DIARILETHYLENE METALOCENIC DERIVATIVES, PREPARATION METHODS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE DERIVATIVESThe present invention relates to the dialoethylene metallocene derivatives, to their preparation processes as well as to pharmaceutical compositions containing these derivatives. Certain classes of triarylethylene derivatives have representatives, such as tamoxifen or nafoxidine, associated with weak estrogenic properties, marked antiestrogenic properties that are the basis of their use as oral contraceptives (RAY et al., J. Med. Chem., 1994, 37, 696), as inducers of ovulation and, above all, as anti-tumor agents (JORDÁN and MURPHY, Endocr. Rev., 1990, 11, 578; DORE et al., J. Med. Chem. 1992, 35, 573; KYM et al. J. Med. Chem., 1993, 36, 3910). This duality of properties, weak estrogenic and pronounced antiestrogenic, results without a doubt from the presence of two distinct functional components in the structure of these compounds. It is, on the one hand, an entity of the type stilbena trans that simulates the structure of synthetic estrogen, diethylstilbestrol and, on the other hand, an additional polar residue consisting, for example, of a group of the type (α-amino-aminoalkoxy) ) phenyl that interferes with the initiation of estrogenic activity and becomes responsible for the antiestrogenic activity. Recently the hypothesis of the presence of coordinating acid Zn ++ in the vicinity of the hormone association site has been launched to explain this behavior (JAOUEN et al., Acc. Chem. Res., 1993, 26, 361). Whatever the nature of the molecular process at play, tamoxifen is used as adjuvant therapy in the control of breast cancers that responds positively to the analysis of estradiol receptors. This molecule has a positive effect on the survival of patients and on the other hand it is very tolerated. However, since the action of tamoxifen is tumoristic rather than tumoricidal, its use in this indication generally justifies a prolonged administration during which certain patients develop resistance to treatment (WOLF and JORDAN, Breast Cancer Res. Treat., 1993, 27, 27). In the extreme, certain tumors of the breast and the endometrium end up developing by stimulation of tamoxifen. This is the reason why the problem arises of developing new molecules endowed with antitumor and appropriate properties to replace the triarylethylene antiestrogens of the prior art and especially tamoxifen in its antitumor applications as the treatment of estrogen-dependent breast cancers. The problem is solved by the present invention proposing a new family of compounds capable of conveniently serving as substitutes for the triarylethylene antiestrogens of the prior art, especially tamoxifen, in view of their superior antitumor activity to the latter. of preparation of these new compounds as well as the pharmaceutical compositions containing said compounds. The subject of the present invention is therefore the compounds of general formula (I):in which: the group -0 (CH2) nZ is in the meta or para position with respect to the group -CR3 = CR4R5, n represents an integer between 2 and, Z represents a basic or polar coordinate chosen from the groups -N ^ in which R] and R2, identical or different, represent an alkyl group with 1 to 6 carbon atoms optionally substituted by one or more halogen atoms, the heterocyclic groups contain a nitrogen atom or the groups -OR], -SRj, -SOR! or -S02Rj in which R1 has the same meaning as above, and in which: either R3 represents a phenyl group optionally substituted by one or many hydrogen atoms or halogen atoms or hydroxyl groups or alkyl or alkoxy groups of 1 to 3 carbon atoms and R5 represents a metallocene group, while R4 represents a hydrogen atom or a halogen atom or a group N02 or a chloroethyl group or a CN group or also an alkyl group having from 1 to 3 carbon atoms whose terminal carbon may optionally be bonded to the carbon located in position 2 of the phenyl group of R3, whether R3 represents a metallocene group and R5 represents a phenyl group optionally substituted by one or more hydrogen atoms or halogen