WO2013021105A2 - Novel derivatives of furanones and pharmaceutical composition containing same - Google Patents

Abstract

The invention relates to a compound of general formula (I) wherein R is a phosphoryl group of formula (II), R¹ and R² are selected from alkyl, alkene, aryl, arylalkyl, hetero-arylalkyl, and R⁴ is H.

Description

 Novel furanone derivatives and pharmaceutical composition containing them Technical field

 The invention relates to pharmaceutical chemistry, and more particularly to novel heterocyclic furan-2 (5H) -one derivatives, to a process for their preparation, to compositions containing them and to their use in the manufacture of medicaments.

More particularly, the invention relates to novel heterocyclic furan (5H) -one derivatives having anticancer activity. State of the art

 Vitamin C (ascorbic acid L) has long been thought to have other therapeutic effects than scurvy. According to a controversial hypothesis (see the publication of Rath and Pauling "Hypothesis: Lipoprotein (a) is a surrogate for ascorbate", published in 1990 in Proc Natl Acad Sci USA, vol 87, p 6204-6207), a high plasma concentration of ascorbate could decrease the concentration of lipoprotein Lp (a) and thus act against cardiovascular diseases, cancer and diabetes. US Patent 5,278,189 (Rath and Pauling) describes the effect of a drug comprising ascorbate, a lipoprotein inhibitor Lp (a) and an antioxidant against occlusive cardiovascular diseases.

The antiproliferative effect of high-dose ascorbic acid L (vitamin C) on certain types of cancer has been demonstrated in vitro and in vivo in a mouse model of colon cancer by Professor Fontes' team in Marseille (see for example the electronic publication "Antiproliferative effect of Ascorbic Acid Is Associated with the Inhibition of Genes Necessary to Cell Cylation Progression" by S. Belin et al., published in February 2009 in PlosOne 4 (2), e4409). This effect seems to be related to the role of this molecule in the regulation of the expression of genes encoding the synthesis of two classes of proteins necessary for the progression of the cell cycle: the tRNA synthetases and the translational initiators. This has been observed both in vitro and in vivo, resulting in the death of cancer cells by necrosis (see the previously cited publication and the publication "Ascorbic Acid and Gene Expression: Another Example of Regulation of Gene Expression by Small Molecules" by S Belin, F. Kaya et al., Published in 2010 in Current Genomics, Vol 11, pp. 52-57).

In addition, it has been observed that ascorbic acid corrects the phenotype of an animal model of Charcot-Marie-Tooth disease type 1A (CMT1A), a hereditary peripheral neuropathy. This work has been described in the publication by E. Passage et al, Nature Medicine 2004 (doi: 10.1083 / nm1023) and in the patent application WO 2004/006911 on the basis of a mouse model. However, the effects observed in humans are less conclusive (see the publication of J.Micaleff et al., "Effect of ascorbic acid in patients with Cjharcot-Marie-Tooth disease type 1A: multicenter, randomized, double-blind, placebo-cotnrolled trial "published in 2009 in Lancet Neurol., (12): 1 03-10).

 Kaya et al. (FEBS Letters 528 (2008), pp. 3614-1618) have shown that ΓΑΑ is involved in the regulation of PMP22 gene expression, the expression of which also depends on cyclic ((c-AMP). This property is probably responsible for the phenotypic correction of the CMT1A phenotype. Kaya et al, 2008, have shown that ascorbic acid is a global regulator of the cAMP pool. This is due to an unknown property of ΓΑΑ, discovered by these authors. AA is a competitive inhibitor of adenylate cyclase, probably by the presence of a common structural element in ΑΤΡ and ascorbic acid, namely the furanic ribose nucleus. The biological effects of certain ascorbic acid derivatives with a furanic ribose ring have been explored for a long time. Thus, WO 91/16055 and EP 0 579 769 (Allergan), EP 0 799 218 (Merck Frosst Canada & Co) and EP 1 106 175 (Nippon Hypox Laboratories Inc.) describe certain molecules of this type having an anti-aging effect. Inflammatory in vitro and in vivo in a murine model. EP 0 202 589 and EP 0 339 486 (Takeda Chemical Industries, Inc.) disclose a prophylactic and curative effect of blood circulation disorders for certain ascorbic acid derivatives L; US 5,541,221 (Allergan) describes type 3 (4H) substituted furanoses (5H) and their use for the prevention of osteoporosis; EP 0 768 314 (Senju Pharmaceutical Co. Ltd.) discloses diesters of phosphoric acid with ascorbic acid (position 5) and a tocopherol, some of which have an antioxidant effect (ie of free radical scavenger), likely to reduce ischemic-type disorders.

EP 0 875 246 (Showa Denko Kabushiki Kaisha) describes the anticancer effect of certain L ascorbic acid derivatives, and in particular of its 2-phosphate-6-carboxylic derivatives. Other derivatives having a phosphoryl group in position 2 and for the same application are described in EP 0 875 514 of the same applicant. A recent publication by Gazivoda et al. ("Synthesis, structural studies, and cytostatic evaluation of 5,6-di-O-modified L-ascorbic acid derivatives", published in 2006 in Carbohydrate Research, Vol 341, pp. 433-442) suggests a cytostatic effect. for certain chlorinated derivatives at position 6 of 2,3-di-O-benzylated ascorbic acid. Finally, ascorbic acid derivatives have been tested for their dermatological and cosmetological effects, see EP 1 145 710 (L'Oreal), EP 1 409 494 (Tagra Biotechnologies Ltd.) and EP 1 496 889 (Showa Denko KK ).

In view of this multitude of structural and biological approaches to explore the medical utility of ascorbic acid derivatives, the present inventors have focused their attention on novel ascorbic acid derivatives having a structural analogy with ΓΑΤΡ, and in particular on their possible biological effects, with a view to developing new molecules of therapeutic interest.

