WO2003066647A2

WO2003066647A2 - Synthesis of inositolphosphate glycan molecules: treatment of cell proliferation disorders and metabolic disorders characterized by insulin resistance

Info

Publication number: WO2003066647A2
Application number: PCT/FR2003/000345
Authority: WO
Inventors: Yves Jean Marcel Chapleur; Patrick Didier Bogdanowicz; Françoise CHRETIEN; Jean-Pierre Antoine Pujol
Original assignee: (Cnrs) Centre National De Recherche Scientifique
Priority date: 2002-02-05
Filing date: 2003-02-05
Publication date: 2003-08-14
Also published as: AU2003226862A1; FR2835527B1; AU2003226862A8; WO2003066647A3; FR2835527A1

Abstract

The invention concerns a compound of formula A wherein: R1 is selected from the group consisting of OH, an oligosaccharide, a polysaccharide, and R2=R3=OH; or at least one of the groups R1, R2, R3 is a group capable of modifying the lipophilicity of the compound A, the other or the other two of the three groups being OH; and R4 is selected from the group consisting of OH, NH2 and a group capable of modifying the lipophilicity of the compound A; and R6 is H or CH2OH; and X is selected among O, NH, S, CH2; and R5 is selected among OH, an oligosaccharide, a polysaccharide and a group capable of modifying the bioavailability of the compound A, and its pharmaceutically acceptable salts.

Description

Synthesis of glycan inositolphosphate type molecules: treatment of cell proliferation disorders and metabolic disorders characterized by insulin resistance.

The invention relates to compounds related to glycan inositolphosphates, their use as a medicament, in particular for the treatment of diseases associated with impaired glucose metabolism, and for the treatment of diseases associated with excessive cell proliferation.

Among the diseases associated with a deficient glucose metabolism, diabetes is particularly targeted. According to the mechanism in question, the WHO classification distinguishes insulin-dependent diabetes (IDD), requiring daily administration of insulin and which corresponds overall to juvenile or type 1 diabetes, and non-insulin-dependent diabetes (DNID) which corresponds with late-onset or type 2 diabetes. According to the results of the CODE 2 (Costs of Diabetes in Europe, type 2) study published in 1999, the 10 million type 2 diabetics in the eight European countries studied represent an expenditure corresponding on average to 5% of health expenditure. In the United States, this pathology represents the fourth cause of death and the expenses linked to this disease are considerable. The estimated progression of diabetes is worrying, 120 million type 2 diabetics worldwide today, 150 million in 2005, 213 million in 2010. In France, the prevalence of type 2 diabetes in the general population is estimated at About 2%, or 1.2 million people affected.

It is therefore important to study the mechanisms of action of insulin, to synthesize new insulin-mimetic molecules to increase the choice of prescribers and best customize the treatment according to the type of diabetes. The regulation of glucose metabolism by insulin involves various hormones with antagonistic effects, receptors, messengers, glucose transporters, enzymes and their substrates. The alteration of one of the links in the complex regulatory chain is capable of disrupting the entire system. It has been shown that the action of a large number of hormones and growth factors is partially mediated by second messengers belonging to the family of glycan inositolphosphates (IPG). In particular, in subjects with type 2 diabetes, an alteration in the metabolism of glycan inositolphosphates is frequently observed. IPGs originate from free or protein-anchoring glycosylphosphatidylinositols (GPIs). GPIs consist of inositol, non-N-acetylated glucosamine, carbohydrates and saturated fatty acids. Numerous studies have focused on the search for molecules of the IPG family with hypoglycemic properties.

In terms of the mechanism of action of such mediators, it has been shown that, in various cell types, insulin, the "nerve gro th factor" (NGF), interleukin-2 (IL-2), l erythropoietin (EPO) or "transforming growth factor-Bl" (TGF- Bl) controlled the release of IPG after hydrolysis of a GPI by a specific phospholipase (Varela-Nieto et al. (1996) Comp.Biochem.Physiol 15B, 223-241; Bogdanowicz et al. (2001) Med / Sci 17, 577-585).

However, although there are data concerning the composition of these mediators, their precise structure is still poorly understood, and minor variations in their composition seem to be at the origin of the diversity of their biological activity observed in many cell types. . In 1986, Saltiel and Cuatrecasas isolated two substances from plasma membranes of the liver. These two substances, with a molecular weight of approximately 1000 to 2000 Da, were capable of mimicking the action of insulin (Saltiel et al. (1986) Proc. Nat. Acad. Sci 83, 5793-5797). Since then, additional work has shown that these compounds consist of carbohydrates, non-N-acetylated glucosamine, inositol and a variable number of phosphates. Two types of IPG involved in the insulin transduction mechanisms could be isolated. Myo-WG, also called IPG type A, consists of myo-inositol and glucosamine. This isoform has a negative effect on the activity of cAMP-dependent protein kinases by inhibiting adenylate cyclase and activating cAMP phosphodiesterase. In rat adipocytes, it increases lipogenesis via the activation of acetylCoA carboxylase. Chiro-IGP, or P form, consists of methylated cΛ / ro-inositol, also called pinitol, and galactosamine. By stimulating the activity of glycogen synthetase phosphatase, this isoform increases the level of synthesis of glycogen. It also activates pyruvate dehydrogenase phosphatase, but has no effect on lipid metabolism or on the activity of cAMP-dependent protein kinases (US Patent No 4,446,064; Larner et al (1988) Biochem.Biophys.Res.CommA5l, 1416-1426).

The numerous researches carried out led to a large number of compounds intended to have an insulinomimetic action, described in particular in the following documents.

WO 99/06421 describes amino disaccharide compounds involving a slightly modified inositol.

Patent AU 5,116,496 describes IPG compounds purified from living organisms (Trypanosome and bovine liver), but this technique does not make it possible to know the exact composition and structure of IPGs; moreover, the risk of possible contamination by pathogenic agents is far from negligible.

The document Biochemistry, 1998, vol 37, 38, 13421-13436 describes synthetic IPGs comprising a basic motif constituted by a skeleton of three mannose residues, and specifies that an inositol group including the mannose side chain in the appropriate glycosidic binding position. is necessary for insulin-like activity. In addition, this document dissuades a person skilled in the art from using phosphodissacharides which he describes as clearly less effective.

US Pat. No. 6,004,938 describes compounds of the IPG type, in particular of the pentasaccharide type, obtained by chemical synthesis, effective, but the synthesis of which is very complex requiring up to fifty stages of synthesis. Thus, the known compounds do not meet all the desired criteria of efficiency, ease of synthesis, safety.

