidazole (1.0 g - 2.24 mmol). After 3 hours of stirring of the reaction mixture at 120 ° C., triphenylphoshine (0.78 g - 3 mmol) and triiodoimidazole (0.66 g - 1.5 mmol) are added. After 90 minutes of stirring at 120 ° C, the reaction mixture is cooled and hydrolyzed with an aqueous solution of saturated sodium hydrogen sulfate (80 ml); after 5 minutes of stirring, iodine is added until a brown coloration of the organic phase is obtained. After 10 minutes of stirring, the excess iodine is eliminated by adding an aqueous solution of saturated sodium thiosulfate. The organic phase is then diluted in toluene, extracted with water (3 x 40 ml) and then dried. After evaporation under reduced pressure of the toluene, the crude compound 5_c is obtained. It is then purified by means of chromatography on a column of silica gel with methanol / dichloromethane (2/98) as eluent to give pure compound 5_c (1.08 g, 88%), in the form of an oil in first, then in crystalline form after 3 months. F = 31-33 ° C [α] "= - 14.4 ° (c = 1.125; CH ₂ Cl ₂ )

¹ R NMR, 200 MHz, (CDC1 ₃ ): 5.85 (d, 1H, J _1/2 = 4.5, Hl); 4.55 (d, 1H, J _1/2 = 4.5, H-2); 4.4-4.2 (M, 1H, H-5); 4.15-3.75 (M, 6H, H-3, H-4, H-5, H-6 and H-6 ',

-OCH ₂ CH ₂ I); 3.3-1 (m, 2H, -OCH ₂ ÇH ₂ I); 1.5-1.0 (4 s,

¹³ C NMR, 50 MHz, (CDCl3): 111.9-109.0 (Ç (CH ₃ ) ₂ ); 105.2 (Cl); 82.7-82.3-81.1 (C-2, C-3, C- 4); 72.3 (C-5); 71.2 (C-1); 67.3 (C-6); 26.8-26.2-25.4 (-C (CH ₃ ) ₂ ); 2.6 (C2 '). Elementary analysis:

Calculated C (40.59), H (5.60), I (30.63); O (23.18)

Obtained C (40.75), H (5.48), I (30.57), 0 (23.20)

c) Preparation of compound 5.

R = -CH CH I R = -CH.CH „I

2 2 • '• *

^5c compound 5

To compound 5_c obtained in b) (600 mg - 1.45 mmol) in solution in a THF-water mixture (1/1-lOml), Dowex 50 W x 8.50-100 mesh resin (11, 6 g - 67.6 meq) and stirred at 60 ° C for 8 hours. After having filtered the resin and having washed it abundantly with water and with tetrahydrofuran (THF), the THF is removed under reduced pressure, then the aqueous phase is neutralized by means of a sodium hydroxide solution (0.05M), extracted with dichloromethane (3 x 20 ml). Evaporation of the aqueous phase under reduced pressure gives the crude compound 5_. It is then purified by means of chromatography on a column of silica gel, previously washed with methanol and dried, with methanol / dichloromethane (25/75) as eluent to give the mixture of pure anomers _5 which crystallizes (420 mg , 87%). F = 111-113 ° C [af_ ⁵ = + 27.2 ° (after 60 minutes) and + 32.6 ° (after 4 hours) (c = 0.5.H ₂ θ)

¹ H NMR, 200 MHz, (D ₂ 0): 5.25 (broad s, 1 H, H-1α); 4.70 (d, J _1/2 = 7.4, 1H, H-1β); 4.1 (t, J = 6.3, -OCH ₂ CH ₂ I); 4.0-3.25 (M, 20H, H-2, H-3, H-4, H-5, H-6 and H-6 \ -0CH ₂ CH ₂ I). ¹³ C NMR, 50 MHz, (D ₂ 0): 95.8 (C-1β); 92.0 (C-1α); 84.5-81.9-75.75-73.65-73.4-73.3-71.4-71.05- 69.1 (C-2, C-3, C-4, C- 5 "x and β), Cl *); 60.6 and 60.4 (C-6); 3.62 (C-2 '). Elementary analysis:

Calculated C (28.76), H (4.53), 1 (37.98), O (28.73)

Obtained C (29.10), H (4.60), I (38.52), O (28.94).

Example 6; Preparation of 4-deoxy-4-iodo-α and {î-D- glucopyranoses (compound 6) a) Preparation of tert-butyl galactopyranoside 2,3, -6-tri-O-benzoyl-α-D

6a 6b

With tert-butyl alpha-D-galactopyranoside _6a (413 mg- 1.75 mmol) in solution in anhydrous • pyridine (12.8 ml), under argon, with stirring and at -20 ° C, l 'Benzolyl chloride (0.67 ml - 5.78 mmol-3.3 equivalents) is added dropwise over 20 minutes.

After stirring under argon, 18 hours at -20 ° C, 8 hours at 0 ° C and 22 hours at room temperature, the pyridine is evaporated under reduced pressure, without heating. The residue obtained is taken up in dichloromethane (30 ml). The phase obtained is washed successively with a cold aqueous solution 3M hydrochloric acid (15 ml), an aqueous solution of saturated sodium hydrogencarbonate (15 ml) and water (15 ml). After drying the organic phase over anhydrous sulfate and evaporation under reduced pressure, the crude compound 6b is obtained. Purification by chromatography on a silica gel column with the eluent ethyl acetate / hexane (20/80) gives the pure compound _6b (730 mg - 76%), in the form of an amorphous solid.

¹ K NMR, 300 MHz, (C ₆ D ₆ ): 8.2-8.0 (6H, M, H o benzoyles); 7.2-6 / 8 (9H, M, H m and p benzoyl); 6.05-5.97 (dd, 1H, J _{3 /} = 2.2, J _3/2 = 10.7, H-3) 5, 97-5, 90 (dd, 1H, Jι, ₂ = 3, l , J ^ 3 = 10.7, H-2); 5.66 (d, 1H, J = 3.1, Hl); 4.7-4.55 (m, 2H, H-6 and H-6 '); 4.5-4.4 (M, 1H, H-5); 4.2-4.05 (br s, 1H, H-4); 2.1 (broad s, 1H, -OH); 1.05 (s, 9H, -OC (CH ₃ ) ₃ ).

¹³ C NMR, 75 MHz, (CDC1 ₃ ): 166.4-166.1-165.8 (-CO); 133.2-133.0 (-C ipso benzoyles); 129.7-129.6-129.4-128.3 (-C o, m and p benzoyl): 90.9 (Cl); 75.6 (-ÇJCH ₃ ) ₃ ), 71.05-69.1-68.2-67.5 (C-2, C-3, C-4 and .C-5); 63.7 (C-6); 28.3 (-C- (ÇH ₃ ) ₃ ). b) Preparation of 2, -3, -6-tri-O-benzoyl-4- O-trifluoro-methanesulfonyl-α-D-galactopryranoside of tert-butyl 6c

6b 6c

To derivative 6b obtained in a) (188 mg - 0.34 mmol), in solution in pyridine anhydrous (3.8 ml), is added, with stirring, under argon and at -10 ° C, anhydrous trifluromethane sulfonic (141μl-0.84 mmol - 2.45 equivalents), drop by drop in 5 minutes After having stirred under argon, 60 minutes at 0 ° C. and 45 minutes at room temperature, the reaction mixture is hydrolyzed by addition of a water-ice mixture (12 ml). The aqueμse phase is extracted with dichloromethane (5 × The organic phase is then taken up to be dried and evaporated under reduced pressure to give the crude compound 6c.