Objects of the invention

 The first object of the invention

compound of general formula

where R ¹ and R ² are selected from alkyl, alkene, aryl, arylalkyl, heteroarylalkyl and where R ⁴ is H,

and where R ³ is a phosphoryl group of formula (II):

dans lequel R⁷ et R⁷¹ sont OH ou arylalkyle substitués comme décrits ci-dessous ; lesdits radicaux alkyle, aryle, alcène, hétéro-alkylaryle et arylakyle pouvant être substitués par un ou plusieurs radicaux identiques ou différents choisi dans le groupe formé par : halogène, CF₃, OCF₃, nitro, cyano, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, carboxamide (CONH₂), acyle, carboxy libre ou estérifié par un radical alkyle, aryle, alcène ou alcyne ;

wherein R ⁷ and R ⁷¹ are OH or substituted arylalkyl as described below; said alkyl, aryl, alkene, heteroalkylaryl and arylalkyl radicals being substituted by one or more identical or different radicals selected from the group consisting of: halogen, CF ₃ , OCF ₃ , nitro, cyano, hydroxy, alkoxy, aryloxy, mercapto alkylthio, arylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, carboxamide (CONH ₂ ), acyl, free carboxy or esterified with an alkyl, aryl, alkene or alkyne radical;

 knowing that

the halogen term denotes F, Cl, Br and I, and preferably F, Cl and Br; the term alkyl denotes a linear or branched radical containing at most 12 carbon atoms, said alkyl radical being chosen from the group formed by the radicals: methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert- butyl, pentyl, iso-pentyl, sec-pentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and their isomers linear position and branched, said radical preferably containing at most 6 carbon atoms, and said radical being even more preferably selected from the group formed by the radicals: methyl, ethyl, propyl, iso-propyl, n-butyl, iso-propyl butyl, tert-butyl, linear or branched pentyl, linear or branched hexyl;

 the term alkoxy denotes a linear or branched radical containing at most 12 carbon atoms, said alkoxy radical being preferably chosen from the group formed by methoxy, ethoxy, propoxy, iso-propoxy, linear butoxy, secondary or tertiary, pentoxy, hexoxy, heptoxy, as well as their linear and branched positional isomers, and said alkoxy radical being even more preferably selected from radicals of this group containing at most 6 carbon atoms;

the term alkylthio denotes a linear or branched radical containing at most 12 carbon atoms, said alkylthio radical being preferentially chosen from the group formed by methylthio, ethylthio, isopropylthio and heptylthio, knowing that in each of these radicals, the sulfur can be oxidized in radical SO or S0 ₂ , and said alkylthio radical being even more preferably selected from radicals of this group containing at most 6 carbon atoms;

the term carboxyamide denotes CONH ₂ ;

the term sulphonamide denotes SO ₂ NH ₂ ;

the term acyl or R ^A -C (O) - denotes a linear or branched radical containing at most 12 carbon atoms, and wherein R ^A represents a radical chosen from the group formed by: H, alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl heterocycloalkylalkyl aryl, said radicals being optionally substituted; and wherein said acyl radical is preferably selected from the group consisting of: formyl, acetyl, propionyl, butyryl, benzoyl, valeryl, hexanoyl, acroyl, crotonyl and carbamoyl;

the term cycloalkyl preferably denotes a monocyclic or bicyclic carbocyclic radical containing from 3 to 10 carbon atoms in the ring, said radical preferably being chosen from the group formed by the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals; the term cycloalkylalkyl denotes a radical in which cycloalkyl and alkyl are chosen from those indicated above, and preferably from the group formed by: cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl; the term acyloxy denotes an acyl-O radical in which acyl has the meaning indicated above, said acyloxy radical preferably being an acetoxy or propionyloxy radical;

 the term acylamino denotes an acyl-N radical in which acyl has the meaning indicated above;

 the term aryl denotes an unsaturated carbocyclic radical, monocyclic or consisting of condensed rings, and preferably phenyl or naphthyl radicals;

 the term arylalkyl denotes a radical resulting from the substitution of one or more hydrogen atoms of an aryl radical with one or more alkyl radicals, said arylalkyl radical preferably being chosen from the group formed by the benzyl and phenylethyl radicals, phenylethyl, triphenylmethyl and naphthylenemethyl; the term alkene denotes a linear or branched radical containing at most 12 carbon atoms and having from 1 to 4 double bonds, conjugated or otherwise, said alkene radical being preferably chosen from the group formed by vinyl, allyl or 2-butene radicals; ;

 the term "alkyne" denotes a linear or branched radical containing at most 12 carbon atoms and having from 1 to 4 triple bonds, conjugated or otherwise, said alkyne radical being preferably chosen from the group formed by the propargyl, 2-butyne or 2-membered radicals; -pentyne;

 the term "heterocyclic radical" denotes a saturated carbocyclic radical (here called heterocycloalkyl) or a partially or totally unsaturated (here called heteroaryl) radical containing from 4 to 10 carbon atoms in the ring, and one or more heteroatoms, which may be identical or different, chosen from oxygen, nitrogen or sulfur atoms;

said heterocycloalkyl radical being preferably selected from the group consisting of dioxolane, dioxane, dithiolane, thiooxolane, thiooxane, oxiranyl, oxolanyl, dioxolanyl, piperazinyl, N-methylpiperazinyl, piperidyl, pyrrolidinyl, imidazolidinyl, imidazolidin-2, 4-dione, pyrazolidinyl, morpholinyl, tetrahydrofuryl, hexahydropyran, tetrahydro-thienyl, chromanyl, dihydrobenzofuranyl, indolinyl, perhydropyranyl, pyrindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thioazolidinyl, these radicals may or may not be substituted; said heteroaryl radical being preferably selected from the group consisting of furyl, pyrrolyl, tetrazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, isoxazolyl, imidazolyl, pyrazolyl, thienyl, triazolyl, pyridyl, 2- radicals. pyridyl, 4-pyridyl, pyrimidyl, 5-pyridazinyl, pyrazinyl, condensed heteroaryl radicals preferably containing a heteroatom selected from S, O and N;

 wherein the fused heteroaryl radicals are preferably selected from the group consisting of benzothienyl, benzofuryl, benzopyrrolyl, benzothiazolyl, benzimidazolyl, imidazopyridyl, imidazopyrimidinyl, imidazopyrazinyl, purinyl, pyrrolo-pyrimidinyl, pyrrolopyridinyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl radicals. , thionaphthyl, chromenyl, indolizinyl, quinazolinyl, quinoxalinyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, naphthyridinyl;

 the term alkylamino denotes a radical in which the alkyl radical is chosen from the alkyl radicals mentioned above, given that the alkyl radicals having at most

4 carbon atoms are preferred, such as linear or branched methylamino, ethylamino, propylamino or butylamino radicals;

 the term dialkylamino denotes a radical in which the alkyl radicals, which are identical or different, are chosen from the alkyl radicals mentioned above, it being preferred that alkyl radicals having at most 4 carbon atoms, such as the dimethylamino and diethylamino radicals, are chosen, methylethylamino, or dibutylamino, linear or branched;

or a pharmaceutically acceptable salt thereof.