Regarding diseases associated with excessive cell proliferation, it is known that the signaling pathway involving IPG intervenes in the mechanism of action of many cytokines, hormones or growth factors, in particular TGF-β. This growth factor intervenes in particular in the healing processes, in the formation of the extracellular matrix or the control of the cell cycle. It acts via two receptors with serine / threonine kinase activity, called type I and II (TBR-I and TβR-II). Cells lacking these receptors or expressing a mutated form of these receptors become resistant to the effects of TGF-β, as is the case in non-polypotic colorectal cancers, certain cancers of the pancreas, prostate, kidney, certain metastatic cancers of the lung or chronic lymphoid leukemias ...

The binding of TGF-β to its receptors allows the recruitment of cytoplasmic proteins of the Smad family which play a central role both in controlling cell proliferation and in the transcriptional activity of genes of matrix molecules.

In addition to these mechanisms, the inventors have demonstrated that TGF-β stimulates the production of IPG in an epithelial cell line (MV _Î LU), in which it induces an inhibition of proliferation. This IPG, the precise structure of which is not known, contains inositol, phosphate and glucosamine. This IPG, now known to those skilled in the art, is capable of mimicking the effects of TGF-β on the inhibition of DNA synthesis. This antiproliferative effect is exerted independently of the presence of the type I receptor. In fact, the IPG inhibits the proliferation of the R-1B subline which is a mutant of MV _Î LU which does not express the functional TBR-I receptor . The IPG therefore acts on one or more targets, downstream of the receptors. These results indicate that the release of IPG is an important step in the control of cell proliferation by TGF-β. Furthermore, the fact that cells resistant to the antiproliferative effects of TGF-β (line R-1B) remain sensitive to exogenous IPG suggests that resistance to the antiproliferative effects of TGF-β is linked to the absence of generation of IPG after treatment with TGF-β. The alteration of this signaling mechanism could be the cause of certain tumors (Bogdanowicz et al. (1996) Ce / 7. Signal. 8, 503-509; Bogdanowicz et al. (2000) Moll.Cell.Biochem. 20S, 143-150).

The first works attempting to establish structure-activity relationships were carried out with IPG type molecules purified from GPI protein anchors (GPI from T. brucei) or more recently with a synthetic IPG (Frick et al. ( 1998) Bioche is γ 31, 13421-13436). These molecules can induce the phosphorylation of the protein IRS-1, the activation of PI-3kinase and the translocation of GLUT-4 without affecting the state of phosphorylation of the β subunit of the insulin receptor. These results confirm that these molecules must necessarily contain a certain number of sugar residues to mimic the effects of insulin. However, it is difficult to predict the activity of molecules, unless you identify a basic structure which confers the activity, or the essential of the activity, biological desired, demonstrated by biological tests, and on which different radicals can be grafted without undesirably altering this activity. The inventors have succeeded in identifying such a basic disaccharide structure described below.

Furthermore, the biochemical methods currently available make it very difficult to isolate, from microorganisms, IPG having a purity index sufficient to envisage therapeutic applications. To date, only chemical synthesis can make it possible to obtain pure IPG molecules in sufficient quantity (WO 99/38516, WO 99/37309, WO 00/64454, WO 96/29063, US 00/6004938).

In view of the prior art recalled, there is always the need to obtain new therapeutically effective IPG type compounds, the synthesis of which is simple enough for industrial production, and making it possible to act on the same targets as IPG endogenous. The invention also aims to obtain chemically pure compounds, not isolated from mammals, in order to avoid numerous risks of toxicity, for example BSE. Another object of the invention is to obtain compounds which do not have their own toxicity or immunogenicity.

To this end, the subject of the invention is, according to a first aspect, a compound of formula (A):

in which:

- R] is chosen from the group consisting of OH, an oligosaccharide, a polysaccharide, and R ₂ = R ₃ = OH, or at least one of the groups Ri, R ₂ , R ₃ is a group capable of modifying the hpophilicity of the compound A, the other or both of these three groups being OH; and - R "is chosen from the group consisting of OH, NH and a group capable of modifying the hpophilia of compound A, and

- Re is H or CH ₂ OH, and

- X is chosen from O, NH, S, CH, and

- R ₅ is chosen from OH, an oligosaccharide, a polysaccharide and a group capable of modifying the bioavailability of compound A, and its pharmaceutically acceptable salts.

The invention very advantageously relates to a compound A as a medicament. The inventors have in fact, surprisingly, succeeded in obtaining particularly active compounds compared to the prior art, by using a heterocycle instead of an inositol cycle, unlike the known compounds.

The invention also relates to the isomers of compound A.

According to a preferred embodiment, Rι = R ₂ = R ₃ = OH, and R ₄ is OH or NH ₂ .

According to one embodiment, R ₅ = OH, Re = H.

According to one embodiment, X is an α bond, the compound A being:

According to one embodiment X is a β bond, the compound of formula I below:

According to a preferred embodiment, the invention relates to a compound of formula I below:

in which:

- X is chosen from O, S, N

- R is OH or a hexose

- R ₈ is chosen from OH, NH as a medicament.

According to a preferred embodiment, the invention relates to a compound of formula II below:

in which:

- X is chosen from O, S, N

- R is OH or a hexose

- R ₈ is chosen from OH, NH ₂ as a medicament. The invention relates, according to preferred embodiments, to the compounds of formula I or II, in which the non-cyclic phosphate ring is chosen from glucose, mannose, galactose, glucosamine, mannosamine, galactosamine.

The invention relates, according to preferred embodiments, to the compounds of formula I or II, in which the ring carrying the cyclic phosphate is chosen from a pentose (for example lyxose, ribose) in D or L configuration, a hexose (for example glucose, mannose, galactose).

According to particularly advantageous embodiments, the invention relates to the compounds FC663, FC669, FC670, FC671 (see diagrams 1 and 2). According to one embodiment, the invention relates to a compound of formula A, and having a biological activity of at least 10% of that of compound I, preferably at least 30, 50, 80, 100% of this activity.

According to one embodiment, the invention relates to a compound of formula A, and having a biological activity of at least 10% of that of compound II, preferably at least 30, 50, 80, 100% of this activity.

The invention thus also relates to the compounds derived from formula A, the biological activity of which is validated by appropriate in vitro and / or in vivo biological activity tests. Among the appropriate tests, use will be made, according to one embodiment, of the activity test described in detail below in the description produced, developed for the compounds FC663, FC669, FC670, FC671, or related tests which are now carried out without undue difficulty by the skilled in the art on these derivative compounds in view of this document.

