WO2006005856A1

WO2006005856A1 - Use of polyphenol ethylene organometallic derivatives for treating a non-hormone dependent cancer

Info

Publication number: WO2006005856A1
Application number: PCT/FR2005/001752
Authority: WO
Inventors: Gérard Jaouen; Anne Vessieres; Siden Top
Original assignee: Chastenet, Bertrand
Priority date: 2004-07-08
Filing date: 2005-07-07
Publication date: 2006-01-19
Also published as: FR2872814A1

Abstract

The invention concerns polyphenol ethylene organometallic derivatives of formula (I) for preparing a medicine for preventing and/or treating a non-hormone-dependent cancer. The invention concerns novel polyphenol ethylene organometallic derivatives of formula (I), wherein either (i) one of R1 and R2 represents a group (A) and the other represents an organometallic group, or (ii) R2 represents a group (A) and R1 and R3 together with C=C form an organometallic group, or (iii) R2 represents a group (A) and -YR3C=CR1-forms an organometallic group, R'1, R'2, R'3, R''1, R''2, R''3, identical or different represent a group selected among a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group, a halogen atom, a C1-C6 halogenoalkyl group, a -OCOR4 group, wherein R4 represents a C1-C16 alkyl group, a C1-C16 halogenoalkyl group or an aryl group.

Description

USE OF ORGANOMETALLIC DERIVATIVES OF POLYPHENOLS EHTYLENE FOR THE TREATMENT OF NON-HORMONO-DEPENDENT CANCER

The subject of the invention is the use of organometallic derivatives of polyphenol ethylene for the preparation of a medicament for the prevention and / or treatment of non-hormonally dependent cancer. It also relates to some of these derivatives and pharmaceutical compositions comprising them.

Breast cancers are classified into two main categories:

10 hormone-dependent cancers, which are generally sensitive to treatment with tamoxifen derivatives or anti-aromatases, and non-hormone-dependent treatments, for which the chemotherapeutic approach has not yet provided a satisfactory solution.

Other forms of cancer are classified as hormone-independent, including certain cancers of the prostate, ovary, colon, endometrium, kidney, melanoma and retinoblastoma. To date, there are few effective chemical treatments for these cancers.

Ferrocenyl derivatives of diarylethylene have been described in

International Application WO 96/11935. Some of these derivatives, such as

Ferrocifenes 1 and the hydroxyferrocifenes 2 are ferrocenyl analogues of tamoxifen, a drug used for the treatment of hormone-dependent breast cancers.

25

Hydroxyferrocifenes 2 have shown in vitro an antiproliferative effect on hormone-dependent (MCF7) and non-hormone-dependent (MDA-MB231) cancer cell lines (TOP S. et al., Chem., 1996, 955-956; S. et al, Chem Eur Eur, 2003, 9, 5223-5236). However, the metallic nature of these molecules makes it desirable to use them at the lowest possible concentration, in order to avoid the accumulation of metals in the body. It has therefore been sought to develop molecules having an antiproliferative activity greater than that of the compounds of the prior art, so as to be able to use them at lower doses compared to the compounds of the prior art. A particular family of metallocene derivatives of diphenolethylene has shown a particularly important anti-proliferative activity on non-hormone-dependent cancer cell lines and allows their use in the preparation of a medicament for the prevention and / or treatment of non-hormonally dependent cancers. The molecules concerned by the present invention are those which correspond to formula (I) below:

wherein either: (i) one of R ₁ and R ₂ represents a group

and the other represents an organometallic group such as a metallocene,

R ₃ represents a group chosen from: a hydrogen atom, a halogen atom, an NO ₂ group, a CN group, an alkyl halo Ci-C ₁₂ alkyl or C ₁ -C ₁₂ alkyl, a aryl group, is :

(ii) R ₂ represents a grouping

and R 1 and R ₃ taken together with C = C form an organometallic group, that is:

(iii) R ₂ represents a grouping

and -YR ₃ C = CR ₁ - forms an organometallic group,

R'i, R _'2, R' _3, R "i ₅ R ^'5 _2, R' ⁵ 3, identical or different, represent a group selected from a hydrogen atom, a hydroxyl group, an alkyl group CJ C _6, a halogen atom, a haloalkyl group, C ₁ -C _6, a -OCOR ₄ group wherein R ₄ represents an alkyl group C ₁ - ₆ -C (optionally C ₁ -C ₆₎ haloalkyl C ₁ -C ₁₆ (optionally C ₁ -C ₆ ), or an aryl group An organometallic group is by definition a group containing an MC bond between a metal atom (M) and a carbon atom. double (carbene) and triple (carbyne) metal-carbon bonds are also part of this definition.