 Another subject of the invention is a compound addition salt according to the invention with an inorganic or organic acid or with a mineral or organic base.

Another subject of the invention is a pharmaceutical composition comprising as active ingredient at least one compound according to the invention and / or at least one addition salt according to the invention.

A final subject of the invention is the use of a pharmaceutical composition according to the invention for the production of medicaments intended for the treatment or prevention of cancers, and preferably of cancers selected from the group formed by: lung, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, colon cancer, thyroid cancer, carcinoma rectal, glioblastoma, chronic myeloid leukaemias, acute lymphoblastic leukemia, metastatic melanoma, renal carcinoma.

Description of the invention

In the formulas of the structure and the present text, some radicals are marked by the letter R followed by one or more digits which can be, indifferently, an index (for example R ₃ ) or an exponent (for example R ³ ) or be written on the same line as "R", for example R3.

 Unless otherwise stated, for each product of formula (I) and for each radical defined as indicated above, these structural formulas denote all the isomers, and in particular all the tautomeric, diastereoisomeric and enantiomeric forms which may be represented by this formula, as well as mixtures of these forms, including racemic mixtures.

 In the context of the present invention, the stereosiomerism is defined in its broad sense and includes in particular the isomerism of compounds having the same developed formula but whose different groups are arranged differently in space, such as for example in mono-substituted cyclohexanes. whose substituent may be in axial or equatorial position, and in the ethane derivatives which may have different rotational conformations. Stereoisomerism also encompasses the different spatial arrangements of attached substituents, either on double bonds or on rings, also known as geometric isomerism or cis-trans isomerism.

 The structural formulas of the products of formula (I) also cover the addition salts with inorganic and organic acids or with mineral or organic bases.

The term "patient" refers to a human or other mammal.

In a first advantageous embodiment of the invention, the compound of general formula (I) is characterized in that:

(a) R ¹ and R ² are benzyl radicals substituted by one or more identical or different radicals chosen from: H, fluorine, chlorine, bromine, iodine, CF ₃ ,

OCF ₃ , nitro, cyano, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, carboxamide, acyl, carboxy free or esterified with an alkyl, aryl, alkene or alkyne radical;

(b) R ⁷ and / or R ⁷¹ is an OH radical;

(c) R ⁴ is a H radical. In a second advantageous embodiment of the invention, the compound of general formula (I) is characterized in that:

(a) R ¹ and R ² are benzyl radicals substituted by one or more identical or different radicals chosen from: H, fluorine, chlorine, bromine, iodine, CF ₃ ,

OCF ₃ , nitro, cyano, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, carboxamide, acyl, carboxy free or esterified with an alkyl, aryl, alkene or alkyne radical;

(b) R ⁷ and / or R ⁷¹ is an O-benzyl radical substituted with one or more identical or different radicals chosen from: H, fluorine, chlorine, bromine, iodine, CF ₃ ,

OCF ₃ , nitro, cyano, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, carboxamide, acyl, carboxy free or esterified with an alkyl, aryl, alkene or alkyne radical;

(c) R ⁴ is a H radical.

In these two embodiments, R ³ may advantageously be a substituted or unsubstituted dibenzylphosphonate group, or phosphate.

The compounds of formula (I) according to the invention may be prepared according to the following reaction scheme:

où

or

R ⁸ and R ⁸¹ , which are identical or different, are radicals chosen from the group formed by: H, alkyl, aryl and are preferably identical radicals of alkyl type containing between 1 and 4 carbon atoms, and are more preferably radicals methyl;

R ¹ and R ² may be identical or different, as defined above, and are preferably identical benzyl radicals, substituted or unsubstituted by radicals selected from the group consisting of F, Cl, Br, I, CF ₃ , OCF ₃ , nitro, cyano, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, carboxamide, acyl, carboxy free or esterified with an alkyl, aryl, alkene or alkyne radical;

R ⁹ is a protecting group of the alcohol functions, preferably a derivative of the silane, and in particular trialkylsilane;

R ³ is a radical as defined above, and in particular dibenzylphosphonate (possibly substituted as indicated above in the definition of R ⁷ and R ⁷¹ radicals) or phosphate;

R ⁴ is a H radical.

In an advantageous embodiment, R ³ is a dibenzylphosphonate radical (possibly substituted as indicated above in the definition of R ⁷ and R ⁷¹ radicals) or phosphate. As such, the compound of formula (I) can in particular be one of the following compounds (the ASX codes followed by three digits are internal codes used in the context of this document): ASX135 to ASX237 and ASX 401 to ASX453. The structural formulas of these compounds of formula (I) according to the invention are indicated below; they include all isomers and isomeric mixtures:





 In one embodiment of the process represented by this reaction scheme, supplying the compound of formula (III) and transforming it with appropriate reagents successively into compounds (IV), (V), (VI), (VII) , (VIII), (IX) and (I). This embodiment is explained in detail in Example 1 below; this example contains by way of illustration a list of compounds of formula (I) which can be obtained in this way (compounds ASX135 to ASX237).

 In another embodiment of the process represented by this reaction scheme, the compound (VI) is supplied and is converted successively with appropriate reagents into compounds (VII), (VIII), (IX) and (I).