The groups capable of modifying hpophilia are known to those skilled in the art, in particular by determining the Log P value, according to appropriate methods.

The nature and size of the radicals Ri, R, R ₃ , R ₄ , R ₅ , R $ will influence the hpophilia of compound I and / or its bioavailability. Various lipophilic groups, intended to facilitate contact with the cell membrane, are known to those skilled in the art. Overall, if these groups are large, bioavailability will be reduced due to steric hindrance while hpophilia will be increased. The choice of radicals K _\ to Rβ, and in particular of RI and R5, will typically be made according to the difficulty of synthesis of the IPG and the therapeutic efficacy obtained. If necessary, different compounds will be prepared by their synthesis scheme and their therapeutic efficacy as a function of the main objective sought. Among the lipophilic groups, preference is given in particular to an embodiment of the linear or branched, saturated or unsaturated aliphatic chains. According to a preferred embodiment, the group or groups capable of modifying Hpophilia are chosen from: a) an alkyl group, linear or branched, comprising less than 20 carbon atoms; b) a cycloalkyl group comprising less than 10 carbon atoms; c) a linear or branched alkenyl group comprising less than 20 carbon atoms; d) a cyclo-alkenyl group comprising less than 10 carbon atoms; e) an aryl group comprising less than 20 carbon atoms; f) an aralkyl group comprising less than 20 carbon atoms; g) a heteroaryl group comprising 4 to 9 carbon atoms and at least one heteroatom chosen from oxygen, nitrogen, sulfur; h) a heterocyclic group, comprising 2 to 9 carbon atoms and at least one heteroatom chosen from oxygen, sulfur and nitrogen.

However, this embodiment is not limiting, the lipophilic group or groups may be more generally:

- a linear or branched alkylene, alkenyl or alkenylene group, these groups possibly being substituted by an oxa, aza, thia or a combination of at least two groups linked by a single or double bond or an O, S, SO, CON bond ;

- an alkyl, alkenyl, mono- or bi-cycloalkyl, aryl, heteroaryl, mono- or bicycloalkylalkyl, mono- or bicycloalkylalkenyl, arylalkyl, aralkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, darycycloalkylalkylalkylalkylalkylalkyl or diazabicycloalkyl, mono- or bicyclo heteroaromatic;

- a group chosen from:

CH ₃ (CH ₂ ) n CH (COOH) NHCO (CH ₂ ) ₂ CO-, CH ₃ (CH ₂ ) r CONHCH (COOH) (CH ₂ ) ₂ CO-,

-NHCH (COOH) (CH ₂ ) ₄ NH-CO (CH ₂ ) mCH ₃ ,

-NHCH (COOH) (CH ₂ ) ₄ NH-COCH ((CH) ₂ COOH) NH-CO (CH ₂ ) pCH ₃ , n, m, r, p being an integer between 5 and 15;

- an aryl lipophilic group (including bicyclic aryl groups) unsubstituted or substituted with one, two or three substituents independently chosen from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, sulfhydryl radicals , nitro, cyano, carboxaldehyde, carboxy, alkoxycarbonyl, haloalkyl-C (O) -NH-, haloalkenyl-C (O) - NH and carboxamide (in addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl);

- a steroid derivative, a natural or synthetic lipid, a saccharide capped by an aliphatic or cycloaliphatic unit.

The term "alkenyl" refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and also containing at least one C = C double bond. Examples of alkenyl include -CH≈CH ^ -CH ₂ CH = CH ₂ , -C (CH ₃ ) = CH ₂ , -CH ₂ CH = CHCH ₃ , and the like. The term "aryl" refers to a carbocyclic system comprising at least one aromatic ring, and refers in particular to the phenyl, piridyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like radicals.

The term "arylalkyl" refers to a lower alkyl radical to which an aryl group is added. Mention will in particular be made of benzyl and phenylethyl groups, hydroxybenzyl, fluorobenzyl and fluorophenylethyl.

The term "cycloalkyl", mono- or poly-cycloalkyl, preferably refers to an alicyclic group comprising from 3 to 10 carbon atoms, in particular the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl groups. The cycloalkyl groups can be optionally substituted. The term "lower alkyl" refers to alkyl groups of branched or straight chain, optionally substituted, containing one to ten carbon atoms, in particular methyl, ethyl, propyl, isopropyl, butyl, isopentyl groups.

The term "oxo" means (= O). The term "Bn" means benzyl.

The invention relates, according to another aspect, to a compound A in β configuration, and preferably, a compound of formula (II) capable of mimicking the action of insulin for the treatment of diseases due to a deficient glucose metabolism .

The inventors have in fact demonstrated that such compounds (II) are capable of mimicking the action of insulin on the uptake of glucose in adipocytes as well as on the synthesis of glycogen in hepatocytes. Such compounds (II) induce phosphorylation of the insulin receptor β subunit and they are also capable of mimicking the effects of insulin on two cytoplasmic targets involved in signaling: phosphorylation, on one or more tyrosine residues, of IRS-1 (Insulin Receptor Substrat-1) and activation of Erkl / 2 MAPkinases (Extracellular Regulated Kinase 1/2 Mitogen Activated Protein kinase). These molecules can be used in the treatment of disorders of glucose metabolism such as glucose intolerance, hyperglycemia associated with non-insulin dependent diabetes, insulin resistance and their chronic complication. Insulin resistance can result from disorders such as obesity, hyperlipidemia, dyslipidemia, atherosclerosis, hypertension, cardiovascular pathologies, AIDS, cancers, cachexia, septicemia, trauma associated with burns, malnutrition, stress, age, lupus and other autoimmune pathologies, endocrine disorders, hyperuricemia, polycystic ovarian syndrome and complications due to sports activity or inactivity.

The invention also relates to the use of a compound A in the β configuration, and preferably of a compound II, for the preparation of a medicament against disorders due to a deficient glucose metabolism. The invention also relates to a method for the treatment of disorders due to a deficient glucose metabolism comprising the use of a compound A in the β configuration, and preferably of an IL compound

According to another aspect, the invention also relates to the use of a compound A in the α configuration, and preferably a compound of formula I, for the treatment of diseases associated with excessive cell proliferation, in particular cancer, psoriasis and rheumatoid pannus.

The inventors have in fact demonstrated that compounds of formula (I), of the inositolphosphate glycan (IPG) type, are capable of strongly inhibiting the proliferation of cells, and in particular of cells originating from a human adenocarcinoma line SW- 480, as will be described later. These molecules can be used in the treatment of pathologies with excessive cell proliferation such as cancer, psoriasis and the rheumatoid synovial pannus.