Numerous prior art documents describe the use of cisplatin or carboplatin derivatives in the treatment of breast cancer (Yuehua et al., Biochem. & Medic., Chem., Letters, vol.5, No. 19, 2217- 2222, Séné et al, Drug Design and Discovery, 1998, vol.15, p.277-285, G. Grenier et al, Chem Pharm Bull., 46 (9), 1480-1483 (1998). However, the molecules described in these documents are platinum coordination complexes and not organometallic compounds.

Preferably, the molecules of formula (I) above satisfy one or more of the following conditions: - at least one of R _'l5 R' _2, R _'3 is -OH or -OCOR ₄ ;

at least one of R "i, R" ₂ , R " ₃ is a -OH or -OCOR _{4 group} .

Surprisingly, the inventors have indeed found that the presence of a hydroxyl group (or a group -OCOR ₄ , which leads to the formation of a hydroxyl when the molecule is administered in vivo) on each of the phenyl rings confers on these molecules antiproliferative properties which have been observed on non-hormonally dependent cancer cell lines.

In particular, the compound 8 (1,1-bis (4-hydroxyphenyl) -2-ferrocenyl-but-1-ene) below shows an anti-proliferative activity

8

much higher than that of 4-hydroxy tamoxifen and hydroxyferrocifenes 2. Compound 8 has already been described as an intermediate in the synthesis of hydroxy ferrocifenes 2 (Chem Eur, J., 2003, 9, 5223-5226). It has also been described in this document for its affinity for the estrogen receptor ERa. However, the cancer cells of the nonhormone-dependent cancers do not have ERa receptors and there is no reason to suppose that the compounds of the invention, in compound 8 would have anti-proliferative activity on non-hormonally dependent, tamoxifen-resistant cancers.

In addition, this antiproliferative effect can be observed for a molecule of formula (I) having no hydroxyl function or -OCOR ₄ function on its phenyl nuclei, but which is converted by oxidation when administered in vivo. In particular, the molecule can be mentioned:

According to the present invention the term alkyl C ₁ -C _{16 or} C ₁ -C ₂ alkyl group means a linear branched or cyclic, saturated or unsaturated containing from 1 to 16, respectively from 1 to 12 carbon atoms, such as for example a methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-dodecyl, ... n-hexadecyl group. The term aryl designates an aromatic ring optionally substituted with one or more C ₁ -C ₃ alkyl groups.

The term halogen or halo means a chlorine, fluorine, bromine or iodine atom.

The expression metallocene denotes an organometallic group comprising at least one metal atom of group VIII of the periodic classification of chemical elements, said metal atom possibly being in oxidized form.

The present invention relates more particularly to the molecules of formula (I) in which the metallocene group corresponds to formula (II) below:

( 'I)

in which M represents a group VIII metal atom of the periodic classification of chemical elements, said metal atom possibly being in oxidized form and R represents a group chosen from H, CH ₃ or CF ₃ .

The molecules that can be used in the present invention may be those in which the organometallic group has the general formula (III)

wherein M represents a metal atom selected from titanium, vanadium, nobium, hafhium and molybdenum and X represents a halogen selected from chlorine, bromine and iodine. According to a variant of the invention X may designate any other ligand ensuring the electronic stability of the organometallic entity with 16 or 18 electrons.