atoms or hydroxyl groups or alkyl or alkoxy groups with from 1 to 3 carbon atoms carbon, while R4 represents a hydrogen atom or a halogen atom or a group N02 or a chloroethyl group or a CN group or also an alkyl group with 1 to 3 carbon atoms, in all their stereoisomeric forms as well as their salts . Unexpectedly, the Inventors have discovered, in effect, that the fixation on a same skeleton of an antiestrogenic component and of a metallocentric entity leads to its components endowed with tumoristatic properties and marked tumoricides, superior to those of antiestrogens of the prior art, and in fact, appropriate to be used as antitumoral drugs especially in the treatment of estrogen-dependent breast cancers. In the above and in the following, the expression "alkyl having 1 to 6 carbon atoms" denotes any alkyl group having no more than 6 carbon atoms, straight or branched, such as, for example, methyl, ethyl, propyl radicals , butyl, isopropyl or isobutyl. Similarly, the term "alkyl having 1 to 3 carbon atoms" refers to any alkyl group having no more than 3 carbon atoms, straight or branched. By "alkoxy with 1 to 3 carbon atoms" group, the present application seeks to designate any alkoxy group having no more than 3 carbon atoms such as, for example, a methoxy, ethoxy, propoxy or isopropoxy group. The term "heterocyclic group that houses a nitrogen atom" refers to a nitrogen heterocycle that does not comprise more than 6 atoms in the cycle, such as, for example, an N-piperidino, N-morpholino or N-pyrrolidino group. The term "halogen" refers to chlorine, fluorine, bromine or iodine.
In a preferred embodiment of the invention, the metallocene group corresponds to the general formula (II):in which M represents a metal atom of group VIII of the Periodic Classification of the chemical elements, said atom can possibly be under an oxidized form. In another embodiment of the invention, the metallocene group corresponds to the general formula (III):wherein: M represents a metal atom selected from titanium, vanadium, niobium, hafnium or molybdenum, and X represents a halogen atom chosen from chlorine, bromine or iodine.
The subject of the invention is more particularly the compounds as defined above, characterized in that they correspond to the particular formula (I-a):é > in which: the group -0 (CH2) 2Z is in para position with respect to the group -CR3 = CR4R5, Z represents a group -NRjR2 in which Rj and R2, identical or different, represent a methyl group or a group ethyl, or Z represents an N-pyrrolidino group, R3 represents a phenyl group optionally substituted by a hydroxyl group or by a methoxy group, R4 represents a hydrogen atom or a halogen atom or a group N02 or a chloroethyl group or a CN group or also an ethyl group, and M represents a metal atom chosen from iron, ruthenium or osmium, optionally under its oxidized form. These compounds are isomerizable so that in the following, compounds of formula (I-a) having the following configuration will be designated by "trans" isomers:(trans)in which the R3 group and the metallocene group are in position"trans" one with respect to the other on the one hand and on the other hand of the olefinic bond, while "metallocene compounds" having the following configuration will be designated by "cis" isomers;in which the group R3 and the metallocene group are in the "cis" position with respect to one another on the one hand and on the other hand to the olefinic bond. Among the compounds of formula (Ia), those which correspond to the particular formula (I -al) in which R j and R 2 represent a methyl group, R 3 represent a phenyl group substituted in para for a hydroxyl group and R 4 represent an ethyl group. The particular formula (I -al) is represented here in the "trans" configuration:Preferably, M represents an iron atom and the corresponding metallocene compound is l- [4 - (2-dimethylamino ethoxy) phenyl] -1-4- (4-hydroxyphenyl) -2-ferrocenyl-1-butene. Particularly preferably, the metallocene compound is the "trans" isomer of l- [4- (2-dimethylaminoethoxy) phenyl] -1-4- (4-hydroxyphenyl) -2-ferrocenyl-1-butene. Among