According to another aspect, the invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound A as described above, preferably a compound I or a compound II, and a pharmaceutically acceptable vehicle. The invention also relates to the use of a compound A in α configuration, and preferably of a compound of formula I, for the preparation of a medicament against diseases associated with excessive cell proliferation, in particular cancer, psoriasis and rheumatoid pannus.

The invention also relates to a method of treating diseases associated with excessive cell proliferation, in particular cancer, psoriasis, rheumatoid pannus, comprising the use of a compound I.

According to another aspect, the invention relates to a process for obtaining compounds of formula I or II, in which X = O and R4 = OH, comprising the following steps: step 1: mixing of the compounds (1) and (2) formulas

(2)

(1)

step 2: deacetalization of the intermediates obtained in step 1,

-step 3: cyclization and deprotection of the intermediates obtained in step 2.

According to another aspect, the invention relates to a process for obtaining formula I or II, in which X = O and = NH ₂ , comprising the steps:

-step 1: mixture of the compounds (9) and (2) of formulas

(9) (2) -step 2: deacetalization of the intermediates obtained in step 1, -step 3: deprotection of the intermediates obtained in step 2. According to one embodiment, the pharmaceutically effective amount of compound A, and preferably of compound I or II administered, corresponds to a dose typically of the order of 10 μg / kg / day to 100 mg / kg / day of body weight. Preferably the dose will be of the order of 0.1 to 1 mg / kg / day. For continuous parenteral administration, the dosage may for example be of the order of 50 μg / kg / hour to 1 mg / kg / hour, in several injections / day or by continuous subcutaneous infusion.

The pharmaceutical compositions comprising the inositolphosphate glycan type molecules of formula A described above can be formulated in different ways. In addition to one or more synthetic IPGs of formula A, preferably of formula I or II, these pharmacologically acceptable formulations can also comprise an excipient, a transporter, a buffer, a stabilizer or any other suitable substance. The term carrier or vehicle "pharmacologically acceptable" means a non-toxic solid, ^'containing semi-solid or liquid, encapsulating material or auxiliary substance of any type whatsoever. Such substances should not interfere with the effectiveness of the active ingredient (s). The precise nature of the carrier or material depends on the route of administration, for example oral, rectal, intravaginal, topical (such as powders, ointments, transdermal drops or patch), intravenous, cutaneous or subcutaneous, nasal, intramuscular, intrasternal, intraperitoneally, by intra-articular injection or infusion. It is possible, for example, to use water, a saline solution, a Ringer's solution, a dextrose solution, a non-aqueous solution containing oils or liposomes, petrolatum, vegetable, animal, mineral or synthetic oils, as a transporter. . The suitable transporters may contain additives which increase the chemical stability of the composition in particular, for example: buffers (such as phosphates, citrates, succinates, organic acids), antioxidants, low molecular weight peptides, proteins (gelatin, serum albumin), hydrophilic polymers (polyvinyl pyrrolidones), amino acids, saccharides (glucose, dextrin), chelating agents (EDTA), nonionic surfactants (ethylene glycol, propylene glycol, polyethylene glycol). A compound according to the invention is typically formulated at a concentration of about 0.1 mg / ml to 100 mg / ml, in particular from 0.1 to 10 mg / ml. The invention also relates to the use of salts of the compounds according to the invention, the use of certain transporters or other excipients being able to involve the formation of such salts according to the substituents of the disaccharide according to the invention. The compounds of the present invention are typically stored as unit doses in suitable containers, or as an aqueous solution or lyophilized formulation.

The formulations for oral administration can be presented in particular in the form of tablets, capsules, powder or liquid. A tablet may include an excipient / carrier such as gelatin or an adjuvant.

For intravenous, cutaneous or subcutaneous injections, synthetic IPGs of formula A, and preferably of formula I or II, are in the form of an acceptable aqueous solution in parenteral form, that is to say in the absence of pyrogen , at adequate pH, isotonicity and stability (e.g. NaCl, Ringer's solution, or Ringer-lactate solution).

The prescription of the compounds of this present invention is preferably done, for each individual, at prophylactic or therapeutic dosages sufficient to exert a beneficial action (antiproliferative effects, appropriate treatment of disorders of glucose metabolism such as glucose intolerance, hyperglycemia associated with DNID and any form of insulin resistance). The dosage and method of administration will depend on the nature and severity of the condition to be treated.

Treatment decisions, such as dosage, are the responsibility of the treating physicians. They must take into account the pathologies to be treated, the patient, the mode of administration in particular. These various examples mentioned above can be found in: "Remington's Pharmaceutical Sciences,

16 ^th edition, Oslo, A. (ed), 1980 ".

Thanks to the work carried out by the inventors, the compounds obtained present an easier synthesis than that of the known compounds, these compounds being moreover not recognized by enzymes usually in charge of the metabolism of sugars. In addition, the IPG molecules obtained do not exhibit acute (short term) nor chronic (long term) toxicities. Other objects and advantages of the description will emerge from the following detailed description, illustrated by the figures:

- Figure 1.a: effect of compound FC663 on the proliferation of SW-480 cells. The cells are seeded in 96-well plates and incubated in the presence or absence of the test compound FC663 at different concentrations for 24 hours. The colorimetric reagent is added during the last 4 hours. Cell proliferation is measured by densitometric reading at 490 nm (**: p <0.01; *** p <0.005).

- Figure lb: effect of compound FC669 on the proliferation of SW-480 cells. The cells are seeded in 96-well plates and incubated in the presence or absence of the test compound FC669 at different concentrations for 24 hours. The colorimetric reagent is added during the last 4 hours. Cell proliferation is measured by densitometric reading at 490 nm (**: p <0.01; *** p <0.005). - Figure 2. a: effect of compound FC670 on the synthesis of glycogen at the level of HepG2 hepatocytes. The cells are seeded in 9.6 cm ² plates and then incubated for 4 hours with the test compound FC670 or with insulin (positive control) in the presence of D [ ³ H-2] glucose as described in the chapter " Materials and methods". The synthesis of glycogen is measured by the incorporation of tritiated glucose and related to the amount of total protein (*: p <0.05; *** p <0.005).