Purification of the crude thus obtained by chromatography on a column of silica gel with ethyl acetate / hexane (20/80) as eluent, gives pure compound 6c (143 mg - 61%). F = 109-111 ° C [αr] ^ = + 102.6 ° (c = l; CH ₂ Cl ₂ )

1 H NMR, 200 MHz, (C ₆ D ₆ ): 8.25-7.95 (M, 6H, H o benzoyles); 7.1-6.75 (M, 9H, H m, p, benzoyl); 6.2 (dd, 1H, J ₃ , ₄ = 2.9, J _{3 2} = 10.8, H-3); 5.8 (dd, 1H, 2, l = ³ - ⁷ 'J2.3 = ¹⁰ ' ⁸ ' ^H_ 2 ^); 5.6 ⁽ d, 1H, J = 3.7, H-

1); 5.5 (d, 1H, J = 2.7, H-4); 4.7 (dd, part A of

ABM ..., 1H, J = 11.03, H-6); 4.4 (m, 1H, H-5); 4.2

(dd, part B of an ABM ..., 1H, J = 11.05, H-6 '); 0.9 (s, 9H, C- (CH ₃ ) ₃ ).

¹³ C NMR, 50 MHz, (C ₆ D ₆ ): 165.8 (-CO); 133.7-133.4-133.3 (-C ipso benzoyles); 130.4-130.0-129.9-129-128.7 (-Co, m and p benzoyl); 91.3 (Cl); 84.3 (C- (CH ₃ ) ₃ ); 76.3-69.2-68.0-66.2 (C-2, C-3, C-4, and C-5); 62.6 (C-6); 28.2 (C- (C_H ₃ ) ₃ ).

¹⁹ F NMR, 188 MHz, (CDC1 ₃ ): - 74.8 (- OS0 ₂ CF ₃ ). c) Preparation of 4-deoxy-4-iodo-2, -3, -6- tri-O-benzoyl-α-D-tert-butyl glucopyranoside 6d

6c 6à

To the derivative __ c (62.5 mg - 0.092 mmol), sodium iodide (16.6 mg - 0.11 mmol - 1.2 equivalent) is added in solution in acetone (8 ml). After 16 hours of stirring at 50 ° C, the solvent is evaporated under reduced pressure to give • crude od. The residue is then purified on a chromatographic column on silica gel with dichloromethane as eluent and gives pure _6d (53 mg - 88%) F = 114-115 ° C [α] "= + 93.2 ° (c = 0, 5; CH ₂ C1 ₂ )

¹ H NMR, 300 MHz, (CζO ₆ ): 8.25-8.1 (M, 6H, H o benzoyles); 7.2-6.85 (M, 9H, H m and p benzoyl);

6.5 (apparent t, 1H, H, J = 10.5, H-3); 5.6 (d, 1H, J

= 3.4, Hl); 5.2 (dd, 1H, J _2/1 = 3.5, J _2/3 = 9.8, H- 2); 4.9 (m, 1H, H-6); 4.7 (M, 2H, H-5 and H-6 '); 4.05

(apparent t, 1H, J = 10.9, H-4); 0.95 (s, 9H, -

C (CH ₃ ) ₃ ).

¹³ C NMR, 75 MHz, (C ₆ D ₆ ): 165.9-165.4 (-CO)

; 133.3-133.1-133 (-C ipso benzoyles); 130.6-130-129.8-128.6 (-C O, m and p benzoyl); 91.2 (C-1);

76.1 (-C (CH ₃ ) ₃ ); 73.6-73.4-70.9 (C-2, C-3 and C-5);

66.1 (C-6); 28.2 (-C (CH ₃ ) ₃ ); 25.5 (C-4). MS (D / IC; NH ₃ -isobutane): 676 (M + NH4) ⁺ 658 (M) +; 585 (M-OtBu) ⁺ ; 463 (585-HOCOC ₆ H ₅ ) ⁺ ; 341 (463-HOCOC ₆ H ₅ ) +; 336 (463-1) ⁺ ; 187 (314-1) +; 122 (HOCOC ₆ H ₅ ) ⁺ ; 105 (122-OH) ⁺ (100). Elementary analysis:

Calculated C (56.54); H (4.75); I (19.27); O (19.44)

Obtained C (56.56); H (4.56); I (19.41); O (19,18) d) Preparation of 4-deoxy-4-iodo-α-D-tert-butyl glucopyranoside 6th

6d 6th

To the authentic compound (15 mg - 0.023 mmol) in solution in anhydrous toluene (250 μl) and methanol (250 μl), is added under argon, with stirring and at room temperature, a freshly prepared solution of sodium methylate in anhydrous methanol (1M- 5μl). After three days of stirring under argon and protected from light, the reaction mixture is neutralized using a cationic resin (Amberlite IR (+) 120). The mixture is then filtered and diluted in water (4ml). Extraction of the aqueous phase with toluene (3 x 4 ml) gives, after evaporation of the crude aqueous phase. Purification on a chromatographic plate on silica gel with ethanol / dichloromethane (10/90) as eluent gives • Se pure (3.2 mg - 40%). [α] ₀ = + 1, 3 ° (c = 0, 3; MeOH)

¹ H NMR, 300 MHz, (D ₂ 0): 5.35 (d, 1H, J = 3.8, Hl); 4.4-4.3 (M, 1H, H-5); 4.1-3.8 (M, 4H, H-3, H-4, H- 6 and H-6 '); 3.6 (dd, 1H, J _1/2 = 3.8, J ₂ , ₃ = 9.3, H-2); 1.4 (s, 9H, -C (CH3_) ₃ ).

¹³ C NMR, 75 MHz, (D ₂ 0): 92.7 (Cl);

74, 0-72, 2-72.0 (C-2, C-3 and C-5); 62.9 (C-6); 31, 4 (C-4); 27.5 (-C (ÇH ₃ ) ₃ ).

MS (D / IC; NH ₃ -isobutane): 364

(M + NH ₄ ) ⁺ (100); 347, (MH) ⁺ ; 346 (M) ⁺ ; 329 (M-OH) ⁺ ;

290 (MH-> tBu) ⁺ ; 273 (364-OtBu) ⁺ ; 255 (273-H2O) ⁺ ; 236

(364-HD +; 145 (273-HD +; 127 (I or 255-HI or 145-

H ₂ 0) ⁺ . e) Preparation of compound 6

To the 6th derivative (7 mg 0.02 mmol), in solution in distilled water (2 ml), Amberlite IR (+) 120 (36 mg-8 equivalents) is added. After stirring overnight reflux, the reaction mixture is cooled. It is then filtered; after abundant washing of the resin with water, the filtrate is evaporated to dryness, under reduced pressure, without heating, to give the pure compound • £ (4.6 mg - 78%), in colorless form.