The organometallic group may also be a semi-sandwich complex or clusters such as those represented by formulas (IV) and (V) below:

(IV) M = Mn, Tc, Re (V) Semi-sandwich cluster complex

With the exception of compounds for which: according to the variant defined in (i) R ₁ represents para-hydroxyphenyl, R ₂ represents the ferrocenyl group and R ₃ represents the ethyl group, R ' ₂ and R' ₃ represent an atom of hydrogen and R'i represents a hydroxyl in para of the phenyl or R'i represents H, the compounds of formula (I) are new and constitute another object of the invention, as well as the pharmaceutical compositions comprising them.

The present invention relates more particularly to the molecules corresponding to formula (Ia) or formula (Ib) below:

wherein M, R, R _3, R'j, R _'2, R' _3j R "i, R" _2, R _"3 have the same definition as above. The compounds (Ia) and (Ib) are isomerizable and the invention relates to the 2 isomers of each of these formulas.

Advantageously, the molecules that can be used in the present invention are those that satisfy one or more of the conditions below:

- M = Fe,

R ₃ represents a C ₁ -C ₆ alkyl group or a hydrogen atom,

- (R ', R' ₂ , R ' ₃ ) = (OH, H, H), (OH, OH, H)

- (R ",, R" ₂₅ R _"3) = (OH, H, H), (OH ₅ OH, H) ₅

- R represents H

at least one of the hydroxyls is placed in the para position on the phenyl rings. The preferred compound for the practice of the invention is compound 8.

Another family of preferred molecules of the invention consists of molecules corresponding to formula (I), preferentially to formula (Ia) or formula (Ib) in which at least one of R'i, R ' ₂ , R ' ₃ is the group -OCOR ₄ and at least one of R " ₁₅ R" ₂ , R " ₃ is the group -OCOR ₄ , R ₄ having the same definition as above.

The group -OCOR ₄ is advantageously placed in the para position of each of the phenyls. Preferably (R ' _u R' ₂ , R ' ₃ ) = (-OCOR ₄ , H, H) or (-

OCOR ₄ , OH, H) and (R " ₁₎ R" ₂ , R " ₃ ) - (-OCOR ₄ , H, H) or (-OCOR ₄ , OH, H).

The molecules of formula (I) in which each of the two phenyl rings is substituted with a group -OCOR ₄ are new and constitute another object of the invention. Preferably each of the phenyl nuclei of the molecule of formula (I) is represented by formula (VI) below:

(VI)

According to this variant of the invention, the preferred molecules are those of formula (Ic) and (Id) in their two isomeric forms:

R, R ₃ and R ₄ having the same definition as above. Preferably one or more of the conditions below are verified:

R ₃ represents H or a C ₁ -C ₆ alkyl group,

M represents Fe,

R is H,

R ₄ represents a C ₁ -C ₁₆ alkyl group, optionally a C ₁ -C ₆ alkyl group.

The synthesis of the compounds which can be used in the present invention can be easily carried out using methods known to those skilled in the art and described in

WO 96/11935, TOP S. et al., Chem. Eur. J., 2003, 9, 5223-5236. The experimental part illustrates the preparation of some of these compounds.

According to the variant of the invention numbered (ii) R ₂ represents a grouping

and R 1 and R ₃ taken together with C = C form an organometallic group. Two examples of compounds corresponding to this formula are illustrated below:

and According to the variant of the invention numbered (iii) R ₂ represents a grouping

and -YR ₃ C = CR-form an organometallic group. An example of a compound of this formula is shown below:

The compounds of the invention are intended to be administered in a manner known to those skilled in the art in a pharmaceutically acceptable vehicle. Mention may more particularly be made of compositions intended for enteral or parenteral administration: intravenous, intramuscular or subcutaneous, nasal, oral. In particular, compositions in the form of solution, sugar-coated tablets, sublingual tablets, capsules, suppositories, creams, ointments, dermal gels, injectable preparations, oral suspensions.

The dosage may be adapted depending on the nature and severity of the condition, the route of administration, the age and weight of the patient.