In another embodiment, which leads to a compound (I) in which R ³ is a phosphate group, the compound (VII) is supplied and reacted with diallyl diethylphosphoramidite to obtain the compound (VIII) in the form of its diallylphosphate, that is to say in this compound (VIII), the hydrogen atom of each of the two OH functions of the phosphate R ³ is substituted by an allyl residue. This compound (VIII) is then successively converted into compounds (IX) and (I). This embodiment is explained in detail in Example 3 below; this example contains by way of illustration a list of compounds of formula (I) which can be obtained in this way (compounds ASX401 to ASX 453). To evaluate their biological effects, and in particular their toxicity and their therapeutic effect, the compounds according to the invention, obtained by synthesis according to the process described above, were tested in two ways: firstly on carcinogenic human cell cultures. to determine their IC ₅₀ value, then, for compounds that appear particularly promising, on an animal model of colon cancer that involves monitoring the evolution of the tumor in volume every three days.

 The inventors have found that the toxicity of the compounds of formula (I) is generally low. This promotes their use as a medicine.

The inventors have furthermore found that the compounds of formula (I) show a biological effect which makes it possible to envisage their therapeutic use in pharmaceutical compositions.

 By way of example, in a typical embodiment, Dibenzyl (S) -1 - [(R) - 3,4-bis (benzyloxy) -5-oxo-2,5-dihydrofuran-2-yl is used. 2-hydroxyethylphosphate (ASX234), derived from ascorbic acid (AA), which is found to be a cytotoxic molecule for cancer cells, at concentrations between 10 and 20 times lower than that of the original molecule (AA) . On the other hand, ASX234 is non-toxic for normal cells, which is rare in the treatment of cancer.

 The treatment of an animal model of colon cancer with this molecule, using concentrations 250 lower than that of ascorbic acid, shows that it exhibits no toxicity in vivo on non-pathological cells and that it decelerates strongly. the progression of tumors.

 As a result, the inventors have found that the compounds according to the invention represent a new class of anti-cancer molecules. Without wishing to be bound by any theory concerning the action mechanism of the compounds according to the invention, the observations made by the inventors in the course of their work enabled them to identify at least one such mechanism of action, which is based on on the role of competitors of ATP compounds according to the invention; this new mechanism induces cell death by necrosis and has no visible side effects on non-cancerous cells.

In general, the compounds according to the invention can be used as active ingredients in pharmaceutical compositions for the treatment or prevention of cancer. This use can implement the compounds as such, and / or a pharmaceutically acceptable salt of said compounds, said salt being a salt addition of said compounds with an inorganic or organic acid or with a mineral or organic base. Thus, a pharmaceutical composition according to the invention comprises as active ingredient at least one compound according to the invention and / or at least one addition salt according to the invention.

Said pharmaceutical compositions may be administered especially orally, for example in solid form or, especially when it is a question of salts, in a form soluble in water and / or in a alcohol compatible with water (such ethanol, propylene glycol, polypropylene glycol and glycerol). They can also be administered parenterally, for example intravenously, intramuscularly, subcutaneously or rectally. They may include other components, including pharmaceutically acceptable carriers and / or excipients, and / or other active ingredients.

Cancers whose treatment and / or prevention may be considered are preferably lung cancers, breast cancers, ovarian cancers, prostate cancers, pancreatic cancers, colon cancers, thyroid cancers, rectal carninomas, glioblastomas, chronic myeloid leukemias, acute lymphoblastic leukemias, metastatic melanomas, renal carninomas.

Examples

 The following examples illustrate embodiments of the invention, but do not limit its scope. 1. Summary

 In these examples, "TA" or "RT" mean indifferently "ambient temperature" and "Yield" means "yield".

Example 1: dibenzyl (S) -1 - [(R) -3,4-bis (benzyloxy) -5-oxo-2,5-dihydrofuran-2-yn-2-hydroxyethyl phosphate (herein referred to as "ASX234" ):

Step 1: (R) -5-f (S) -2,2-dimethyl-1,3-dioxolan-4-yn-3,4-dihydroxyfuran-2 (5H) -one

To a suspension of L (+) - ascorbic acid (10 g, 56.8 mmol) in acetone (50 mL) was added CH ₃ COCI ethanoyl chloride (4.4 mL, 62.5 mmol). ) at TA. After stirring overnight, the white precipitate was filtered, rinsed with acetone and dried under vacuum to give the expected product (8.1 g, 66% yield).

Characterization by ¹ H NMR (200 MHz, DMSO-d6): 1.25 (s, 6H), 3.87 (dd, 1H, J1 = 8.4 Hz, J2 = 6.4 Hz), 4.09 ( t, 1H, J = 8.4 Hz), 4.25 (td, 1H, J1 = 6.6 Hz, J2 = 3.0 Hz), 4.71 (d, 1H, J = 3, 0 Hz), 8.49 (s, 1H), 11.30 (s, 1H). Step 2: (R) -3,4-bis (benzyloxy) -5 - ((S) -2,2-dimethyl-1,3-dioxolan-4-yl) furan-2 (5H) -one

To a suspension of the compound obtained in Step 1 (3 g, 13.88 mmol, 1.0 eq.) In DCM (60 mL) was added DIEA (5.5 mL, 33.33 mmol). , 2,4 eq.), Then bromide of benzyl (3.3 mL, 27.76 mmol, 2.0 eq) at RT. After stirring overnight, the reaction medium was washed with water, dried over Na ₂ SO ₄ , filtered and evaporated. The residue obtained was purified on silica gel to give the expected product (2.4 g, yield 43%).

Characterization by ¹ H NMR (200 MHz, CDCl ₃ ): 1.37 (s, 3H), 1.41 (s, 3H), 3.9-4.3 (m, 3H), 4.54 (d, 1) H, J = 3.2 Hz), 5.0-5.3 (m, 4H), 7.2-7.5 (m, 10H).

Step 3: (R) -3,4-bis (benzyloxy) -5-r (S) _-1-l 2 dihvdroxyethyllfuran-2 (5H) -one

A mixture of the compound obtained in step 2 (9.5 g, 24.2 mmol) in acetic acid (50 mL) and water (15 mL) was heated at 50 ° C overnight. The mixture was evaporated, neutralized with NaHCO ₃ and extracted with DCM. The organic phase is dried over Na ₂ S0 ₄ , filtered and evaporated. The residue was purified on silica gel to give the expected product (6.8 g, 80% yield).