[a] = -3 ° (after 10 minutes) and -11.6 ° (after 70 minutes) (c = 0.33MeOH)

¹ E NMR, 500 MHz, (D ₂ 0) allocations made using TOCSY 1D, GHMQC. 1) α anomer: 5.28 (d, 1H, J = 3.68, Hl); 4.24-4.20 (M, 1H, H-5); 4.00-3.98 (m, 2H, H-6 and H-6 ¹ ); 3.94- 3.92 (m, 1H, H-3); 3.88-3.85 (M, 1H, H-4); 3.53 (dd, 1H, J _1/2 = 3.68 and J _2/3 = 9.2, H-2). 2) β anomer: 4.67 (d, 1H, J = 7.95, Hl); 4.11-4.08 (m, 1H, H-6); 3.96-3.93 (m, 1H, H-6 '); 3.90-3.85 (M, 2H, H-4 ^" and H-5); 3.74. (Dd, 1H, J = 9.14 and J = 10.34, H-3); 3.23 ( apparent t, 1H, J = 8.0 and J = 9.1, H-2). ¹³ C NMR, 125 MHz, (D ₂ 0): 1) α anomer: 92.2 (Cl); 73.71 (C- 3); 72.70 (C-5); 72/1 (C-2).

2) β anomer: 95.9 (C-1); 77.2 (C-3); 76.8 (C-5); 75.15 (C-2).

The carbons C-4 and C-6, corresponding respectively to displacements 30.3-30.9 (C-4) and 63.1-63.05 (C-6), were not assigned for each anomer.

MS (D / IC; NH ₃ -isobutane): 308 (M + NH) +; 290 (M) ⁺ ; 273 (M-OH) ⁺ , 272 (MH ₂ O) ⁺ ; 254 (272-H ₂ 0) ⁺ ; 163 (29 @ -I) +; 145 (163-H ₂ 0) ⁺ ; 127 (I or 254-1) +; 109 (127-H ₂ 0) +.

Example 7 Preparation of 4-deoxy-4-iodo-1,2, -3, -6- tetra-O-acetyl α and j3 -D-glucopyranosides (compound 7)

compound 6 compound 7

To compound _5_ (2.3 mg - 7.9 μmol), dissolved in anhydrous pyridine (200 μl), successively added under argon, with stirring and at -20 ° C, acetic anhydride (16μl-0.17mmol-21 equivalents). After one day of stirring at room temperature, the reaction mixture is hydrolyzed (0.5 ml of water). The aqueous phase is then extracted with dichloromethane (4 times 1 ml), the organic phases are combined to wash them with water and then dry them. After evaporation under reduced pressure, compound 1_ is obtained. It is then purified by chromatography on a column of silica gel with methanol / dichloromethane (2/98) as eluent to give pure compound 1_ (3 mg-82%), in colorless form.

¹ H NMR, 300MHz, (CDCI3):

1) Anomer g: 6.35 (d, 1H, J = 3.4, H-1); 5.35-5.3 (m, 1H, H-3); 5.0-4.95 (m, 1H, H-2); 4.6-4.4 (M, 2H, H-6 and H-6 *); 4.1-3.95 (M, 1H, H-4).

2) β anomer: 5.7 (d, 1H, J = 8.6, H-1); 5.6-5.5 (apparent t, 1H, J = 10.4, H-3); 5.0-4.95 (m, 1H, H-2); 4.6-4.4 (M, 2H, H-6 and H-6 '); 4.1-3.95 (M, 1H, H-4). The two hydrogens H-5 (4.3-4.2 (M) and 4.1-3.95 (M) as well as the singlets at 2.17-2.14-14.08-1.99-1 , 98 (COCH3), were not assigned for each anomer.

Example 8: Preparation of 3-0- (2 '-iodoethyl)

1, 2,, 6-tetra-O-acetyl-g and {j-D-glucopyrano s i de (compound 8)

R = -CH ₂ CH ₂ I

compound 5 compound 8 To compound 5_ (63 mg-0.19 mmmol), in solution in anhydrous dichloromethane (6 ml) and pyridine (1 ml), a crystal of successively is added under argon, with stirring and at 0 ° C.

4-dimethylaminopyridine and acetic anhydride

(250 μl) -2.15 mmmol) dropwise. After three days of stirring at room temperature, the reaction mixture is hydrolyzed with water (2 ml). The aqueous phase is then extracted with dichloromethane (3 × 2 ml), the ^“ organic phases are combined to wash them with water and then dry them. After evaporation under reduced pressure, the two crude anomers of compound _8 are obtained. They are then purified by means of chromatography on a column of silica gel with methanol / dichloromethane (1/99) as eluent to give the pure compounds 8 (70 mg, 74%).

NMR ¹ ^ 300MHz, (CDCI3): allocation carried out using TOCSY 2D-COZYDQF2D-COZY ¹ H- ¹³ C 1) β anomer: 5.5 (d, 1H, Jι ^ ₂ = 8, Hl);

5.1-5.0 (M, 2H, H-4 and H-2); 4, 2-4, 0 (M, 2H, H-6 and H-6 '); 3, 9-3, 75 (M, 2H, -OCH ₂ CH ₂ I); 3.75-3.65 (M, 1H, H-5); 3.6 (t, 1H, J _2/3 = J _3/4 = 10, H-3); 3.2 (apparent quadruplet, 2H, J = 7, 3-OCH ₂ CH ₂ D. 2) Anomer g: 6.2 (d, J _1/2 = 4, H-1); 5.1-5.0

(m, 1H, H-4); 5.0-4.9 (m, 1H, H-2); 4.2-4.0 (M, 2H, H-6 and H-6 '); 4.0-3.9 (M, 4H, H-5, H-3 and -OCH ₂ CH ₂ I); 3.2 (apparent quadruplet, J = 7, 3, -OCH ₂ CH ₂ I).

The 8 singlets (COCH3) at 2.11-2.07-2.06-2.05 (2 peaks) -2.03-2.025 and 2.02 were not assigned specifically for each anomer. ¹³ C NMR, 75 MHz, (CDCI3):

1) β anomer: 91.8 (Cl); 80.25 (C-3); 72.8 (C-5); 71.1 (C-2); 61.55 (C-6). 2) Anomere α: 89.2 (Cl); 77.1 (C-3); 71.1 (C-2); 70.05 (C-5); 61.55 (C6).

The following resonances have not been assigned specifically for each anomer: 170.6-169.4-169, 1-168, 9-168, 6 (CO), 73.0 and 72.3 (-OCH ₂ CH ₂ I), 68.7 and 68.6 (C-4), 20.9-20.7-20.6 (-COCH ₃ ), 2.3 and 2.05 (-OCH ₂ CH ₂ I).

Elementary analysis:

Calculated C (38.26), H (4.62)

Obtained C (38.49), H (4.91) Example 9: Preparation of 2-Q-

(2 '-iodoethyl) -1, -3, -4, -6-tetra-O-acetyl-g and β -D-glucopyranoside (compound 9) a) preparation of the

2-Q- (2'-hydroxyethyl) -1, -3, -4, -6-tetra-0-acetyl-g and β -D-glucopyranoside (compound 9b)

9a 9b

The mixture of

2-0-allyl, -l, -3, -4, -6-tetra-0-acetyl-α and β -D-glucopyranose (25 mg-0.064 mmol) dissolved in anhydrous dichloromethane (7 ml) and anhydrous methanol (2 ml), is placed under argon, with stirring and at -78 ° C; then, a stream of ozone, "bubble to bubble", is passed, with stirring at -78 ° C for 30 minutes.

After a blue color persists for twenty minutes, the excess ozone is eliminated by a stream of oxygen. Then, we pass a current of argon. Dimethyl sulfide (600 μl-8.18 mmol) is added dropwise at -90 ° C. The cooling bath is removed. When the mixture has returned to ambient temperature, the solvent is evaporated under reduced pressure, to give the intermediate aldehyde, in the form of a colorless oil.