The subject of the invention is therefore the use of a compound of formula (I) for the preparation of a medicament for the treatment of non-hormone dependent cancer. It also relates to the use of a compound of formula (I) for the preparation of a medicament for the prevention of non-hormone dependent cancer. In particular, after the treatment of such a cancer, the compounds of formula (I) would make it possible to prevent and / or to delay the reappearance of a proliferative syndrome. The compounds of formula (I) may also be used for the preparation of a medicament intended for the prevention and / or treatment of heterogeneous type of cancers, that is to say having both a hormone-dependent and a non-hormonally dependent aspect.

EXPRESS PART I- SYNTHESIS

1. Synthesis of 1β-bis (4-hydroxyphenyl) -2-phenyl-but-1-ene (compound 6)

The initial preparation is based on the method of Dodds et al., Proc. R. Soc. London Ser. B ₅ 1939, 127, 140-167. It was taken over by Lubezyk et al. For the synthesis of compound 6, D; Robertson et al., J. Steroid Biochem., 1982, 16, 2-13; Mr. R. Schneider, J. Med. Chem., 1986, 29, 1494-98; V. Lubczyk et al., J. Med. Chem., 2002, 45, 5358-5364, the method requires several reaction steps. The synthesis of tamoxifen was facilitated by the use of the McMurry coupling reaction applied by Coe and Scriven, J; Chem. Soc. Perkin Trans I, 1986, 475-477. On the other hand, this coupling reaction is not yet applied for the synthesis of compound 6.

Applying this reaction, propiophenone couples with dihydroxyphenone to provide 6 with a yield of 73% according to Scheme 1 below:

2. Synthesis of 1-bis (4-hydroxyphenyl) -2-ferrocenyl-but-1-ene (compound 8)

The 1,1-bis (4-hydroxyphenyl) -2-ferrocenyl-but-1-ene compound 8 was prepared according to the McMurry coupling reaction, a reaction used for the preparation of the organic compound 6. The propionylferrocene is reacted with dihydroxybenzophenone in the presence of McMurry TiCl ₄ / Zn reagent. Compound 8 is obtained with a yield of 52.5%.

3. Experimental part

Anhydrous THF is obtained by distillation over benzophenone / sodium. The NMR spectra are recorded on the Bruker 200 MHz and 300 MHz nuclear magnetic resonance spectrometers. Column chromatography is performed with Merck silica gel with a technical eluent. The elementary analyzes were carried out by the Analysis Department of the University of Jussieu. In a Schlenk tube surmounted by a condenser and purged with argon, 2,00 g (30 mmol) of zinc powder and 60 mL of anhydrous THF. The mixture is cooled to -10 ° C. Under good stirring, 3.11 g (1.8 mL, 16 mmol) of TiCl ₄ is slowly added to the mixture. The dark gray medium obtained is refluxed for 2 hours. After allowing to cool to room temperature, a solution of THF (20 mL) containing propiophenone (0.67 g, 5 mmol) and 4,4'-dihydroxybenzophenone (1.07 g, 5 mmol) is gently added to the medium. After complete addition, the mixture is refluxed for 2 hours. After having allowed to cool to room temperature, the reaction medium is hydrolyzed with a solution of 10% K ₂ CO ₃ . The products are extracted with dichloromethane and dried with MgSO ₄ . The crude product obtained after evaporation of the solvent is chromatographed on a column of silica gel eluting with CH ₂ Cl ₂ : acetone 95: 5. Compound 6 is finally isolated as a colorless solid (73% yield, mp 165 ° C). ¹ H NMR (300 MHz, CD ₃ OH) d 7.13-7.06 (m, 5H, C ₆ H ₅ ); 7.01 and 6.76 (d, d, 2H, J = 8.7 Hz C ₆ H ₄ ); 6.65 and 6.39 (d, d, 2H, 2H, J = 8.7 Hz, C ₆ H ₄ ); 2.47 (q, 2H, J = 7.4 Hz, CH ₂ ); 0.90 (t, 3H, J = 7.4 Hz, CH ₃ ).

The spectroscopic characteristics are identical to those of the product of the literature which had been obtained by another synthetic route (V. Lubcyk, H. Bachmann, R. Gust, J. Med Chem, 2002, 45, 5358-5364). .