Characterization by H NMR (200 MHz, CDCl ₃ ): 2.80 (Si, 1H), 3.07 (Si, 1H), 3.6-4.0 (m, 3H), 4.68 (d, 1 H, J = 2.2 Hz), 5.07 (s, 2H), 5.17 (d, 2H, J = 3.2 Hz), 7.1-7.4 (m, 10H).

Step 4: (R) -3,4-bis (benzyloxy) -5-i (S) -2- (tert-butyldimethylsilyloxy) -1-hydroxyethynfuran-2 (5H) -one

To a solution of the compound obtained in step 3 (4.26 g, 11.97 mmol) and imidazole (1.6 g, 23.93 mmol) in DCM (60 mL) at RT under N ₂ TBDMSCI (3.6 g, 23.93 mmol) was added. After 4h, the reaction mixture was filtered and rinsed with DCM. The filtrate was washed with water and then with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The residue obtained was purified on silica gel to give the expected product (3.7 g, 66% yield).

Characterization by ¹ H NMR (300 MHz, CDCl ₃ ): 0.05 (s 6H), 0.87 (s, 9H), 1.94 (d, 1H, J = 7.0 Hz), 3.74 ( m, 2H), 3.95 (m, 1H), 4.73 (s, 1H), 5.08 (s, 2H), 5.19 (d, 2H, J = 4.8 Hz), 7.2-7.5 (m, 10H).

Step 5: (dibenzyl) -N, N-diethylphosphoramidite

A une solution de PCI₃ (10 g, 72,82 mmol) dans Et₂0 (300 mL) refroidie à 0°C sous N₂, on a ajouté de la triéthylamine (10,1 mL, 72,82 mmol) et de la diéthylamine (7,5 mL, 72,82 mmol). Après avoir agité le milieu pendant une nuit à TA, le précipité obtenu a été filtré et lavé avec Et₂0. Le filtrat résultant a été placé dans un tricol de 500 mL sous N₂ à 0°C. A cette solution, ont été ajoutés de la triéthylamine (22,3 mL, 160,2 mmol) et de l'alcool benzylique (15,1 mL, 145,6 mmol) en gardant T<5°C. Après agitation pendant la nuit, le mélange a été filtré et lavé avec Et₂0. Le filtrat a été évaporé à sec pour donner le phosphoramidite attendu (23g, Rdt 96%).

To a solution of PCI ₃ (10 g, 72.82 mmol) in Et ₂ O (300 mL) cooled to 0 ° C under N ₂ was added triethylamine (10.1 mL, 72.82 mmol) and diethylamine (7.5 mL, 72.82 mmol). After stirring the medium overnight at RT, the resulting precipitate was filtered and washed with Et ₂ O. The resulting filtrate was placed in a 500 mL three-neck N ₂ at 0 ° C. To this solution was added triethylamine (22.3 mL, 160.2 mmol) and benzyl alcohol (15.1 mL, 145.6 mmol) keeping T <5 ° C. After stirring overnight, the mixture was filtered and washed with Et ₂ O. The filtrate was evaporated to dryness to give the expected phosphoramidite (23 g, 96% yield).

Characterization by ¹ H NMR (200 MHz, CDCl ₃ ): 1.10 (t, 6H, J = 7.0 Hz), 3.12 (q, 2H, J = 7.0 Hz), 3.13 (q, 2H, J = 7.0Hz), 4.77 (m, 3H), 4.91 (d, 1H, J = 8.0Hz), 7.34 (m, 10H).

Step 6: dibenzyl (S) -1 - [(R) -3,4-bis (benzyloxy) -5-oxo-2,5-dihydrofuran-2-yn-2- (tert-butyldimethylsilyloxy) ethyl phosphate

To a mixture of the compound obtained in step 4 (2.0 g, 4.25 mmol) was added NaHCO ₃ (2.2 g, 20.1 mmol) and triazole (0.6 g, 8.5 mmol) in DCM (40 mL); then a solution of the phosphoramidite obtained in step 5 (3.2 g, 10.2 mmol) in DCM (60 mL) was added at RT. After 6h, the reaction medium was cooled to 0-5 ° C and H ₂ O ₂ (9 mL) was slowly added. After stirring overnight, the medium was quenched with a solution of NaS ₂ O ₃ (30 mL). Water was added and the product was extracted with DCM. The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated. The residue obtained was purified on silica gel to give the expected product (2.2 g, yield 70%).

Characterization by H NMR (200 MHz, CDCl ₃ ): 0.02 (s, 3H), 0.03 (s, 3H), 0.85 (s, 9H), 3.80 (m, 2H), 4.65 (m, 1H), 4.92 (m, 5H), 5.02 (s, 2H), 5.16 (d, 2H, J = 6.0 Hz), 7.2-7.4 (m , 10H).

Step 7: dibenzyl (S) -1- (R) -3,4-bis (benzyloxy) -5-oxo-2,5-dihydrofuran-2-yl-2-hydroxyethyl phosphate

To a solution of the compound obtained in step 6 (100 mg, 0.136 mmol) in THF (2 mL), TBAF (1 M in THF, 0.14 mL, 0.136 mmol) was added at 5-10. ° C. After 20 min, the reaction was quenched with NH ₄ CI solution and the product was extracted with DCM. The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated. The residue obtained was purified on silica gel to give the expected product (8 mg, yield 10%)

Characterization by ¹ H NMR (300 MHz, CDCl ₃ ): 2.76 (d, 1H, J = 6.9 Hz), 4.00-4.15 (m, 3H), 4.56 (d, 1H) , J = 2.1 Hz), 4.95-5.25 (m, 8H), 7.20-7.50 (m, 10H). The following compounds are prepared in a similar manner:

 ASX135, ASX136, ASX137, ASX138, ASX139, ASX140, ASX141, ASX142, ASX143, ASX144, ASX145, ASX146, ASX147, ASX148, ASX149, ASX150, ASX151, ASX152, ASX153, ASX154, ASX155, ASX156, ASX157, ASX158, ASX159 , ASX160, ASX161, ASX162, ASX163, ASX164.ASX165, ASX166, ASX167, ASX168, ASX169, ASX170, ASX171, ASX172, ASX173, ASX174, ASX175, AXS176, ASX177, ASX178, ASX179, ASX180; ASX181, ASX182, ASX183, ASX184, ASX185, ASX186, ASX187, ASX188, ASX189, ASX190, ASX191, ASX192, ASX193, ASX194, ASX195, ASX196, ASX197, ASX198, ASX199, ASX200, ASX201, ASX202, ASX203, ASX204, ASX205, ASX206, ASX207, ASX208, ASX209, ASX210, ASX211, ASX212, ASX213, ASX214, ASX215, ASX2 6, ASX2 7, ASX218, ASX219, ASX220, ASX221, ASX222, ASX223, ASX224, ASX225, ASX226, ASX227, ASX228, ASX229, ASX230, ASX231, ASX232, ASX233, ASX234, ASX235, ASX236, ASX237. Example 2: (S) -1- (R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yn-2-hydroxyethyl dihydroxy phosphate (herein referred to as "ASX300")

The compound obtained in step 6 of Example 1 (150 mg) was dissolved in methanol (5 ml). Palladium on charcoal (15mg, 10% w / w) was added and the medium was placed in an autoclave under 4 bar of hydrogen at room temperature for 4h. The medium was then filtered through Celite, the methanol evaporated and the residue purified on RP18 phase. The fractions were lyophilized and 25 mg of pure product was recovered as an oil.

Characterization by ¹ H NMR (200 MHz, CD ₃ OD): 3.36 (m, 1H), 3.77 (m, 1H), 3.91 (m, 1H) 4.51 (m, 1H) ), 4.84 (brs, 4H), 4.98 (m, 1H). Example 3: (S) -1 - [(R) -3,4-bis (benzyloxy) -5-oxo-2,5-dihydro-furan-2-yl] -2-hydroxyethyl dihydrogen phosphate (herein referred to as "ASX400")

Step 1: diallyl diethylphosphoramidite

To a solution of PCI ₃ (10 g, 72.82 mmol) in Et ₂ O (300 mL) cooled to 0 ° C under N ₂ was added triethylamine (10.1 mL, 72.82 mmol) and diethylamine (7.5 mL, 72.82 mmol). After stirring the medium overnight at RT, the resulting precipitate was filtered and washed with Et ₂ O. The resulting filtrate was placed in a 500 mL three-neck N ₂ at 0 ° C. To this solution was added triethylamine (22.3 mL, 160.2 mmol) and allyl alcohol (9.95 mL, 145.6 mmol) keeping T <5 ° C. After stirring overnight, the mixture It was filtered and washed with Et ₂ O. The filtrate was evaporated to dryness to give the expected phosphoramidite (15 g, yield 96%).

Characterization by ¹ H NMR (300 MHz, CDCl ₃ ): 1.10 (t, 6H, J = 7.0 Hz), 3.12 (m, 4H), 4.18 (m, 4H), 5.18 ( m, 2H), 5.35 (m, 2H), 5.95 (m, 2H). Step 2: Diallyl (S) -1- (R) -3,4-bis (benzyloxy) -5-oxo-2,5-dihydrofuran-2-yn-2- (tert-butyldimethylsilyloxy) ethyl phosphate

To a solution of the product of Step 4 of Example 1 (500mg, 1.06mmol) in DCM (10mL) was added triazole (150mg, 2.12mmol), NaHCO ₃ (535mg, 6.36mmol), then a solution of the compound of step 1 (550mg, 2.55mmol) in DCM (15mL) dropwise at RT. The medium was stirred under nitrogen for 6 h. The medium was then brought to 0 ° C. and then a solution of H ₂ 0 ₂ (2.5 mL) in THF (25 mL) was added and the medium was stirred at RT for 18 h. Saturated Na ₂ S ₂ O ₃ solution was added dropwise at 0 ° C. The mixture was extracted with DCM, the organic phases were dried with Na ₂ S0 ₄ and the solvent was evaporated. The residue was purified on silica gel (EP / EA 9/1) and the pure product was obtained (260 mg, yield 46%).

Characterization by ¹ H NMR (300 MHz, CDCl ₃ ): 0.088 (s, 6H), 0.89 (s, 9H), 3.85 (m, 1H), 3.95 (m, 1H), 4, 50 (m, 5H), 4.97 (s, 1H), 5.12 (m, 2H), 5.29 (m, 6H), 5.95 (m, 2H), 7.39 (m, 10H).

Step 3: (S) -1-r (R) -3,4-bis (benzyloxy) -5-oxo-2,5-dihydro-furan-2-yn-2- (tert-butyldimethylsilyloxy) ethyl dihydrogen phosphate

To a solution of the product of step 2 (135mg, 214pmol) in THF (5mL) was added formic acid (125μ, 3.3mmol), triphenylphosphine (35mg, 128mol), butylamine (62mg, 857μιηοΙ), then palladium tetrakis (25mg, 21 ιηοΙ). The medium was stirred under nitrogen for 18h. The medium was purified on silica gel (DCM → DCM / MeOH 9/1) and the expected product was obtained (40 mg, yield 34%).

Characterization by ¹ H NMR (300 MHz, CDCl ₃ ): 0.088 (s, 6H), 0.89 (s, 9H), 3.95 (m, 2H), 4.25 (m, 1H), 4.97 (m, 3H), 5.22 (m, 2H), 7.39 (m, 10H), 11.50 (brs, 2H).

Step 4: (S) -1 - [(R) -3,4-bis (benzyloxy) -5-oxo-2,5-dihydrofuran-2-yn-2-hydroxyethyl dihydrogen phosphate

To a solution of the compound obtained in step 3 (75 mg, 0.136 mmol) in THF (2 mL), TBAF (1 M in THF, 0.14 mL, 0.136 mmol) was added at 5-10. ° C. After 20 min, the reaction was quenched with a solution of NH ₄ Cl and the product was extracted with DCM. The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated. The residue obtained was purified on silica gel (DCM → DCM / MeOH 9/1) to give the expected product (10 mg, yield 17%)

Characterization by H NMR (300 MHz, CDCl ₃ ): 3.85 (m, 1H), 3.95 (m, 2H), 4.78 (s, 1H), 4.97 (m, 3H), , 22 (m, 2H), 7.39 (m, 10H), 11.48 (brs, 2H).