¹ H NMR, 300MHz, (CDC1 ₃ ): 9.6 (m, 1H, -CHO); 6.4 (d, 1H, J = 3.4, H-1 α); 5.6 (d, 1H, J = 8.3, H-1β); 5.4-4.95 (M, 4H); 4, 6-4, 4 (M, 1H); 4.3-3.2 (M, 11H); 2.14; 1.98 (s, -COCH3).

The crude product obtained is then rapidly dissolved in methanol (4 ml) at 0 ° C and sodium tetraborohydride (18 mg-0.48 mmol) is added in two portions. After 30 min of stirring at 0 ° C., the excess hydride is eliminated by addition of acetone (1 ml). The reaction mixture is then neutralized with a 0.5N hydrochloric acid solution and concentrated under reduced pressure. The aqueous phase is then extracted with dichloromethane (4x5 ml), then the organic phases are dried over anhydrous sodium sulfate. After evaporation of the dichloromethane under reduced pressure, the crude mixture is purified by chromatography on a column of silica gel with the eluent mixture methanol / dichloromethane (2/98) to give pure 9b_ (20 mg-80%), in the form of a colorless residue. .

IR: 3500 cm ^-1 (OH), 1750 cm_! (CO) RMN ¹ ^ 500MHz, (CDCI3): allocations made by TOCSY 1D

1) Anomer g: 6.30 (d, 1H, J = 3.7, Hl); 5.28 (t, 1H, J = 9.7, H-3); 5.11 (t, 1H, J = 9.8, H-4) 4.25-4.0 (M, 3H, H-5, H-6 and H-6 '); 3.8-3.5 (M, 5H, H-2, -OCH ₂ CH ₂ OH). 2) β anomer: 5.55 (d, 1H, J = 8.2, Hl) 5.13 (t, 1H, J = 9.4, H-3); 4.98 (t, 1H, J = 9.8, H-4) 4.25-4.00 (M, 2H, H-6 and H-6 ¹ ); 3.80-3.70 (M, 1H, H-5) 3.8-3.5 (M, 4H, -0CH ₂ CH ₂ 0H); 3.44 (t, 1H, J = 8.2, H-2). The 8 singlets (3H each) at 2.118; 2,100

; 2,018; 2013; 2.008; 2.003; 1,972 and 1,963 (-COCH3) were not allocated for each anomer.

¹³ C NMR, 50 MHz, (CDCI3): 170.5-170.3-170.2-169.5-169.3-168.8 (C0); 93.3 (C1 anomer β): 89.6 (C1 anomer α); 78.9-77.4-74.0-72.4-71.7-69.7-67.7 (C-2, C-3, C-4, C-5 • of the α and β anomers) ; 74.4 and 73.6 (Cl and C-2 of the α and β anomers); 61.6-61.4 (C-6 of α and β); 20.9-20.8-20.6-20.5 (-COCH3). _ MS (D / IC; NH3 ~ isobutane): 410 (M + NH ₄ ) + (100); 350 (M-AcOH) +; 333 (392-OAc) +; 273 (333-AcOH) +; 255 (273-H ₂ 0) +; 213 (273-AcOH) +; 153 (213-C ₂ 0 ₂ H ₄ ) +. SMHR:

Calculated: CιgH ₂₄ 0ιι + Na: 415, 1216 Obtained: C ₁₆ H ₂₄ 0n + Na: 415, 1219 b) preparation of compound 9

9b compound 9

To compound 9b (18 mg-0.46 mmol) dissolved in toluene (3 ml), triphenylphosphine (18 mg-0.069 mmol) and triiodoimidazole (101) (16 mg) are added with stirring -0.036 mmol). After 3 hours of stirring at 120 ° C., triphenylphosphine (12 mg-0.046 mmol) and triiodoimidazole (12 mg-0.027 mmol) are added. After 14 hours of stirring at 120 ° C, the reaction mixture is cooled and hydrolyzed with a saturated aqueous solution of sodium hydrogensulfate (3 ml); after 5 minutes of stirring, iodine is added until a brown coloration of the organic phase is obtained. The mixture is then stirred for 10 minutes and the excess iodine is removed by adding a saturated aqueous solution of sodium thiosulfate. The organic phase is diluted in a toluene / acetone mixture. The organic phase is then washed with water (3 × 4 ml), then dried over anhydrous sodium sulfate. After evaporation of the organic phase under reduced pressure, the crude compound _9 is obtained. It is then purified by chromatography on a column of silica gel with the methanol / dichloromethane mixture (0.5 / 99.5) as eluent to give 9_ pure (20 mg-86%), in the form of an oil.

IR: 1750 cm ^-1 (CO)

RMN-H, 500MHz, (CDCI3): allocations made using TOCSY 1D, COZY DQF

1) Anomer g: 6.38 (d, 1H, J = 3.6, H-1) 5.38 (t, 1H, J = 9.7, H-3); 5.04 (t, 1H, J = 9.8, H-4) 4.32-4.27 (m, 1H, H-6 or H-6 '); 4.1-4.05 (M, 2H, H-5 e H-6 or H-6 '); 3.94-3.60 (M, 2H, -0CH ₂ CH ₂ I); 3.65 (dd 1H, J = 9.9, H-2); 3.18-3.14 (M, 2H, -0CH ₂ CH ₂ I) 2.19-2.10-10.08 and 2.04 (s, 12H, -COC-H3). 2) β anomer: 5.61 (d, 1H, J = 8.1, Hl)

5.2 (t, 1H, J = 9.4, H-3); 5.02 (t, 1H, J = 9.7, H-4) 4.32-4.27 (m, 1H, H-6 or H-6 '); 4.1-4.05 (m, 1H, H-6 or H-6 '); 3.9-3.67 (M, 3H, H-5 and -0CH ₂ CH ₂ D; 3.51 (dd 1H, J = 8.5, H-2); 3.18-3.14 (M , 2H, -0CH ₂ CH ₂ I) 2.18-2.09-2.07-2.03 (s, 12H, -COCH ₃ ). ¹³ C NMR, 50 MHz, CDC1 ₃ ): 170.5-170.1-169, 6-169.0-168, 6 (C0); 93.9 (C-1β); 89.2 (Cl α); 78.5-76.9-73.8-72.4-71.2-69.7-68.0-67.9 (C-2, C-3, C-4 and C-5 of α anomers and β); 73.2 and 71.9 (-0ÇH ₂ CH ₂ I of α and β); 61.52 (C-6 of α and β); 21, 1-21, 0-20,7-20, 6 (-COCH3 of the α and β anomers); 2.1 (-OCH ₂ CH ₂ I of α and β).

MS (DCI): 520 (M + NH4) ⁺ , 443 (502-OCOCH ₃ ) +; 442 (502-AcOH) +; 383 (443-AcOH) +; 323 (383-AcOH) +; 197 (383-C ₈ H ₁₀ θ5) +; ¹⁸⁶ (383-C ₄ H ₇ IO) +; 168 (323-CH ₂ CH ₂ I) +; 155 (-CH ₂ CH ₂ I) + (100); ^' 127 (155-CH ₂ = CH ₂ or I) +; 108 (168-AcOH) +.