- Figure 2.b: effect of compound FC671 on glycogen synthesis in HepG2 hepatocytes. The cells are seeded in 9.6 cm ² plates and then incubated for 4 hours with the test compound FC671 or with insulin (positive control) in the presence of D [ ³ H-2] glucose as described in the chapter " Materials and methods". The synthesis of glycogen is measured by the incorporation of tritiated glucose and related to the amount of total protein (*: p <0.05; *** p <0.005). Figure 3.a: effect of compound FC670 on the uptake of glucose at the level of 3T3-L1 adipocytes. The cells are seeded in 9.6 cm ² plates then incubated for 20 minutes with the compound FC670 or with insulin (positive control), then [ ³ H] deoxy-D-glucose is added to the environment as described in the chapter "materials and methods". Glucose uptake is measured by the incorporation of 2- [ ³ H] deoxy-D-glucose (*: p <0.05; *** p <0.005).

Figure 3.b: Effect of compound FC671 on the uptake of glucose at the level of 3T3-L1 adipocytes. The cells are seeded in 9.6 cm ² plates and then incubated for 20 minutes with compound FC671 or with insulin (positive control), then [H] deoxy-D-glucose is added to the medium as described in the chapter "materials and methods". Glucose uptake is measured by the incorporation of 2- [H] deoxy-D-glucose (*: p <0.05; *** p <0.005).

Figure 4.a: effect of insulin on the phosphorylation of IRS-1 and of the β subunit of its receptor at the level of HepG2 hepatocytes, measured according to method 2.C. Figure 4.b: Effect of compound FC670 on the phosphorylation of IRS-1 and of the β subunit of its receptor at the level of HepG2 hepatocytes, measured according to method 2.C.

- Figure 4.c: effect of compound FC671 on the phosphorylation of IRS-1 and the β subunit of its receptor at the level of HepG2 hepatocytes, measured according to method 2.C. - Figure 5.a: effect of insulin on the activation of Erkl / 2 MAPkinase at the level of HepG2 hepatocytes, measured according to method 2.D.

- Figure 5.b: effect of compound FC670 on the activation of Erkl / 2 MAPkinase at the level of HepG2 hepatocytes, measured according to the method 2.D.

Figure 5.c: effect of compound FC671 on the activation of Erkl / 2 MAPkinase at the level of HepG2 hepatocytes, measured according to method 2.D.

The synthetic diagrams and the test results described in detail are presented by way of illustration and not limitation, using four example compounds, corresponding to formulas I or II, having particularly advantageous properties, and designated FC663, FC669 , FC670, FC671. The synthesis of compounds FC663 and FC671 was carried out according to the following reaction schemes. Diagram 1

FC663 FC671

The synthesis and structure of the molecules are detailed below.

Synthesis of compounds 3 and 4.

0.580 g (2.07 mmol) of compound 2 (GE Keck, TT Wager, J. Org. Chem. 61 (1996) 8366-8367) and 2.12 g (3.1 mmol) of compound 1 are dissolved in 20 ml of anhydrous methylene chloride then 1 g of molecular sieve (4 Å) are added. The suspension is stirred at -30 ° C for 15 minutes and then 1 ml of a 0.2 molar solution of trimethylsilyltrifluoromethane sulfonic acid in methylene chloride is added. The reaction mixture is stirred at -30 ° C for 1 hour then it is allowed to return to room temperature. The suspension is filtered through celite and the filtrate is concentrated under reduced pressure. Compounds 3 (0.750 g, 45%) and 4 (0.450 g, 27%) are obtained pure by chromatography on silica gel. Compound 3 is a colorless oil. Ry = 0.39 (hexane / ethyl acetate 8: 2); [α]> = +52 (c = 3.1

CHCl3); * H NMR (CDCI3) δ 5.32 J = 4 Hz, signal characteristic of an anomeric proton of configuration α of a glucose residue; analysis calculated for C4QH54OIO ^: % C = 73.3,% H = 6.8; found:% C = 73.59,% H = 6.61.

Compound 4 is a colorless oil. Ry = 0.35 (hexane / ethyl acetate 8: 2); [\ τ =

+24 (c = 1.4 CHCI3); 1 H NMR (CDCI3) δ 4.55 J = 8 Hz, signal characteristic of an anomeric proton of configuration β of a glucose residue; analysis calculated for C49H54O10:% C = 73.3,% H = 6.8; found:% C = 73.42,% H = 6.75

Synthesis of compound 5.

0.750 g (0.93 mmol) of compound 3 are dissolved in 3 ml of tetrahydrofuran (THF) and then 20 ml of an aqueous solution of acetic acid at 70% are added to this solution. The reaction mixture is heated at 60 ° C for 5 hours. The solvents are evaporated under reduced pressure and the residue is coevaporated 2 times with toluene. Compound 5 (0.524 g, 74%) is obtained pure in the form of a colorless oil by purification on a column of silica gel. R = 0.51 (hexane / ethyl acetate 5: 5);

[α] D = +60 (c = 0.9 CHCI3); analysis calculated for C46H50O10:% C = 72.4,% H =

6,6; found:% C = 72.71,% H = 6.69.

Synthesis of compound 7.

Compound 7 (0.314 g, 70%) is obtained in the form of a white powder by treatment of 0.450 g (0.59 mmol) of compound 4 according to the protocol described for the preparation of compound 5. Ry = 0.46 (hexane / ethyl acetate 5: 5); F = 139 ° C, [a] D = +41 (c = 0.7 CHCI3); analysis calculated for C46H50O10:% C = 72.4,% H = 6.6; found:% C = 72.35,% H = 6.45.

Synthesis of compounds FC663 and FC671. 3 g of triazole are dissolved in 80 ml of THF, the resulting solution is cooled to 10 ° C., then 1.35 ml of phosphorus oxychloride and then 6 ml of triethylamine are added successively dropwise. The reaction mixture is then stirred at room temperature for 15 minutes. The precipitate formed during the reaction is filtered and then washed with a little anhydrous THF. 0.2 g (0.26 mmol) of compound 5 or 7 are dissolved in 2 ml of anhydrous THF and then 30 ml of the previously obtained filtrate are added. The reaction volume is reduced to 5 ml by concentration under reduced pressure. The reaction mixture is stirred at room temperature for 15 minutes and then diluted with 70 ml of ethyl acetate. The organic phase is washed twice with 2 ml of water, decanted, dried magnesium sulphate, then concentrated. The residue contains cyclic phosphate (31p NMR δ 14.2 ppm) which is used without purification for the deprotection step. The cyclic phosphate is dissolved in 20 ml of a THF / EtOH / H2θ mixture (1: 1: 1) and then stirred for 20 hours under a hydrogen atmosphere in the presence of 20 mg of triethylammonium hydrogen carbonate and 160 mg of palladium. on 10% charcoal. The catalyst is filtered through celite and rinsed with water. The filtrate is concentrated under reduced pressure. The residue is diluted with 1 ml of water and purified using a Cl 8 isolute SPE column to provide, after lyophilization, the compound FC663 or FC671 in the form of triethylammonium salt.