1, 1-bis (4-hydroxyphenyl) -2-ferrocenyl-but-1-ene

In a Schlenk tube surmounted by a condenser and purged with argon, 3.90 g (60 mmol) of zinc powder and 60 ml of anhydrous THF are placed. The mixture is cooled to -1O ⁰ C. Under good stirring, 5.70 g (30 mmol) of TiCl ₄ are slowly added to the mixture. The dark gray medium obtained is refluxed for 2 hours. After allowing to cool to room temperature, a solution of

THF (30 mL) contained propionylferrocene (2.42 g, 10 mmol) and 4,4'-dihydroxybenzophenone (2.14 g, 10 mmol) was gently added to the medium. After complete addition, the mixture is refluxed for 15 hours. After allowing to cool to room temperature, the reaction medium is hydrolyzed with a solution of 10% Na ₂ CO ₃ . The products are extracted with ethyl ether and dried with MgSO ₄ . The purpose obtained after evaporation of the solvent is chromatographed on a column of silica gel with 1: 2 ethyl etherpentane eluent. 2.23 g of compound 8 is finally isolated as an orange solid (52.5% yield, mp 219 ° C.).

¹ H NMR (200 MHz, CDCl ₃ ) d 7.08 and 6.80 (d, d, 2H, 2H, J = 8.5 Hz, C ₆ H ₄ ); 6.90 and 6.68 (d, d, 2H, 2H, J = 8.5 Hz, C ₆ H ₄ ); 5.04 (s, 2H, OH); 4.11 (s, 5H, Cp); 4.07 and 3.90 (t, t, 2H, 2H, C ₅ H _4); 2.58 (q, 2H, J = 7.5 Hz, CH ₂ ); 1.02 (t, 3H, J = 7.5 Hz, CH ₃ ). Analysis: Calcd for C ₂₆ H ₂₄ O ₂ Fe: C, 73.44; H, 5.70. Found: C, 73.44; H, 5.83.

II- BIOLOGICAL ACTIVITY

FIG. 1 is a graph illustrating the proliferative / antiproliferative effect on MDA-MB231 cells (ERa negative, ERβ positive, non-hormonally dependent cancer cells) of 1 nM of 17β-estradiol (E2), 1 μM of 4- OH-Tamoxifen (OH-TAM), 1 and 10 μM compounds 6 and 8 after 5 days of culture. The values are expressed from the 100% control. Results of a representative experiment (8 points, ± confidence limit P = O ₅ I, T = 2.35).

FIG. 2 is a graph illustrating the proliferative / antiproliferative effect on DU-145 cells (hormone-independent cells of prostate cancer)) of 1 nM and 1 μM of testosterone (Testo) and dihydrotestosterone (DHT) and 1 μM of compound 8 after 5 days of culture. The values are expressed from the 100% control. Results of a representative experiment (8 points, ± confidence limit P = O ₅ I, T = 2.35). FIG. 3 is a graph illustrating the proliferative / antiproliferative effect on PC3 cells (hormone-independent prostate cancer cells) of 1 nM and 1 μM of testosterone (Testo) and dihydrotestosterone (DHT) and 1 μM of compound 8 after 5 days of culture. The values are expressed from the 100% control. Results of a representative experiment (8 points, ± confidence limit P = O ₅ I, T = 2.35).

1. Biological Behavior of Compounds 6 and 8 The ARL (Relative Relative Binding Affinity) measurements of 6 and 8 were determined on the α and β forms of the estrogen receptor. By definition the ARL value of Poestradiol, the reference hormone is 100%. LogPo / w lipophilicity values were also measured using the method previously described by Minick et al., J. Med. Chem., 1988, 31, 1923. These values are summarized in Table 1.

Table 1: Relative Binding Affinity (ARL) for estrogen receptors (ERa and ERβ ^* ) and logPo / w values

Measurements made from 1x10 ^" 3M solutions in DMSO with an incubation of 3h30 at 0 ^° C.

These molecules therefore recognize both forms of the estrogen receptor with a better affinity for the beta form. The partition coefficients, expressed as logPo / w, were measured according to the method developed by Minick et al., J. Med. Chem., 1988, 31, 1923.