SMHR:

Calculated: Ci 6H ₂ 3lOι o + Na: 525, 0233

Obtained: Ci 6H ₂ 3lθ! 0 + Na: 525, 0247 Example 10: Preparation of 2-0- (2 '-iodoethyl) -g and β -D-glucopyranose (compound 10)

compound 9 compound 10

Compound 9 (44 mg-0.088 mmol, dissolved in anhydrous methanol (2.3 ml), is added, with stirring and at -30 ° C, a catalytic amount of sodium methylate in IM solution in anhydrous methanol (10.8 μl). After stirring for 14 days at -30 ° C., the reaction mixture is diluted in water (10 ml) and concentrated under reduced pressure. The aqueous phase is then neutralized using acid 0.012M sulfuric. After extraction of the aqueous phase with dichloromethane (3 × 10 ml), the aqueous phase is evaporated to dryness to give crude 1JD. The residue thus obtained is purified by means of chromatography on silica gel with ethyl acetate / isopropanol (90/10) as eluent to yield the pure compound 10 (23.4 mg-80%) crystallized.

F = 139-143 ° C [α] "= + 27.6 ° (60 min utes) (c = 0.25; H ₂ θ) NMR + 1H, 500MHz, (D ₂ 0): assignments made to the help from TOCSY 1D, GHMQC

1) β anomer: 4.7 (d, 1H, J = 7.9, Hl); 3.87 (part A of an ABM ..., 1H, J _AB = 12.3, H-6 or H-6 '); 3.69 (part B of an ABM ..., 1H, J _Aβ = 12.3, H-6 or H-6 '); 3.53 (apparent t, 1H, J = 9.0, H-3); 3.45-3.37 (M, 2H, H-5 and H-4); 3.34 (M, 2H, -0CH ₂ CH ₂ I). 3.12 (dd, 1H, J = 9.3 and J = 7.9, H-2).

2) Anomer g: 5.4 (d, 1H, J = 3.6, Hl); 3.82-3.60 (M, 4H, H-3, H-5, H-6 and H-6 '); 3.4-3.37 (M, 2H, H-2 and H-4); 3.34 (M, 2H, -0CH ₂ CH ₂ I).

The two masses, respectively, 4.12-4.0 (M) and 3.94-3.92 (t), corresponding to -0CHCH ₂ I, were not allocated for each anomer. ¹³ C NMR, 125 MHz, (D ₂ 0): 1) β anomer: 95.7 (Cl); 82.6 (C-2); 75.8

(C-5); 75.2 (C-3); 73.1 or 71.4 (C-1); 69.6 or 69.5 (C-4); 60.7 (C-6); 3.3 (C * -2).

2) Anomer g: 90, 2 (C-1); 79, 55 (C-2); 73.1 or 71.4 (C-1); 72-71.2 (C-3 and C-5); 69.6 or 69.5 (C-4); 60.5 (C-6); 3.3 (C-2).

The two carbons, of each anomer, carrying the iodine (C-2) are confused; therefore, they have the same chemical shift.

MS (D / IC; NH ₃ -isobutane): 352 (M + NH) +; 334 (M) +; 317 (334-0H) +; 299 (334-2H ₂ 0) +; 281 (334-3H ₂ 0) +; 239 (299-H0CH ₂ -CH0) +; 171 (0 = CH ₂ CH ₂ I) +155 (+ CH ₂ CH ₂ I) + (100); 154 (281-1) +; 146 (317-0CH ₂ CH ₂ D +; 144 (299-CH ₂ CH ₂ D ⁺ ; 127 (1) +; 126 (144-H ₂ 0) +. Example 11: Preparation of the compound t labeled with 123 ^ Ce labeling is carried out by carrying 1 ml of a solution of radioactive sodium iodide Nal 3χ in acetone, which contains 5 mg of compound 1 _, _ at a temperature of 105 ° C. for 30 minutes After elimination of the charged iodine species negatively by passage over an anionic resin, the acetone is evaporated under vacuum without heating, the pure radioactive iodine derivative of glucose is taken up in physiological saline. The marking yield R is calculated as follows:

_{^ # n%} RAglc iodized

R (%) = —- xlOO

Total RA with iodized glc RA being the radioactivity of the eluate containing the pure iodized glucose derivative and total RA being the total radioactivity used. The specific activity AS is given by the formula:

RA glc iodized

AS = mass of iodized glu cos derivative

The results obtained are the followings:

R> 90%

AS = 0.8 mCi / mg (~ 0.4 Ci / mmol) Example 12:

In this example, the biological properties of the compound _1 marked with 123χ obtained in example 11 are tested to verify whether it is suitable for the assessment of the cellular uptake of glucose. For this purpose, the iodine-labeled derivative must cross the cell membrane using the same transporter as glucose. Furthermore, as the number of membrane glucose transporters is increased under the influence of insulin and as these transporters are inhibited by phloretin or cytochalasin B, the iodine derivative must have cell uptake increased by insulin and decreased by phloretin or cytochalasin B. Finally, in the cytoplasm, the iodine derivative must accumulate without undergoing or degradation or backscattering so that the study in SPECT (Single Photon Emission Co puted Tomography) is possible.

Its biological behavior must therefore be very close to that of 2-deoxy-D-glucose.

To test these properties, the following experiments are carried out.

A) In vivo study: bio-distribution in mice. For this experiment, female mice of strain S ISS of an average weight of 20 g are used, fed with a standard diet (type A04-UAR). One injects into one of the lateral veins of the tail of mice 100 μl of solutions of compound 1 labeled with iodine 123 (148 kBq / ml of isotonic solution of D-glucose at 5%). After 2 min, 5 min, 10 min or 15 min, the mice are sacrificed by cervical dislocation, their organs are removed, rinsed and dried. These organs are then weighed and the radioactivity captured by each of them is measured. The results of the bio-distribution are expressed in% of the dose injected per gram of organ, which is defined as follows:

• • _^ . DPSpargdetissu, _ΛΛ

% dosemjected = - xlOO

DPS injected with DPS = disintegrations per second

The results obtained are given in Table 1 below. B) Ex vivo study: isolated and perfused heart of rat.

The method involves removing the heart from a live rat and placing it in an infusion. After injection of the iodized derivative, the time course of the cardiac radioactivity is measured for 30 min, by means of an external radioactivity detector placed in front of the heart.

This model offers the advantage of allowing variations in the perfusion media and in particular of appreciating the influence ^" of insulin which increases glucose transport by increasing the number of transporters, and of phloretin which decreases its uptake by fixing on these same transporters. Also, if the uptake of the iodine derivative is increased by insulin or decreased by phloretin, it meets the fixed criteria, namely that it enters the cell thanks to the glucose transporters. In this study, male rats of the WISTAR strain weighing 250 to 280 g fed on a standard diet (type A04 / UAR) are used. The rats are anesthetized by peritoneal injection of monosodium pentobarbital 6% (2 ml per kg of body weight) After an injection of heparin (1000 IU / kg), the heart is rapidly removed and perfused by the aortic route, at a constant flow rate of 10.5 ml / min.

The perfusion medium is derived from that described by Krebs Henseleit: NaCl (118 mM), KCI (5.6 mM), CaCl ₂ (1.5 mM), NaHC0 ₃ (10 M), MgCl ₂ ( _1.2 mM) and KH2P0 ₄ (1.2 mM). The medium perfused at 37 ° C is saturated with a gas mixture (95% 02 - 5% CO2). According to the experimental protocols, the perfusion medium is supplemented with insulin (10 IU / 1) or phloretin (4 x 10 ^-5 M). After 20 minutes of pre-infusion, compound 1 radioactive iodine is injected at the entrance of the coronary network in the form of a 0.1 ml embol (4 μmol / ml of the perfusion medium). Myocardial radioactivity is measured by continuous external detection using a probe (Nal) coupled to a multi-channel analyzer operating at the ultra-scale (TRACOR NORTHERN TN7200). When studying the effect of phloretin, the inhibitor infusion begins after 20 minutes of pre-infusion, and 5 minutes before injection of the radioactive iodine compound.