The synthesis of the compounds FC669 and FC670 was carried out according to the following reaction schemes. Diagram 2

FC669 FC670

Synthesis of compounds 10 and 11.

0.500 g (1.78 mmol) of compound 2 (GE Keck, TT Wager, J. Org. Chem. 61 (1996) 8366-8367) and 1.65 g (2.67 mmol) of compound 9 (W. Kinzy , RR Schmidt, Liebigs Ann. Chem. (1985), 1537-1545) are dissolved in 20 ml of chloride anhydrous methylene then 1 g of molecular sieve (4 Å) are added. The suspension is stirred at -30 ° C for 15 minutes and then 1 ml of a 0.2 molar solution of trimethylsilyltrifluoromethane sulfonic acid in methylene chloride is added. The reaction mixture is stirred at -30 ° C for 1 hour then it is allowed to return to room temperature. The suspension is filtered through celite and the filtrate is concentrated under reduced pressure. Compounds 10 (0.537 g, 41%) and 11 (0.557 g, 44%) are obtained pure by chromatography on silica gel. Compound 10 is a white powder.

0.41 (hexane / ethyl acetate 8: 2); Mp 85 ° C; [α] D = +73 (c =

0.54 CHCI3); ! H NMR (CDCI3) δ 5.34 J = 4 Hz, signal characteristic of an anomeric proton of configuration α of a glucose residue; analysis calculated for C42H47N3O9:% C = 68.4,% H = 6.4,% N = 5.7; found:% C = 68.71,% H = 6.64,

% N = 5.46.

Compound 11 is a white powder. Ry = 0.38 (hexane / ethyl acetate 8: 2); F =

89 ° C [CC] D = +15.3 (c ≈ 1.2 CHCI3); H NMR (CDCI3) δ 4.42 J = 7.5 Hz, signal characteristic of an anomeric proton of configuration β of a glucose residue; analysis calculated for C42H47N3O9:% C = 68.4,% H = 6.4,% N = 5.7; found:% C = 68.52,% H = 6.35,% N = 5.82.

Synthesis of compound 12. 0.287 g (0.39 mmol) of compound 10 is dissolved in 3 ml of tetrahydrofuran (THF) and then 20 ml of an aqueous solution of acetic acid at 70% are added to this solution. The reaction mixture is heated at 60 ° C for 5 hours. The solvents are evaporated under reduced pressure and the residue is co-evaporated 2 times with toluene. Compound 12 (0.293 g, 75%) is obtained pure in the form of a gum by purification on a column of silica gel. R ≈ 0.56 (hexane / ethyl acetate 5: 5);

[α] D = +60.5 (c = 1.3 CHCI3); analysis calculated for C39H49N3O9:% C = 67.1,% H = 6.2,% N = 6.0; found:% C = 66.95,% H = 5.89,% N = 5.78.

Synthesis of compound 14. Compound 14 (0.334 g, 84%) is obtained in the form of white foam by treatment of 0.400 g (0.54 mmol) of compound 11 according to the protocol described for the preparation of compound 12. Ry = 0.39 (hexane / ethyl acetate 5: 5); [α] = +41.4 (c = 1.2 CHCI3); analysis calculated for C39H49N3O9:% C = 67.1,% H = 6.2,% N = 6.0; found:% C = 66.99,% H = 6.02,% N = 5.88.

Synthesis of compounds FC669 and FC670.

3 g of triazole are dissolved in 80 ml of THF, the resulting solution is cooled to 10 ° C., then 1.35 ml of phosphorus oxychloride and then 6 ml of triethylamine are added successively dropwise. The reaction mixture is then stirred at room temperature for 15 minutes. The precipitate formed during the reaction is filtered and then washed with a little anhydrous THF.

0.209 g (0.3 mmol) of compound 12 or 14 are dissolved in 2 ml of anhydrous THF and then 30 ml of the previously obtained filtrate are added. The reaction volume is reduced to 5 ml by concentration under reduced pressure. The reaction mixture is stirred at room temperature for 15 minutes and then diluted with 70 ml of ethyl acetate. The organic phase is washed twice with 2 ml of water, decanted, dried magnesium sulphate, then concentrated. The residue contains cyclic phosphate (31p NMR δ 14.2 ppm) which is used without purification for the deprotection step. The cyclic phosphate is dissolved in 20 ml of a THF / EtOH / H2θ mixture (1: 1: 1) and then stirred for 20 hours under a hydrogen atmosphere in the presence of 20 mg of triethylammonium hydrogen carbonate and 160 mg of palladium. on 10% charcoal. The catalyst is filtered through celite and rinsed with water. The filtrate is concentrated under reduced pressure. The residue is diluted with 1 ml of water and purified using a Cl 8 isolute SPE column to provide, after lyophilization, the compound FC669 or FC670 in the form of triethylammonium salt.

The activity of the compounds was evaluated according to the following methods. The molecules synthesized are tested on various parameters, to determine their anti-proliferative and insulin-mimetic properties. The measurements made to assess insulin-mimetic activity systematically include a positive control (insulin). The experiments described below evaluate the biological activities of the four previously described molecules, designated: FC663, FC669, FC670 and FC671. Material The RPMI 1640, the DMEM, the fetal calf serum "SVF" and the donor calf serum "SVD" are supplied by Life Technologies. D [2- ³ H] glucose (21.00 Ci / mmol) and [6- ³ H] 2-deoxy glucose (6.10 Ci / mmol) are obtained from NEN Life Science. The Celltiter 96 ^® reagent comes from Promega. The anti-phosphotyrosine (4G10), anti-Erkl / 2MAPkinase and anti-phospho-Erkl / 2MAPkinase antibodies come from Upstate Biotechnology. The chemiluminescence antibody revelation kit comes from Amersham. All chemicals as well as insulin, glycogen, dexamethasone and isobutylmethylxanthine (IBMX) come from SIGMA. 3T3-L1 cell lines: line of pre-adipocytes selected from the mouse fibroblast line 3T3 for their ability to differentiate into adipocytes under certain experimental conditions.