the compounds of the formula (I-a), the compounds corresponding to the particular formula (I-a2) in which Ri and R2 represent a methyl group, R3 represents a phenyl group, and R4 represents an ethyl group are likewise preferred. The particular formula (I-a2) is represented here in the "trans" configuration:Preferably, M represents an iron atom and the corresponding metallocene compound is l- [4- (2-dimethylaminoethoxy) phenyl] -l-phenyl-2-ferrocenyl-1-butene. The invention also relates more particularly to the compounds corresponding to the general formula (I) characterized in that, in this formula (I): the group -0 (CH2) 2Z is para to the group -CR3 = CR4R5 , n is equal to 2 and Z represents an N-pyrrolidino group, R3 represents a phenyl group substituted in para for a hydroxyl group and alkoxy with 1 to 3 carbon atoms, while R4 represents an alkyl group in C2 whose terminal carbon is linked to the carbon located at the 2-position of the phenyl group of R3, M represents a metal atom chosen from iron, ruthenium, or osmium, optionally under its oxidized form. These compounds respond to the particular formulawherein R ^ represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms. According to the invention, the compounds of general formula (I) can be prepared according to a process characterized in that: a) a compound of general formula (IV) is reacted:in which the group -0 (CH2) 2Z is in the meta or para position with respect to the group -CR3 = CR4R5, n represents a January number between 2 and 10, z represents a basic or polar coordinate chosen between the groups - NR, R2 in which R] and R2, identical or different, represent an alkyl group with 1 to 6 carbon atoms optionally substituted by one or more halogen atoms, the heterocyclic groups contain a nitrogen atom or groups -OR !, -SR ,, -SOR, or -S02R? in which R, has the same meaning as above, and in which: either R3 represents a phenyl group optionally substituted by one or many hydrogen atoms or halogen atoms or hydroxyl groups or alkyl or alkoxy groups of 1 to 3 carbon atoms and R5 represents a bromine atom, while R4 represents a hydrogen atom or a halogen atom or a group N02 or a chloroethyl group or a CN group or also an alkyl group with 1 to 3 carbon atoms whose The terminal carbon can optionally be bonded to the carbon located in position 2 of the phenyl group of R3, whether R3 represents a bromine atom and R5 represents a phenyl group optionally substituted by one or more hydrogen atoms or halogen atoms or hydroxyl groups or alkyl or alkoxy groups with 1 to 3 carbon atoms, while R 4 represents a hydrogen atom or a halogen atom or a group N 0 2 or a chloroethyl group or a CN group or else a group alkyl with 1 to 3 carbon atoms, with a metal salt of cyclopentadienyl to obtain replacement of the bromine atom by a cyclopentadiene group; b) the compound obtained in step a) is reacted with a strong base to obtain the formation of a cyclopentadienyl anion, c) the compound obtained in step b) is reacted with an organometallic compound of the formula: Cp-M- (C0) 2-X in which Cp represents a cyclopentadiene group, M represents a metal atom of group VIII of the Periodic Classification of the chemical elements and X represents a halogen atom chosen from chlorine, bromine or iodine, or with a organometallic compound of formula Cp-MX in which Cp and X have the same meaning as above, M represents a metal atom chosen from titanium, vanadium, niobium, hafnium or molybdenum and m is an integer equal to 3 or 4. The compounds of general formula (IV) can be prepared according to the procedures that have been proposed in the prior art for the synthesis of triarylethylene antiestrogens (Cur. Med. Chem., 1994, 1, 61-104). A suitable metal cyclopentadienyl salt for carrying out step a) of this process is represented by sodium cyclopentadienate. The strong base useful for carrying out step b) can, for example, be NaH or NaHH2. Whether the compounds of particular formula (I-al) could be prepared according to the preparation method described hereinabove, the subject of the invention is also a process for