The results obtained are given in Table 2 which follows.

The results in this table are expressed as a% of the dose injected per gram of heart. This table shows that insulin increases the fixation of the iodized compound 1 while phloretin decreases it. C) In vitro study a) suspended erythrocytes. A suspension of human erythrocytes is prepared from fresh blood according to the method described by Levine et al in Biochim. Biophys. Acta Sci 225: pages 291-300. The erythrocytes are suspended in an isotonic buffer (NaCl (1%), sodium phosphate (25 mM, pH 7.4) at a hematocrit of approximately 10%.

To 2.5 ml of cell suspension, 1.5 ml of phosphate buffer is added and the red blood cells are incubated at 25 ° C or 4 ° C depending on the protocol chosen. One mililiter of compound JL of iodine analog (42 nmol / ml of phosphate buffer) is added to this suspension. The capture is stopped at variable times by adding 30 ml of stopping solution at 4 ° C (2mM HgCl ₂ , 1.25 mM Kl in 1% NaCl). The suspension is centrifuged and the pellet is washed a second time with 10 ml of quenching solution. The pellet is taken up with 4 ml of trichloroacetic acid (TCA) at 10% W / V and, after centrifugation, 1 ml of supernatant is removed and counted. A standard (control time 0) is carried out by adding the stopping solution before the radioactive iodized compound _1.

When studying the effect of the concentration of D-glucose on the uptake of iodinated analogs of glucose, the erythrocytes are preincubated for 15 minutes at 4 ° C with D-glucose at different concentrations (1-20 mM) and uptake is measured after ^"a minute. for all the studies in the presence of cytochalasin B (5 x 10 ^-5 M), the cell suspension is preincubated for 20 minutes with the inhibitor at 4 ° C. the results obtained are given in Tables 3 and 4 and they are expressed in μmoles of compound taken up by l of cells. Table 3 illustrates the binding kinetics of compound 1 at 25 ° C., at 4 ° C. and at 4 ° C. in the presence of 50 μmol / 1 of cytochalasin B. The results of this table show that the fixation of the iodized compound 1_ is not modified by a decrease in temperature from 25 ° C to 4 ° C: this result is in favor of a fixation of the molecule on the outside of the cell membrane. We also notice that it fixed it tion of the iodized compound _1 is significantly reduced in the presence of cytochaline B, an inhibitor of glucose transport.

Compound 1_ iodized therefore has the characteristics of a marker of glucose transporters, on the outer face of the plasma membrane.

In Table 4, the uptake results of compound _1 are given in the presence of concentrations of cytochalasin B ranging from 0 to 500 μmol / 1 after 20 minutes of incubation at 4 ° C. The results in Table 4 show that the binding of compound 1 is significantly inhibited (p <0.001) for low doses of cytochalasin B. b) The cardiomyocytes of cultured newborn rats.

Cardiomyocyte cultures of newborn rats are prepared from hearts of ISTAR strain rats aged 1 to 4 days according to the technique described by Harary and Farley (1963) and modified by Blondel et al. (1971). The ventricles are ground and subjected to consecutive trypsinizations (Difco Trypsin 1: 250 - 0.1%) at 33 ° C. The isolated cells obtained are suspended in Ham's F10 medium (TechGen International) supplemented with 20% fetal calf serum (TechGen International) and 1% penicillin-streptomycin (500 x) (Boehringer) and adjusted to ImM of CaCl2.

This cell suspension is subjected to 2 pre-seedings of 30 and 90 minutes at 37 ° C, in order to eliminate the non-muscular cells. The suspension enriched in cardiomyocytes is seeded at a density of 10 ^ cells / ml in Petri dishes with a diameter of 35 mm and incubated at 37 ° C in an atmosphere containing 95% air - 5% CO2 • Cardiomyocytes are used after 4 days of culture and incubated 2 hours previously in Ham's F10 medium devoid of glucose and fetal calf serum. Fifty microliters of iodinated compound 1_ (840 nmol / ml of Ham's F10 medium) are added to each dish. After varying times, the collection is stopped by rinsing the dishes 3 times with a phosphate buffer [NaCl (136.5 mM), KCl (0.054 mM), KH ₂ P0 ₄ (1.1 mM) and Na ₂ HP0 ₄ x 2H ₂ 0 (1.8 mM); pH 7.4] at 4 ° C. The cells are detached with a 1% solution of sodium dodecyl sulfate in 10 mM sodium borate. The suspension is withdrawn and counted. A standard

(control time 0) is carried out by stopping the capture immediately after the injection of the iodized JL compound. To study the effect of the D-glucose concentration on the uptake of iodine compound, cardiomyocytes were preincubated 30 minutes with D-glucose (1-20 mM) and uptake ^is measured after one minute. In all studies, the cells are preincubated for one hour with insulin (100 IU / 1) and 30 minutes with cytochalasin B (5 x 10 ^-5 M).

Content ^"protein of each box was measured by the method of Lowry et al. (1951), after heating for 15 minutes at 70 ° C in sodium dodecyl sulfate solution containing the cardiomyocytes. The counting the γ emission is performed in a scintillation γ counter (NOVELEC).

The results obtained are given in table 5. The results of this table are expressed in nmol of captured compound / ml of protein. The results of this table show that the binding of compound 1 is increased by insulin and decreased by cytochalasin B.

D. Scintigraphic study in dogs in vivo Compound 1 labeled with Iodine 123 (3 mCi) was injected intravenously into a dog subjected to an intravenous infusion of glucose-insulin-potassium. The scintigraphic images are acquired using a standard gamma camera equipped with a high resolution collimator, and the spectral range is set to 160 ke V with a 20% window. The time course of radioactivity is measured for 60 minutes, at the rate of one image per minute. The results obtained are given in table 6, and are expressed in strokes / minute.pixel.mCi injected.

Figure 1 also illustrates the results.

This figure represents the evolution of radioactivity (in counts / min.pixel.mCi) as a function of time (in min.). In this figure, curve 1 refers to the heart, curve 2 refers to the liver, curve 3 refers to background noise and curve 4 refers to the lungs.

The results in Table 6 show that cardiac activity is important.

The biological results of Tables 1 to 6 concerning the compound 1 labeled with iodine 123 show that this compound has a cellular fixation, stimulated by insulin and inhibited by phloretin and cytochalasin B.

On human erythrocytes in suspension, its fixation is not affected by temperature variations, which indicates that the molecule does not cross the double lipid layer.

Injected into the dog, its myocardial activity is very high and remains stable for a sufficient time for excellent quality scintigraphies to be performed. This compound 1 is therefore a marker for glucose transporters. Example 13:

In this example, the same biological studies are carried out on the iodized compound, 6-deoxy-6-iodo-D-glucose of formula: compound 11

after having marked it with iodine 123 using the same technique as in Example 11. The results obtained with this compound are given in Tables 7 to 11.

This iodine compound also has cell uptake stimulated by insulin and inhibited by phloretin and cytochalasin B; it competes with glucose for its cellular entry. This compound enters the cell through the same transporter as glucose, and can therefore serve as a marker for cellular uptake of glucose.