HepG2: human hepatocarcinoma line (ATCC number: HB-8065). SW-480: human colorectal adenocarcinoma line (ATCC number: CCL-228). The cells are kept in culture in DMEM + SVF 10% (SW480), in RPMI + SVF 10% + insulin 0.5% + BSA 5% (HepG2) and in DMEM + SVD 10% (3T3-L1) , in an atmosphere with 5% CO ₂ and 95% air. These media are added with penicillin (lOOU / ml), streptomycin (lOOμg / ml) and fungizone (0.25μg / ml). Differentiation of 3T3-L1 cells

The cells (3T3-L1) are cultured in 6-well plates (3.10 cells / well) in the presence of DMEM + 10% SVD. At confluence, the medium is replaced by DMEM + 10% FCS containing dexamethasone (25 μM), isobutylmethylxanthine (100 μM) and insulin (170 nM) in order to induce the differentiation of fibroblasts (3T3-L1) adipocytes. Two days later, the cells are incubated for 4 to 6 days in the DMEM differentiation medium + 10% FCS + insulin 170 nM. The cells are used for the measurement of glucose uptake when approximately 80 to 90% contain lipid vacuoles (phenotypic marker). Measurement of glucose uptake

When the cells are differentiated, 2 washes are carried out with DMEM followed by another washing with KRH buffer + 1% BSA + 5 mM Glc. Then, the cells are incubated in the presence of the different molecules at the indicated concentrations (100, 50 and 25 μM) for 20 minutes. Then, 10 μl of the mixture [6- H] 2- deoxyglucose + glucose with ImM are added to each well. Twenty minutes later, 3 washes are carried out with KRH + 5 mM Glc (4 ° C.), followed by lysis of the cells with 1 ml of 0.1N NaOH containing 0.1% SDS. Finally, the measurement is carried out in a liquid scintillation counter. Colorimetric measurement of cell proliferation

The principle of this method is based on the capacity of living cells to convert the tetrazolium salts, contained in Celltiter96®, into formazan. The cells (SW480) are seeded in 96-well plates (5.10 cells / well) in DMEM + 10% FCS. After 48 hours, the cells are incubated in the presence of the different concentrations of the molecules for 24 hours. After 20 h, 20 μl of reagent are added to each well and the absorbance is measured at 490 nm, after 4 hours, with a plate reader (SpectraCount ™; Packard).

Glycogen synthesis

The hepatocytes are seeded in 6-well plates (2.10 cells / well) in the presence of RPMI + 10% SVF + 0.5% insulin + 5% BSA. After 2 days, the cell mats are incubated for 3 h in RPMI + glucose 5 mM, then incubated with the different molecules. After 30 minutes, the 6 [ ³ H] -D glucose is added (2 μCi / ml). After 4 h of metabolic labeling, the cell mats are rinsed with PBS 4 ° C, then lysed with 0.1 M sodium hydroxide. An aliquot of 50 μl is taken to measure the protein concentration by the Bradford method. The glycogen is precipitated, 2 h at -80 ° C, with 5 volumes of ethanol in the presence of a entrainer (5 mg of glycogen). After centrifugation (15 min. At 6000 g) the pellet is taken up in 500 μl of H O and then the radioactivity is measured. Western blot The concentration of cytoplasmic or nuclear extracts is determined by the Bradford method. The samples (15 to 30 μg) are taken up in buffer

Laemmli 5X supplemented with Na ₃ VO ₄ 1 mM (Laemmli et al (1970) Nature 227, 680-

685). The migration of the samples is carried out, under denaturing condition (SDS-PAGE), in electrophoresis buffer, then the proteins are transferred to a

TM PVDF membrane (Polyvinylidene difluoride; NEN Life Science Products). This transfer is carried out in electrotransfer buffer (75 min at 100 V), then the non-specific sites are blocked in TBS-T buffer containing 10% skimmed milk or 5% bovine serum albumin (BSA). The membrane is then washed 3 times in TBS-T buffer and then incubated with the primary antibodies. The membrane then undergoes numerous successive baths in TBS-T buffer, then is incubated for one hour with a solution of secondary antibodies, coupled to an HRP. After washing, the revelation of the antibodies is carried out by chemiluminescence (Kit ECL +; Amersham). The membranes can be "washed" 30 min at 50 ° C in a denaturation solution and then reincubated with a different primary antibody. Statistical analyzes

The results are the average of 4 wells (glycogen synthesis and glucose uptake tests) or 8 wells (proliferation). The significance of the results is determined using the Student test (*: p <0.05; **: p <0.01; ***: p <0.005).

1) Antiproliferative effects of type (I) molecules

After 24 hours of incubation, the compound FC663 exerts, on proliferation, an inhibitory effect directly proportional to the concentrations. Thus, we measured an inhibition of approximately 34% from 25 μM to reach 65% at 100 μM (Fig. La). The compound FC669 also exerts a very marked inhibitory effect which is measurable from 25 μM (-35%). The inhibitory effect depends on the concentration used since it reaches 70% at 100 μM (Fig. Lb). In Figures 1a and 1b, the cells are seeded in 96-well plates and incubated in the presence or absence of the test compounds FC663 and FC669 at different concentrations for 24 hours. The colorimetric reagent is added during the last 4 hours. Cell proliferation is measured by densitometric reading at 490nm (**: p <0.01; ***: p <0.005). 2) Insulin-mimetic effects of type (II) A molecules / Effects on glycogen synthesis in hepatocytes

The hepatocytes of the HepG2 line were incubated for 4 hours in the presence of different concentrations (100, 50, 25 and 10 μM) of the test compounds, or in the presence of insulin (5 and 1 μM) used as a positive control. . We have measured an increase in glycogen neo-synthesis in the presence of insulin. From one experiment to another, this stimulation amounts to approximately 30 to 35%) for the concentration of 5 μM to reach 40 to 50% at 1 μM. (Fig. 2 a, b). The compound FC670 clearly stimulates the synthesis of glycogen by 50%) at 100 μM and by 35% at 50 μM. No significant effect was measured at the lower concentrations (Fig. 2a). The compound FC671 also exerts a stimulating effect on the synthesis of glycogen. This effect can be measured from the concentration of 25 μM with an increase of 30%. This stimulation reaches 65% at 50 μM and 52% at 100 μM (Fig. 2b). In FIGS. 2a and 2b, the cells are seeded in 9.6 cm plates and then incubated for 4 hours with the compounds FC670 and FC671 or with insulin (positive control) in the presence of D [ ³ H-2] glucose as described in the chapter "materials and methods". Glycogen synthesis is measured by the incorporation of tritiated glucose and related to the amount of total protein. (*: p <0.05; ***: p <0.005). B / Effects on glucose uptake in adipocytes