the specific preparation of the compounds of formula (I-al), characterized because: a) a metallocene ester of formula (V) is subjected to:wherein M represents a metal atom chosen from iron, ruthenium or osmium, to an addition reaction with the organic lithium CH3-0-C6H4-Li or an organic magnesium of the formula: CH3-0-C6H4-MgX in which X represents a chlorine, bromine or iodine atom, which leads to the formation of an intermediate alcohol, followed by a dehydration reaction of said alcohol, b) the compound obtained in step a) is subjected to a demethylation reaction, c) the compound obtained in step b) is subjected to an alkylation reaction by sodium ethanolate and 2-dimethylaminoethyl chloride hydrochloride. A mixture of two "cis" and "trans" isomers of a compound of formula (I-al) is thus obtained. The dehydration of the intermediate alcohol can be advantageously carried out by the action of a strong acid such as hydrochloric acid. The demethylation reaction can be advantageously carried out by the action of boron tribromide in the presence of a suitable solvent such as, for example, dichloromethane. In a preferred embodiment of the process according to the invention, this process comprises in advance the preparation of metallocene ester of formula (V) by esterification of the corresponding metallocetylacetic acid, followed by an alkylation reaction of the carbon in position a of the metallocenil cycle of said ester. The esterification of the metallocenylacetic acid can be carried out by means of a strong base such as potassium tertiobutylate (t-BuOK). A suitable alkylating reagent is represented by iodoethane. This alkylation is advantageously carried out in the presence of a strong base such as, for example, t-BuOK or sodium or potassium hexamethyldisilazane and a suitable solvent such as, for example, dimethylsulfoxide (DMSO). The metallocetylacetic acid can be prepared according to the method described in the literature (LEDNICER et al., J. Org. Chem., 1958, 23, 653) which consists of reacting a metallocenylmethyl trimethyl ammonium iodide with potassium cyanide to obtain the metallocenylacetonitrile. corresponding after hydrolysing the latter. Insofar as the preparation of a metallocene derivative of formula (I-al) according to this process always leads to the obtaining of two "cis" and "trans" isomers of said derivative and where generally only one of the two isomers, a Knowing the "trans" isomer has the pronounced antiestrogenic properties, it may be advantageous to proceed to a separation of the two isomers obtained at the output of stage c) previously mentioned.According to the invention, the specific preparation process of the compounds of formula (I-al) further comprises a step of separating "cis" and "trans" isomers of these compounds. This separation can advantageously be carried out by fractional crystallization. However, it is possible to use other techniques of the prior art such as thin layer chromatography with the aid of an appropriate eluent. Although the compounds of particular formula (I-a2) can also be obtained by the process for the preparation of compounds of general formula (I), the invention also relates to a process for the specific preparation of these compounds of particular formula (I-a2) which is characterized in that: a) a metallocene acid chloride of formula (VI) is reacted:wherein M represents a metal atom chosen from iron, ruthenium or osmium, with zinc diphenyl to obtain the substitution of the chlorine atom by a phenyl group, b) the compound obtained in step a) is subjected to an addition reaction with organic lithium (CH3) 2-N- (CH2) 2-0-C6H4-Li or an organic magnesium of the formula: (CH3) 2-N- (CH2) 2-0-C6H4-MgX in which X represents a halogen atom chosen from chlorine, bromine or iodine, which leads to the formation of an intermediate alcohol, followed by a dehydration reaction of said alcohol. A mixture of two "cis" isomers and"trans" of a compound of formula (I-a2). The metallocene chloride can be obtained by the action of trichloride or phosphorus pentachloride or thionyl chloride or also triphosgene on