Example 14: The same procedure is followed as in Example 12, to test the biological properties of

Methyl 6-deoxy-6-iodo-α-D-glucopyranoside of formula:

compound 12

which was labeled with iodine 123 as compound 1 in Example 11. The results of these biological studies are given in Tables 12 to 17 and in Figure 3.

Figure 2 illustrates the results of the in vivo study in dogs. In this figure, curve 1 refers to the heart, curve 2 refers to the liver, curve 3 refers to background noise and curve 4 refers to the lungs.

The iodized compound 12 behaves in the same way as the compounds 1 and 11 described in examples 12 and 13.

Indeed, its uptake is increased by insulin and decreased by phloretin and cytochalasin B. It competes with glucose for cell entry and its cardiac activity is important.

The iodinated derivatives of the invention are therefore of interest in the diagnosis of all pathologies linked to disturbances in carbohydrate metabolism, these pathologies being characterized by a variation in the number of glucose transporters, and / or a variation in glucose uptake. . The field of application of these derivatives is extremely wide since it relates to oncology, degenerative cerebral diseases, epilepsy, diabetes, myocardial ischemia, non-ischemical cardiomyopathies and finally myopathies.

TABLE 1: Biodistribution in mice (% of the dose injected per g of organ)

Time Heart Liver Lungs Kidneys Brain Blood

2 min 5.48 + 0.55 8.47 + 1.51 8.21 + 1.07 19.94 + 4.00 1.36 + 0.17 7.27 + 0.63

5 min 3.40 + 0.86 5.30 + 0.10 6.00 + 0.50 29.90 + 1.90 1.55 + 0.05 5.88 + 0.82

10 min 2.43 + 0.66 4.37 + 0.26 5.50 + 0.36 19.23 + 2.15 1.8 4.57 + 0.25

15 min 3.08 + 0.66 3.47 + 0.41 4.73 + 0.53 17.15 + 0.04 1.7 5.67 + 1.31

TABLE 2: Isolated rat heart (% of the dose injected per g of heart)

Comparison with control values ^r p <0.05. ** p <0.01 TABLE 3: Red blood cells (μmol of compound 1 per liter of cells)

"p <0.01 *** p <0.001 25 ° Cvs4 ° C 4 ° Cvs4 ° C + cytoB

TABLE 4: Red blood cells (umol of compound 1 per liter of cells)

TABLE 5: Cardiomyocytes of newborn rats (nmol / mg protein)

Time (min) OmM glucose +100 IU / I insulin + 50μMcyt.B

1 0.10 + 0.02 0.13 + 0.01 0.09 + 0.03

15 0.23 + 0.03 0.33 + 0.04 * 0.15 + 0.01 ^*

60 0.29 + 0.03 0.42 + 0.07 ^* 0.24 + 0.01

120 0.31 + 0.04 0.36 + 0.03 0.24 + 0.01

Comparison with values in the absence of glucose. * P <0.005

TABLE 6:

TABLE 7: Biodistribution in mice (% of the dose injected per g of organ

Time Heart Liver Lungs Kidneys Brain Blood

2 min 7.97 + 0.18 11.1 ± 0.51 7.80 + 0.49 8.97 + 0.68 2.70 + 0.14 11.9 * 0.10

5 min 7.00 + 0.77 '9.57 + 0.50' 8.30 + 0.57 6.97 + 0.54 '3.53 + 0.33' 10.2 + 0.6

10 min 6.99 + 0.62 * 8.50 + 0.64 * 7.37 + 0.66 6.90 + 0.59 ^* 3.97 + 0.57 '7.53 + 0.28

15 min 6.25 + 1.14 ^* 6.60 + 0.22 ^*** 6.40 + 0.14 * 6.27 + 0.41 "3.80 + 0.25" 7.48 + 0, 53

60 min 3.78 + 1.04 * "3.67 + 0.39 ^*** 3.90 + 0.37 *** 3.77 + 0.33" ^* 2.40 + 0.16 4.90 +0.60

TABLE 8: Isolated rat heart (% of the dose injected per g of heart)

CONTROL TIME + lnsulin (10μl / ^) + Phloretin (min) (n = 5) (n-5) (40μM) (n = 4)

1 2.67 + 0.63 2.52 + 0.78 1.24 + 0.26 "

2 1.08 + 0.15 0.57 + 0.18 ^* * 0.72 + 0.2 ^*

3 0.60 + 0.06 0.25 + 0.07 ** 0.49 + 0.11

4 0.39 + 0.06 0.16 + 0.06 "0.43 + 0.09

5 0.26 + 0.06 0.10 + 0.02 "0.34 + 0.05

Comparison with control values: * p <0.05; ** p <0.01 TABLE 9: Red blood cells (μmol of compound 11 per liter of cells)

** p <0.05 ** p <0.01 *** p <0.01 25 ° Cvs4 ° C

4 ° Cvs4 ° C + cytoB

TABLE 10:

Red blood cells (μmol of compound 11 captured per liter of cells)

Glucose concentration Capture (μmol per liter) (mM) (n = 6)

0 0.547 + 0.054

1 0.426 + 0.050 *

2.5 0.357 + 0.011 **

5 0.277 + _0.015 **

10 0.214 + _0.008 ***

20 0.100 + 0.013 ***

40 0.038 + 0.002 ***

* p <0.05 ** p <0.01 *** p <0.001 TABLE 11: Cardiomyocytes of newborn rats (nmol / mg protein)

Time (min) OmM glucose +100 IU / 1 + 50μMcγt.B insulin

1 0.046 + 0.006 0.068 + 0.004 *** 0.035 + 0.008 *

15 0.126 + 0.010 0.137 + 0.007 * 0.070 + 0.014 ***

. 60 0.151 + 0.019 0.161 + 0.025 * 0.103 + 0.005 ***

120 0.169 + 0.020 0.162 + 0.003 ** 0.128 + 0.011 **

Comparison with values in the absence of glucose. * P <0.05 ** p <0.01 *** p <0.001

TABLE 12: Biodistribution in mice (% of the dose injected per g of organ)

Time Heart Liver Lungs Kidneys Brain Blood

2 min 7.58 + 1.15 7.06 + 1.02 6.84 + 0.94 9.58 + 0.69 0.72 + 0.08 7.30 + 0.095

5 min 6.38 + 0.83 6.49 + 1.44 5.68 + 0.95 9.20 + 0.63 0.94 7.39 + 1.26

10 min 5.92 + 0.34 6.52 + 0.91 5.65 + 0.52 8.58 + 1.21 1.03 + 0.09 5.75 + 0.075

15 min 4.95 + 0.57 6.34 + 0.32 5.27 + 0.46 8.76 + 0.23 1.73 + 0.055 5.47 + 0.225

60 min 2.55 + 0.48 3.58 + 0.56 3.13 + 0.56 6.24 + 0.63 1.99 + 0.53 4.86 + 0.31

TABLE 13: Isolated rat heart (% of the dose injected per g of heart)

TIME CONTROL + Insulin + Phloretin (min) (n = 5) (10μl / n (0μM) (n = 4) (n = 5)

1 3.12 + 0.84 6.95 + 1.47 * "1.37 + 0.41"

2 0.97 + 0.19 1.94 + 0.56 ** 0.59 + 0.19 *

5 0.21 + 0.04 0.30 + 0.12 0.17 + 0.03

10 0.10 + 0.02 0.13 + 0.06 0.08 + 0.01

15 0.07 + 0.01 0.09 + 0.03 0.06 + 0.004

20 0.07 + 0.01 0.07 + 0.03 0.04 + 0.004

25 0.05 + 0.01 0.05 + 0.01 0.04 + 0.01

30 0.06 + 0.005 0.04 + 0.005 0.04 + 0.01

TABLE 14: Red blood cells (μmol of compound 12 per liter of cells)