The following compounds are prepared in a similar manner:

 ASX401, ASX402, ASX403, ASX404, ASX405, ASX406, ASX407, ASX408, ASX409,

ASX410, ASX411, ASX412, ASX413, ASX414, ASX415, ASX416, ASX417, ASX418, ASX419, ASX420, ASX421, ASX422, ASX423, ASX424, ASX425, ASX426, ASX427,

ASX428, ASX42, ASX430, ASX431, ASX432, ASX433, ASX434, ASX435, ASX436,

ASX437, ASX438, ASX439, ASX440, ASX441, ASX442, ASX443, ASX444, ASX445, ASX446, ASX447, ASX448, ASX449, ASX450, ASX451, ASX452, ASX453. 2. Biological activity

 In order to test the anti-proliferative effect of the ascorbic acid analogues, various cancer lines, cells outside the control of the cell cycle, have been treated in vitro with these molecules. The MTT test, to study cell viability, was used.

In this context, cells derived from lymphoma, multiple myeloma and colon cancer were used. These lines, obtained from the American Type Culture Collection (ATCC), are recognized as representative of these cancers.

 The first line studied is derived from a plasmocytoma (RPMI 8226), responsible for multiple myeloma, which is an abnormal multiplication of plasma cells (a variety of white blood cells that synthesize circulating antibodies) in the bone marrow.

The second cancer line (Raji) is derived from Burkitt's lymphoma cells. This lymphoma constituting a particularly aggressive malignant tumor has become a model of oncogenesis of lymphomas.

 The third line is derived from an adenocarcinoma of the colon (HT29c2), which is the most common cancer in France (more than 15% of all cancers), which makes it a major public health problem.

 Two molecules were tested under these conditions: (ASX234 and AA).

Here we describe the test methodology. I - In vitro test

Cytotoxicity: 10,000 cells were incubated in wells of microtiter plates with 100 μl of O / N culture medium at 37 ° C., 5% CO ₂ . The plating medium was replaced by 100 μl / well of the test molecules. The cells were incubated 24h, at 37 ° C., 5% CO _2. The cell viability was evaluated by the MTT test described by Mosmann in 1983, well known to those skilled in the art, using a microplate reader (Victor4x). the company Perkin Elmer).

 Proliferation: The same incubation protocol was used with the cells. Proliferation was evaluated using the Perkin Elmer Deifia Proliferation Kit, using the protocol recommended by the supplier.

 II - In vivo tests, on animal models.

20 female Athymic Nude (Harlan) mice, 8 weeks old, were used. 3 x 10 ⁶ cells (HT29, human colonic adenocarcinoma cell line) resuspended in PBS, were injected subcutaneously in a volume of 0.2 ml per mouse. Mice were maintained in a sterile environment throughout the test. After 20 days, when the tumor sizes were between 300 and 500 mm ³ , the animals were randomized into 2 groups (homogeneous average sizes), a treated group (T) and a placebo group (P). The T group then received a daily IP injection of the ASX234 molecule at 6 mg / kg / day (of which 25% DMSO), while the P group received a daily IP injection of NaCl (0.9%) (25% DMSO). Tumor volume was evaluated every three days, using an electronic caliper. After 2 weeks of treatment the animals were sacrificed, the tumors removed and weighed.

 - Statistical treatment: The data were evaluated when their statistical significance by the Mann-Whitney test. In accordance with international conventions, the data were considered significant when the value of p was less than 0.05.

Here we describe the results of the tests.

 I - Impact of treatment on human tumor cells

Cell lines, derived from cancer cells of patients, with solid tumors (liver, colon) or liquid tumors (myeloma, lymphomas), were treated with increasing concentrations of either the ASX234 or ascorbic acid (AA) molecule. . Cell death and cell proliferation were assessed. It appears from the results shown in FIG. 1 that the ASX234 molecule presented at one and the same time an effect cytotoxic for cancer cells and an antiproliferative effect; this molecule is between 10 and 20 times more active than itself.

 It is known (Belin et al, 2009) that ΓΑΑ acts only on cancer cells. The toxicity of ASX234 was therefore assessed on human primary cell cultures (fibroblasts and primary hepatocytes). From the results gathered in FIG. 2, it appears that at concentrations 2 to 3 times higher than the IC50 of cytotoxicity observed on the cancer cells, this molecule is not toxic for normal, non-pathological cells. These data, as well as their statistical treatment, are presented in Table 1.

 Table 1

It - Impact of AA treatment on animal models of cancer

The in vitro evidence being only an indication, the potential efficacy of the molecules was tested on an in vivo model of the most common cancer in humans, colon cancer. For this purpose, node-immunodeficient nude mice were xenographed with colonic adenocarcinoma cells (HT29). Mice with visible tumors were treated either with placebo or with ASX234 at a concentration 250-fold lower than the effective concentration of ΓΑΑ (Belin et al, 2009). The progression of the tumor, as well as the final weight, were evaluated. The results shown in Figure 3 and Table 2 show that tumor progression was significantly slowed by ASX234 treatment.

Claims

 1. Compound of general formula

 or : R ¹ and R ² are radicals chosen from: alkyl, alkene, aryl, arylalkyl, heteroarylalkyl substituted by one or more radicals chosen from: H, fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , nitro, cyano hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, carboxamide, acyl, carboxy free or esterified with an alkyl, aryl, alkene or alkyne radical; and where R ³ is a phosphoryl group of formula (II):