The study of the proliferative / antiproliferative effect on a breast cancer cell line (MDA-MB231) was carried out. Figure 1 shows the result obtained with the cell line MDA-

MB231. The MDA-MB231 cells, classified as "Estrogen Receptor Negative ER", do not contain an ERα receptor, but it has recently been known that the second form of ERβ receptor is present (EA Vladusic et al, Cancer Res., 1998, 58 , 210-214).

The result is spectacular. 17B-estradiol, 4-OHTAM and compound 6 do not have the same effect on this cell line whereas the compound

8 has a very important antiproliferative effect with a decrease of 80% observed at a concentration of 1 μM. This effect is greater than that previously observed with the hydroxyferrocifenes 5.

2. Effect on cell lines derived from cancerU-145 and PC3 prostate cancer

Compound 8 was tested on two independent hormone cancer cell lines derived from prostate cancer (DU-145 and PC3) and compared to the effect of testosterone and dihydrotestosterone (DHT). The results obtained are shown in FIGS. 2 and 3. Testosterone and dihydrotestosterone have no effect on these independent hormone lines, which is expected. On the other hand, compound 8 shows a very marked antiproliferative effect on these two lines.

3. Conclusion

The biological tests clearly showed the antiproliferative activity of the ferrocenic compound 8 on the MDA-MB231 cell line. Treatments Breast cancers face a serious problem of drug resistance, especially tamoxifen. Compound 8 appears as a promising product, it exhibits antiproliferative activity against the MDA-MB231 cell lines, tamoxifen-resistant lines, but also on independent hormonal prostate cancer lines.

Claims

1. Use of a molecule corresponding to formula (I)

in which either:

(i) one of R ₁ and R ₂ represents a group

and the other represents an organometallic group

R ₃ represents a group chosen from: a hydrogen atom, a halogen atom, an NO ₂ group, a CN group, an alkyl halo C ₁ -C ₁₂ alkyl or C ₁ -CJ ₂ an aryl group, that is:

(ii) R ₂ represents a grouping

(iii) R ₂ represents a grouping

and -YR ₃ C = CR ₁ - forms an organometallic group, R'i, R ' ₂ , R' ₃ , R "j, R" ₂ , R " ₃ , identical or different, represent a group chosen from an atom of hydrogen, a hydroxyl group, an alkyl group Cj-C _6, a halogen atom, a haloalkyl group, C ₁ -C _6, a -OCOR ₄ group wherein R ₄ represents an alkyl group C ₁ - C ₁₆ , C ₁ -C ₁₆ haloalkyl or an aryl group, for the preparation of a medicament for the prevention and / or treatment of a non-hormone-dependent cancer.

2. Use according to claim 1, characterized in that the cancer belongs to the following list: breast cancer, prostate cancer, colon cancer, melanoma, ovarian cancer, endometrial cancer, kidney cancer, melanoma , retinoblastomas.

3. Use according to claim 1 or claim 2, characterized in that the organometallic group comprises at least one metal atom of group VIII of the periodic classification of the chemical elements, said metal atom possibly being in oxidized form.

4. Use according to claim 1 or claim 2, characterized in that in formula (I) the organometallic group is selected from those corresponding to one of formulas (II), (III), (IV) and (V) ) below :

• Formula (II):

CO in which M represents a metal atom of group VIII of the periodic classification of the chemical elements, said metal atom possibly being in oxidized form and R represents a group chosen from H, CH ₃ , CF ₃

Formula (III)

wherein M represents a metal atom selected from titanium, vanadium, nobium, hafhium and molybdenum and X represents a halogen selected from chlorine, bromine and iodine

Formulas (IV) and (V)

(IV) M = Mn, Tc, Re (V)

Semi-sandwich cluster complex

5. Use according to any one of claims 1 to 5, characterized in that the molecule (I) satisfies one or more of the conditions below:

at least one of RZ ₁ , R ' ₂ , R' ₃ is a group -OH or -OCOR ₄

at least one of R ", R" ₂ , R " ₃ is a -OH or -OCOR _{4 group} ,

6. Use according to any one of claims 1 to 5, characterized in that the compound of formula (I) is selected from the molecules corresponding to formula (Ia) or formula (Ib) below:

and their isomers, M representing a metal atom of group VIII of the periodic classification of the chemical elements, said metal atom possibly being in oxidized form and R representing a group chosen from H, CH ₃ , CF ₃ .