Time 25 ° C 4 ° C 4 ° C + (min) (n = 3) (n = 3) cytochalasin B

(50μM) (n = 3)

1 3.42 + 0.06 0.38 + 0.15 * "0.03 + 0.09 ^*

5 3.78 + 0.25 1.36 + 0.19 ^* "1.50 + 0.08

15 4.04 + 0.09 2.86 + 0.05 ^* "1.61 + 0.15 *"

60 3.91 + 0.14 3.24 + 0.70 3.99 + 0.40

Cytochalasiin B inhibits uptake. TABLE 15: Red blood cells (μmol of compound 12 captured per liter of

Glucose concentration Capture (μol per liter) (mM) (n = 6)

0 0.74 + 0.19

1 0.28 + 0.15 * "

2.5 0.49 + 0.14 *

5 0.42 + 0.17 *

10 0.44 + 0.20 *

20 0.33 + 0.09 ^* "

40 0.26 + 0.07 "*

TABLE 16: Cardiomyocytes of newborn rats (nmol / mg protein)

Time (min) OmM glucose +100 IU / 1 + 50μM-cyt.B insulin

1 0.08 + 0.025 0.09 + 0.02 0.04 + 0.01 "

15 0.10 + 0.01 0.10 + 0.01 0.08 + 0.01 *

60 0.10 + 0.01 0.11 + 0.01 0.09 + 0.01

120 0.11 + 0.01 0.13 + 0.01 "0.11 + 0.01

Comparison with values in the absence of glucose, TABLE 17: Study in dogs in vivo (strokes / min. Pixel. MCi)

Time Heart Lungs Liver Noise Background

5 min 48.0 25.0 54.0 20.8 0 min 37.5 22.0 44.0 25.0 5 min 34.7 23.0 40.0 25.0 0 min 33.3 22.0 39.7 26.4 0 min 31.6 21.5 37.7 27.2 5 min 29.4 20.5 37.7 24.4

Claims

Iodized monosaccharide derivative of formula

in which

- R ¹ represents a hydrogen atom, an alkyl group, a group of formula -C (O) R ⁷ with R ⁷ being an alkyl group, or a group of formula - (CH) ₂ - (OCH ₂ CH ₂ ) _m I with m equal to 0 or to 1;

- R ² and R ³ which may be the same or different, represent a hydrogen atom, a group of formula -C (O) R ⁷ or C (0) OR ⁷ with R ⁷ being an alkyl group, or a group of formula - (CH ₂ ) ₂ - (OCH ₂ CH ₂ ) _m I with m equal to 0 or 1;

- R ⁴ and R ⁶ which may be identical or different, represent I, OH, an alkyl group, a group of formula OR ⁷ , -OC (0) R ⁷ , or -OC (0) OR ⁷ with R ⁷ being a alkyl group, or a group of formula - (OCH ₂ CH ₂ ) _n I with n equal to 1 or 2; only one of R ¹ , R ² , R ³ , R ⁴ and R ⁶ representing I or a group comprising I, provided that:

1) in the case where R ³ represents -CH ₂ CH ₂ I, R ¹ and R ² do not represent H or COCH ₃ and R ⁴ and R ⁶ do not represent OH or OCOCH ₃ ,

- 2) in the case where R ⁶ represents I, R ¹ does not represent H or CH ₃ , R ² and R ³ do not represent H and R ⁴ does not represent OH, and - 3) in the case where R represents I, R ² and R ³ do not represent H, R ¹ does not represent H or C (CH ₃ ) ₃ and R ⁶ does not represent OH.

2. Iodine derivative of glucose according to claim 1, characterized in that it corresponds to the formula:

in which R ¹ , R ² , R ³ , R ⁴ and R ^δ have the same meanings given in claim 1,

3. Iodized derivative according to claim 2, characterized in that R ¹ represents -CH ₂ CH ₂ I or

- (CH ₂ ) ₂ OCH ₂ CH ₂ I, R ² and R ³ represent a hydrogen atom, and R ⁴ and R ^δ represent OH.

4. Iodized derivative according to claim 2, characterized in that R ¹ , R ² and R ³ represent a hydrogen atom or -C (0) CH ₃ , R ⁴ represents I and R ⁶ represents OH or -OC (0 ) CH ₃ . 5. Iodized derivative according to claim 2, characterized in that RI represents -CH ₂ CH ₂ I or

- (CH ₂ ) ₂ OCH ₂ CH ₂ I, R ² and R ³ represent the group -C (0) CH ₃ , and R ⁴ and R ⁶ represent the group -OC (0) CH ₃ . β. Iodine derivative according to claim 2, characterized in that R ¹ represents -CH ₂ CH ₂ I, R ² and R ³ represent the group -C (0) CH ₃ , and R ⁴ and R ⁶ represent the group 0C (0) CH ₃ .

7. Iodized glucose derivative according to any one of claims 1 to 6, characterized in that I is ¹²³ I or ¹³¹ I. 8. Radiopharmaceutical product, characterized in that it comprises an iodized monosaccharide derivative of formula:

in which

- R ⁴ and R ⁶ which may be identical or different, represent I, OH, an alkyl group, a group of formula OR ⁷ , -OC (0) R ⁷ , or -OC (0) OR ⁷ with R ⁷ being a alkyl group, or a group of formula - (OCH ₂ CH ₂ ) _n I with n equal to 1 or 2; at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁶ representing I or a group comprising I with I being

¹²³ I or ¹³¹ I provided that in the case where R ³ represents -CH ₂ CH ₂ I, R ¹ and R ² do not represent H or COCH ₃ and R ⁴ and R ⁶ do not represent OH or OCOCH ₃ .

9. A radiopharmaceutical product for determining the importance of the membrane transport of glucose, characterized in that it comprises a radiopharmaceutical product according to claim 8. 10. Radiopharmaceutical product for determining the importance of the membrane transport of glucose, characterized in that it comprises an iodized derivative of glucose of formula:

011.11 compound 1

where I is ¹²³ I or ¹³¹ I.

11. Radiopharmaceutical product for determining the importance of the membrane transport of glucose, characterized in that it comprises an iodine derivative of glucose of formula:

dial 12

25 where I is ¹²³ I or ¹³¹ :

12. Use of an iodine derivative of glucose from

in which - R ¹ represents a hydrogen atom, an alkyl group, a group of formula -C (O) R with R ⁷ being an alkyl group, or a group of formula - (CH) ₂ - (OCH ₂ CH ₂ ) _ra I with m equal to 0 or 1; - R ² and R ³ which may be the same or different, represent a hydrogen atom, a group of formula -C (O) R ⁷ or C (0) OR ⁷ with R ⁷ being an alkyl group, or a group of formula - (CH ₂ ) ₂ - (OCH ₂ CH ₂ ) mI with m equal to 0 or 1; - R ⁴ and R ⁶ which may be identical or different, represent I, OH, an alkyl group, a group of formula OR ⁷ , -OC (0) R ⁷ , or -OC (0) OR ⁷ with R ⁷ being a alkyl group, or a group of formula - (OCH CH2) _n I with n equal to 1 or 2; at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁶ representing I or a group comprising I, for the preparation of a radiopharmaceutical intended for determining the importance of the membrane transport of glucose.