the corresponding metallocenyl-2-butanoic acid. The dehydration of the intermediate alcohol can be carried out by the action of a strong acid such as hydrochloric acid. The preparation of a compound of formula (I-a2) according to this process always leads to the obtaining of the two "cis" and "trans" isomers of said compound so that it further comprises a step of separating these "cis" isomers and "trans", which can be carried out, for example, by fractional crystallization. The subject of the present invention is also a process for the preparation of the compounds of formula (I-b), characterized in that: a) a tetralone of formula (VII) is reacted:wherein Rg represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, with organic lithium) "N- (CH2) 2-Q-C6H4-Li or an organic magnesium of formula | ^ N- (CH2) 2-Q-C6H4-MgX in which X represents a halogen atom chosen from chlorine, bromine or iodine, which leads to the formation of an intermediate alcohol, followed by a dehydration reaction of said alcohol; b) the compound obtained in step a) is subjected to a bromination reaction to obtain the compound of formula (VIII):c) the compound of formula (VIII) thus obtained is subjected to a coupling reaction with an organometallic compound of the formula: Cp-M- (C5H4) -Y in which Cp represents a cyclopentadiene group, M represents a metal atom selected from iron, ruthenium or osmium and Y represents a lithium atom, a copper atom, a SnBu3 group or a HgCl group. The bromination reaction to which the compound of formula (VIII) is subjected can be carried out with the hydrobromic acid in the presence of a suitable solvent such as, for example, pyridine. The products of general formula (I) and their addition salts with pharmaceutically acceptable acids can be administered to man as medicaments, alone or in the form of pharmaceutical compositions that allow enteral or parenteral application and which contain, as a constituent active, an effective dose of at least one product of formula (I) or an acid addition salt of such a compound, furthermore, harmless excipients and additives placed therebetween as is ordinarily made in pharmacy. The products of general formula (I) as well as their salts find, due to its tumoristic and tumoricidal properties, an application in the preparation of procured anti-tumor drugs especially for the treatment of estrogen-dependent breast cancers. In addition to the above provisions, the invention also includes other provisions that derive from the following description, made by way of example, and with reference to the accompanying drawings in which: Figures 1A, IB and 2 show the results of the cytotoxicity tests carried out respectively with the two isomers of a metallocene derivative according to the invention and tamoxifen. It should be well understood, however, that these examples are given by way of illustrations of the invention and that they do not constitute in any way a limitation. EXAMPLE 1; Preparation of "trans" and "cis" isomers of l- [4- (2-dimethylamino ethoxy) phenyl] -1- (4-hydroxyphenyl) -2-ferrocenyl-1-butene. 1.1: Preparation of ferrocenylacetonitrile 8.00 grams (20.8 mmol) of ferrocenyl-methyl-trimethyl-ammonium iodide (STREM) and 8 grams of KCN (123 mmol) are dissolved in 80 milliliters of water. The mixture is placed in a flask superimposed on a coolant. Heat to reflux for 2 hours and allow the mixture to cool to room temperature. The product is extracted 3 times in 40 milliliters of ethyl ether. The organic phase is first washed twice in 30 milliliters of water then dried over magnesium sulfate. After filtration and evaporation, 4.1 grams of ferrocenylacetonitrile are recovered. Chemical formula: C12H ,, NFe Mass: 225 Yield: 87.7 percent. 1.2: Preparation of ferrocenylacetic acid 4.10 grams (18.2 mmol) of ferrocenylacetonitrile are dissolved in 80 milliliters of ethanol. Dissolve 10.08 grams of KOH(180 mmol) in 80 milliliters of water. The potassium solution is poured into the first solution and the mixture is refluxed for 4 hours. The reaction medium is concentrated to remove the majority of ethanol. The product is extracted 3 times in 30 milliliters of ether. The aqueous phase is acidified by hydrochloric acid to pH 1 and extracted again 4 times in 50 milliliters of ethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and then evaporated. 