The 3T3-L1 differentiated into adipocytes were incubated for 40 minutes in the presence of insulin (positive control) or of the compounds FC670 and FC671 (100, 50 and 25 μM). In both experiments, the insulin stimulated the uptake of [6- ³ H] 2-deoxy glucose by the adipocytes by about 40% compared to the control (Fig. 3a, b). FC670 (50 or 100 μM) stimulated uptake by around 55% (Fig. 3a). In the presence of compound FC671, an increase in uptake of approximately 60% was measured at 100 μM. The effect is even more pronounced at 50 μM since the increase amounts to + 95% (Fig. 3b). In Figures 3a and 3b, the cells are seeded in 9.6 cm ² plates and then incubated for 20 minutes with the compounds FC670 and FC671 or with insulin (positive control) then 2- [ ³ H] deoxy-D-glucose is added to the medium as described in the chapter "materials and methods". The Glucose uptake is measured by the incorporation of 2- [ ³ H] deoxy-D-glucose. (*: p <0.05; ***: p <0.005).

C / Effects on the phosphorylation of the insulin receptor and IRS-1 β subunit in hepatocytes The hepatocytes of the HepG2 line were incubated in the presence of insulin

(1 μM), of compound FC670 (50 μM) or of compound FC671 (50 μM), for 5, 15, 30 and 60 minutes. In the presence of insulin, we observed, from 5 minutes of incubation, an increase in the phosphorylation of the β subunit of the insulin receptor (P-IR-B: 95kDa), with a maximum after 15 minutes incubation. A return to the basal state is measured after one hour of incubation (Fig. 4 a). In addition, after 15 minutes of incubation, insulin also increases the phosphorylation of IRS-1 (P-IRS-1: 165kDa) Like insulin, the compounds FC670 (Fig. 4 b) and FC671 (Fig. 4 c) stimulate both the phosphorylation of the insulin receptor ^β (P-IR-β: 95kDa) subunit and of IRS-1. D / Effects on the activation of Erkl / 2MAPkinases in hepatocytes

The hepatocytes of the HepG2 line were incubated in the presence of insulin (1 μM), of the compound FC670 (50 μM) or of the compound FC671 (50 μM), for 5, 15, 30 and 60 minutes. In the presence of insulin, we observed, from 15 minutes of incubation, the activation of Erkl / 2MAPkinases. A return to the basal state is measured after one hour of incubation (Fig. 5 a). The compounds FC670 (Fig. 5 b) and FC671 (Fig. 5 c) activate Erkl / 2 incubation after 5 minutes. This activation is maximum after 15 minutes of incubation, then decreases slightly after one hour of incubation.

BIBLIOGRAPHICAL REFERENCES

Bogdanowicz et al. (2001) Med / Sci 17, 577-585;

Bogdanowicz et al. (1996) Cell. Signal. 8, 503-509;

Bogdanowicz et al. (2000) Mol. Cell. Biochem. 208, 143-150;

Frick and α /. (1998) Biochemistry 37, 13421-13436

G. E. Keck, T. T. Wager, J. Org. Chem. 61 (1996) 8366-8367;

Lamer et al (1988) Biochem. Biophys. Res. Comm. 151, 1416-1426;

Laemmli et al (1970) Nature 227, 680-685,

Saltiel et al. (1986) Proc. Nat. Acad. Sci. 83, 5793-5797;

Varela-Nieto et al. (1996) Co / rcp. Biochem. Physiol. 115B, 223-241;

W. Kinzy, R. R. Schmidt, Liebigs Ann. Chem. (1985) 1537-154

Biochemistry, 1998, Structure- Activity relationship of synthetic phosphoinositolglycans mimicking metabolic insulin action, vol 37, 38, 13421-13436

Remington's Pharmaceutical Sciences, 16 ⁰¹ edition, Oslo, A. (ed), 1980;

Claims

1. Compound of formula A

in which:

- Ri is chosen from the group consisting of OH, an oligosaccharide, a polysaccharide, and R ₂ = R ₃ = OH; or at least one of the groups Ri, R ₂ , R ₃ is a group capable of modifying the hpophilia of compound A, the other or the other two of these three groups being OH, and; - R ₄ is chosen from the group consisting of OH, NH ₂ and a group capable of modifying the hpophilia of compound A, and

- Re is H or CH ₂ OH, and

- X is chosen from O, NH, S, CH ₂ , and

2. Compound according to claim 1 characterized in that Rι = R ₂ = R ₃ = OH, and R4 is OH or NH ₂ .

3. Compound according to claim 1 or 2 characterized in that R = OH, R _Ô = H.

4. Compound according to any one of claims 1 to 3 characterized in that the group or groups capable of modifying hpophilia are chosen from a) an alkyl group, linear or branched, comprising less than 20 carbon atoms b) a cycloalkyl group comprising less than 10 carbon atoms c) a linear or branched alkenyl group comprising less than 20 carbon atoms d) a cyclo-alkenyl group comprising less than 10 carbon atoms e) an aryl group comprising less than 20 carbon atoms) an aralkyl group comprising less than 20 carbon atoms g) a heteroaryl group comprising 4 to 9 carbon atoms and at least one heteroatom chosen from oxygen, nitrogen, sulfur h) a heterocyclic group, comprising 2 to 9 carbon atoms and at least one heteroatom chosen from oxygen, sulfur and nitrogen.

5. Compound according to any one of claims 1 to 4 characterized in that X is in the α configuration

6. Compound according to any one of claims 1 to 4 characterized in that X is in the β configuration

7. Compound of formula I,

in which:

X is chosen from O, S, N

R ₇ is a hexose

R ₈ is chosen from OH, NH ₂

8. Compound of formula II,

in which: - X is chosen from O, S, NR is a hexose R ₈ is chosen from OH, NH ₂

9. Compound according to any one of claims 1 to 8, as a medicament.

10. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any one of claims 1 to 8, and a pharmaceutically acceptable vehicle.

11. Compound according to one of claims 6 or 8 for the treatment of diseases due to a deficient glucose metabolism.

12. Use of a compound according to one of claims 6 or 8 for the preparation of a medicament against disorders due to a deficient glucose metabolism.

13. Compound according to one of claims 5 or 7 for the treatment of diseases associated with excessive cell proliferation, in particular cancer, psoriasis and rheumatoid pannus.

14. Use of a compound according to one of claims 5 or 7 for the preparation of a medicament against diseases associated with excessive cell proliferation, in particular cancer, psoriasis and rheumatoid pannus.