wherein R ⁷ and R ⁷¹ are substituents selected from OH or arylalkyl substituted or unsubstituted as described above, and where R ⁴ is a radical of type H,  said compound comprising all the isomers which can be represented by the formula (I), thus all the mixtures of said isomers. 2. Compound according to claim 1, characterized in that: (a) R ¹ and R ² are benzyl radicals substituted by one or more identical or different radicals chosen from: H, fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , nitro, cyano, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, carboxamide, acyl, carboxy free or esterified with an alkyl, aryl, alkene or alkyne radical; (b) R ⁷ and / or R ⁷¹ is an OH radical; (c) R ⁴ is a type H radical. 3. Compound according to claim 1, characterized in that (a) R ¹ and R ² are benzyl radicals substituted by one or more identical or different radicals chosen from: H, fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , nitro, cyano, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, carboxamide, acyl, carboxy free or esterified with an alkyl, aryl, alkene or alkyne radical; (b) R ⁷ and / or R ⁷¹ is an O-benzyl radical substituted with one or more identical or different radicals chosen from: H, fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , nitro, cyano, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, carboxamide, acyl, free carboxy or esterified with an alkyl, aryl, alkene or alkyne radical; (c) R ⁴ is a type H radical. 4. Compound according to any one of claims 1 to 3, characterized in that:  said alkyl radicals are linear or branched radicals containing at most 12 carbons, and being chosen from the group formed by the radicals: methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl, sec-pentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and preferably in the group formed by radicals: methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, linear or branched pentyl, linear or branched hexyl;  said alkoxy radicals contain at most 12 carbon atoms and are preferably chosen from the group formed by methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy, hexoxy, heptoxy, and even more preferentially from the radicals of this group containing not more than 6 carbon atoms; said alkylthio radicals are linear or branched radicals containing at most 12 carbon atoms, and are preferably chosen from the group formed by methylthio, ethylthio, isopropylthio and heptylthio, knowing that in each of these radicals, the sulfur can be oxidized to a radical SO or S0 ₂ , and said alkylthio radicals are even more preferably selected from radicals of this group containing at most 6 carbon atoms; said acyl radicals or R ^A -C (O) - are linear or branched radicals containing at most 12 carbon atoms, and wherein R ^A represents a radical selected from the group consisting of: H, alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, said radicals being optionally substituted, and said acyl radicals being preferably selected from the group consisting of: formyl, acetyl, propionyl, butyryl, benzoyl, valeryl, hexanoyl, acroyl, crotonyl and carbamoyl;  said aryl radicals being preferably phenyl or naphthyl radicals;  said arylalkyl radicals are preferably chosen from the group formed by the benzyl, phenylethyl, 2-phenylethyl, triphenylmethyl and naphthylenemethyl radicals;  said alkene radicals are linear or branched radicals containing at most 12 carbon atoms and having from 1 to 4 double bonds, conjugated or otherwise, said alkene radical being preferably chosen from the group formed by vinyl, allyl or 2- radicals; butene;  said alkyne radicals are linear or branched radicals containing at most 12 carbon atoms and having from 1 to 4 triple bonds, conjugated or otherwise, said alkyne radicals being preferably chosen from the group formed by propargyl, 2-butyne or 2-radicals; -pentyne;  said alkylamino radicals are radicals in which the alkyl radical is chosen from the alkyl radicals mentioned above, and preferably from alkyl radicals having at most 4 carbon atoms, and even more preferentially from the group formed by the methylamino radicals, ethylamino, propylamino or butylamino, linear or branched;  said dialkylamino radicals are radicals in which the alkyl radicals, which are identical or different, are chosen from the alkyl radicals mentioned above, and preferably from alkyl radicals having at most 4 carbon atoms, and even more preferentially from the group formed. by linear or branched dimethylamino, diethylamino, methylethylamino or dibutylamino radicals. 5. Compound according to claim 1 or 3 selected from the group consisting of ASX135, ASX136, ASX137, ASX138, ASX39, ASX40, ASX41, ASX142, ASX143, ASX144, ASX145, ASX146, ASX147, ASX148, ASX149 molecules. , ASX150, ASX151, ASX152, ASX153, ASX54, ASX155, ASX156, ASX157, ASX158, ASX159, ASX160, ASX161, ASX162, ASX63, ASX64, ASX165, ASX166, ASX167, ASX168, ASX169, ASX170, ASX171, ASX72 , ASX173, ASX174, ASX175, AXS 76, ASX177, ASX178, ASX179, ASX180; ASX181, ASX182, ASX183, ASX184, ASX 85, ASX 86, ASX187, ASX188, ASX189, ASX190, ASX191, ASX192, ASX193, ASX194, ASX195, ASX 96, ASX197, ASX198, ASX199, ASX200, ASX201, ASX202, ASX203, ASX204 , ASX205, ASX206, ASX207, ASX208, ASX209, ASX210, ASX211, ASX212, ASX213, ASX214, ASX215, ASX216, ASX217, ASX218, ASX219, ASX220, ASX221, ASX222, ASX223, ASX224, ASX225, ASX226, ASX227, ASX228, ASX229, ASX230, ASX231, ASX232, ASX233, ASX234, ASX235, ASX236, ASX237, these molecules being defined in the description.  6. Compound according to claim 1 or 2 selected from the group consisting of ASX401, ASX402, ASX403, ASX404, ASX405, ASX406, ASX407, ASX408, ASX409, ASX410, ASX411, ASX412, ASX413, ASX414, ASX415, ASX416, ASX417 molecules. , ASX418, ASX419, ASX420, ASX421, ASX422, ASX423, ASX424, ASX425, ASX426, ASX427, ASX428, ASX42, ASX430, ASX431, ASX432, ASX433, ASX434, ASX435, ASX436, ASX437, ASX438, ASX439, ASX440, ASX441, ASX442, ASX443, ASX444, ASX445, ASX446, ASX447, ASX448, ASX449, ASX450, ASX451, ASX452, ASX453, these molecules being defined in the description. 7. Addition salt of a compound according to any one of claims 1 to 7 with an inorganic or organic acid or with a mineral or organic base. 8. Pharmaceutical composition comprising as active ingredient at least one compound according to any one of claims 1 to 6 and / or at least one addition salt according to claim 7. 9. Use of a pharmaceutical composition according to claim 8 for the production of medicaments for the treatment or prevention of cancers, and preferably of cancers selected from the group consisting of: lung cancers, breast cancers, ovarian cancer, prostate cancer, pancreatic cancer, colon cancer, thyroid cancer, rectal carninoma, glioblastoma, chronic myeloid leukemia, acute lymphoblastic leukemia, metastatic melanoma, renal carninoma.