7. Use according to any one of claims 1 to 6, characterized in that the molecule (I) satisfies one or more of the conditions below:

- M - Fe,

R ₃ represents a C ₁ -C ₆ alkyl group or a hydrogen atom,

- (R'i, R ' ₂ , R' ₃ ) = (OH, H, H) or (OH, OH, H),

- (R "i, R" ₂ , R " ₃ ) = (OH, H, H) or (OH, OH, H),

- R represents H,

at least one of the hydroxyls is placed in the para position on the phenyl rings.

8. Use according to claim 7, characterized in that the compound of formula (I) is compound 8:

8

9. Use according to any one of claims 1 to 6, characterized in that in the formula (I), at least one of R ' _1} R' ₂ , R ' ₃ is the group -OCOR ₄ and the at least one of R " ₁₅ R" ₂ , R " ₃ is the group -OCOR ₄ .

10. Use according to claim 9, characterized in that the group -OCOR ₄ is placed in the para position of each of the phenyls.

11. Use according to claim 9 or claim 10, characterized in that:

(R 'i, R' ₂ , R ' ₃ ) = (-OCOR ₄ , H, H) or (-OCOR ₄ , OH, H)

(R "], R" ₂ , R " ₃ ) = (-OCOR ₄ , H, H) or (-OCOR ₄ , OH, H).

12. Use according to any one of claims 9 to 11, characterized in that the compound of formula (I) is selected from those corresponding to formula (Ic) or formula (Id):

Use according to claim 12, characterized in that one or more of the following conditions are satisfied:

R ₃ represents H or a C ₁ -C ₆ alkyl group, M represents Fe,

R ₄ represents a C ₁ -C ₆ alkyl group, R represents H.

14. Molecule corresponding to formula (I):

in which either:

(i) one of R ₁ and R ₂ represents a group

and the other represents an organometallic group such as a metallocene,

R ₃ represents a group chosen from: a hydrogen atom, a halogen atom, an NO ₂ group, an NC group, a C ₁ -C ₁₂ haloalkyl group or a C ₁ -C ₁₂ alkyl group, an aryl group, that is:

(ii) R ₂ represents a grouping

and R ₁ and R ₃ taken together with C = C form an organometallic group, that is:

(iii) R ₂ represents a grouping

and -YR ₃ C = CR ₁ - form an organometallic group, R'i, R ' ₂ , R' ₃ , R " ₁₅ R" ₂ , R " ₃ , identical or different, represent a group chosen from a hydrogen atom a hydroxyl group, a C ₁ -C ₆ alkyl group, a halogen atom, a C ₁ -C ₆ haloalkyl group, a -OCOR ₄ group in which R ₄ represents a C ₁ -C ₆ alkyl group, a halo alkyl, Cj-C ₁₆ or an aryl group, at least one of R _'ls R' _2, R _'3 being -OH or -OCOR _4, and at least one of R "i, R" ₂ , R " ₃ being a group -OH or -OCOR ₄ , the organometallic group being selected from those corresponding to one of formulas (II), (III), (IV) and (V) below: Formula (II)

(H)

in which M represents a metal atom of group VIII of the periodic classification of the chemical elements, said metal atom possibly being in oxidized form and R represents a group chosen from H, CH ₃ , CF ₃

• Form (III):

• Formulas (IV) and (V):

(IV) M = Mn ₁ Tc (V)

Semi-sandwich cluster complex excluding the case of compounds (i) where R ₁ is parahydroxyphenyl, R ₂ is a ferrocenyl group and R ₃ is ethyl, R _'2 and R' ₃ represent a hydrogen atom and R _'Ï represents a hydroxyl para phenyl or a hydrogen atom.

A pharmaceutical composition comprising a compound of claim 14 and a pharmaceutically acceptable carrier.