4.20 grams of ferrocenylacetic acid are obtained in the form of a yellow solid: Chemical formula: C12H1202Fe Mass: 244 Yield: 94.5 percent. NMR 'H (200 MHz, CDC13): d 4.23 (m, 2H, substituted Cp), 4.15 (s, 7H, Cp and substituted Cp), 3.42 (s, 2H, CH2). 1.3: Preparation of ethyl ferrocenylacetate 2.00 grams (8.2 mmol) of ferrocenylacetic acid are dissolved in 50 milliliters of ethanol. 0.5 milliliters of concentrated sulfuric acid are added. The mixture is refluxed for 1 hour. After cooling, the reaction medium is poured into 100 milliliters of ice water. The product is extracted 3 times in 40 milliliter of ether. The ether phase is washed first with water (2 times 40 milliliters), then dried over magnesium sulfate, filtered and evaporated. 2.22 grams of ethyl ferrocenylacetate are obtained. The yield of the reaction is 100 percent. Chemical formula: C14Hj02Fe Mass: 272 NMR "H (200 MHz, CDC13): 6 4.23 (m, 2H, substituted Cp), 4.18 (m, 2H, 0-CH2), 4.14 (s, 5H, Cp), 4.13 (m, 2H, substituted Cp), 3.34 (s, 2H, Cp-CH2), 1.31 (t, 3H, J = 7.12 Hz, Me) 1.4: Preparation of ethyl 2-ethyl-2-ferrocenylacetate 2.22 grams (8.2 mmol) of ethyl ferrocenylacetate are dissolved in 25 milliliters of anhydrous DMSO under an argon atmosphere, 1.01 gram (9 mmol) of t-BuOK is added, and after 5 minutes of stirring, 1.5 grams (9.6 mmol) of iodoethane are added. The stirring is continued for 2 minutes after the reaction medium is poured into 100 milliliters of ice water.The product is extracted 3 times with 560 milliliters of ether.The etherified phase is washed twice in 50 milliliters of water, dry over magnesium sulfate, filter and then evaporate The crude product obtained is chromatographed on silica gel plates 60GF254 (MERCK 7730) of 1 millimeter thickness cm as eluent a mixture that of ether / pentane 1: 9. 1.16 grams of ethyl 2-ethyl-2-ferrocenylacetate (Rf = 0.6) are obtained with a yield of 47 percent. Chemical formula: C, 6H20O2Fe Mass: 300 NMR "H (200 MHz, CDC13): d 4.23 (m, 2H, substituted Cp), 4.16(m, 2H, 0-CH2), 4.13 (s, 5H, Cp), 4.12 (m, 2H, substituted Cp), 3.19 (m, 1H, Fc-CH-), 1.77 (m, 2H, Fc-CH -CH2), 1.35 (t, 3H, J = 7.14 Hz, 0-CH2-CH3), 0.92 (t, 3H, J = 7.38 Hz, CH-CH2-CH3). 1.5: Preparation of 1,1-Bis- (4-methoxyphenyl) -2-ferrocenyl-1-butene 1.20 grams (5.5 mmol) of 4-iodoanisole are dissolved in 20 milliliters of anhydrous ether under an argon atmosphere. The solution is cooled to 0 ° C then 2.9 milliliters (4.6 mmol) of a normal butyl lithium solution is added dropwise to 1.6 M. After complete addition, the mixture is kept at 0 ° C for 15 minutes. A solution of ethyl 2-ethyl-2-ferrocenylacetate (0.69 grams, 2.3 mmol) dissolved in 10 milliliters of anhydrous ether is placed in the ampoule with bromine. The latter solution is added dropwise to the first solution maintaining the temperature at 0 ° C. Stirring is maintained for 30 minutes at 0 ° C and 2 hours at room temperature. A solution of IN hydrochloric acid is then added to a pH of 1 and the reaction medium is heated at reflux for 4 hours. After cooling, the product is extracted with ether. The etherified phase is first washed with water, dried over magnesium sulfate, filtered and then evaporated. The crude obtained is chromatographed on 60GF254 silica gel plates with a 1: 9 ether / pentane mixture as eluent. 0.65 grams of the desired compound is obtained (Rf = 0.45) with a yield of 62.5 percent. Chemical formula: C28H2802Fe Mass: 452 NMR! H (200 MHz, CDC13): d 7.12 and 6.16 (dd, 4H, J = 8.4 Hz, C6H4), 6.98 and 6.87 (dd, 4H, J = 8.4 Hz, C6H4), 4.14 (s, 5H, Cp), 4.10 (m, 2H, substituted Cp), 3.95 (m, 2H, substituted Cp), 3.82 and 3.78 (s, s, 3H, 3H, O-Me), 2.56 (q, 2H, J = 7.4 Hz, -CH2-CH3), 1.02 (t, 3H, J = 7.3 Hz, -CH2-CH3). 1.6: Preparation of 1,1-Bis- (4-hydroxyphenyl) -2-ferrocenyl-1-butene 0.55 grams (1.28 mmol) of 1,1-Bis- (4-methoxy-phenyl) -2-ferrocenyl-1- butene are dissolved in 5 milliliters of dichloromethane under an argon atmosphere. The solution is cooled to -78 ° C then 0.3 milliliter (2.84 mmol) of BBr3 is added. After complete addition, the cold bath is removed and stirring is maintained for 30 minutes. The reaction medium is then poured into ice water. After 10 minutes of stirring, NaCl is added to saturation and the product is extracted with dichloromethane (4 times in 40 milliliters). The organic phase is washed first with water, dried over magnesium sulfate, filtered and then evaporated. The crude product obtained is chromatographed on silica gel plates 60GF254 with a 3: 2 ether / pentane mixture as eluent. 0.43 gram of the desired compound is obtained (Rf = 0.4; yield = 79 percent). Chemical formula: C26H2402Fe Mass: 424 NMR lK (200 MHz, CDC13): 6 7.07 and 6.6.8 (d, d, 4H, J = 8.6 Hz, C6H4), 6.92 and 6.80 (d, d, 4H, J = 8.5 Hz, C6H4), 4.88 and 4.42 (s, S, H, H, 20H), 4.11 (S, 5H, Cp), 4.08 (m, 2H, substituted Cp), 3.91 (m, 2H, substituted Cp), 2.58 (q, 2H, J = 7.5 Hz, -CH2-CH3), 1.02 (t, 3H, J = 7.5 Hz, -CH2-CH3). 1.7: Obtaining the "trans" and "cis" isomers of l- [4- (2-dimethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2-ferrocenyl-1-butene A solution of ethanolate of sodium by reacting 0.120 grams (5.2 mmol) of sodium with 20 milliliters of ethanol. This solution is then added with 0.450 grams (1.06 mmol) of 1,1-Bis- (4-hydroxyphenyl) -2-ferrocenyl-1-butene dissolved in 10 milliliters of ethanol. After stirring for 1 hour at 80 ° C, 0.302 grams (2.1 mmol) 2-dimethylaminoethyl chloride hydrochloride is added and the mixture is refluxed for 3 hours. The solution to be cooled down to room temperature is immediately left. Hydrolyze with 100 milliliters of water and extract the product with ether (4 times 50 milliliters). The organic phase is washed first with water, dried over magnesium sulfate, filtered, then evaporated. The crude product obtained is chromatographed on silica gel plates 60GF254 with as eluent a mixture (C2H5) 3N / chloroform 1: 9. First, 0.280 grams of the "trans" isomer mixture and the "cis" isomer of 1- [4- (2-dimethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2-ferrocenyl-1-butene are obtained (yield = 53 percent). The second fraction, more polar, corresponds to 1,1- Bis [4- (2-dimethylaminoethoxy) phenyl] -2-ferrocenyl-1-butene(0.050 grams; Yield = 9.5 percent). 1.8: Separation of the "trans" and "cis" isomers of l- [4- (2-dimethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2-ferrocenyl-1-butene The mixture of the two isomers obtained above it is dissolved in a mixture of ether / hexane (5: 1) and the obtained solution is left in a refrigerator overnight. The ether solubility of the "cis" isomer is weaker than that of the "trans" isomer, the "cis" isomer crystallizes first after a slow evaporation of the solvent. The crystals of the "cis" isomer are isolated and the waste water is cooled in the freezer part (-15 ° C) of the refrigerator for one day. The "trans" isomer then crystallizes in turn in the form of fine needles.
EXAMPLE 2: Characterization of the "trans" and "cis" isomers of 1- [4- (2-dimethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2-ferrocenyl-1-butene 2.1: Chemical formula and molar mass Chemical formula: C30H33O2NFe Molar mass: 495.4 2.2: NMR spectrometric data * H The H-NMR spectra of the two "trans" and "cis" isomers are recorded on an BR200 spectrometer AC200 MHz in DMSOd6 (JANSSEN) for the reason of that this solvent does not have an isomerization of the two isomers. The H-NMR values of the two isomers are as follows: "Trans" isomer: d 9.34 (s, 1H, OH), 6.97 and 6.71 (d, d, 4H, J = 8.7 Hz, C ^ -OH), 6.89 and 6.80 (d, d, 4H, J = 8.5 Hz, C6H4-CH2), 4.11 (s, 5H, Cp), 4.07 (m, 2H, substituted Cp), 3.99 (t, 2H, J = 6.0 Hz, 0 -CH2), 3.80 (m, 2H, substituted Cp), 2.60 (t, 2H, J = 6.0 Hz, N-CH2), 2.49 (masked by the DMSO signal, 2H, -CH2-CH3), 2.20 (s) , 6H, NMe2), 0.98 (t, 3H, J = 7.3 Hz, -CH2-CH3).
"Cis" isomer: d 9.29 (s, 1H, OH), 7.08 and 6.89 (d, d, 4H, J = 8.5 Hz, C ^ - OCH2), 6.80 and 6.63 (d, d, 4H, J = 8.4 Hz , C ^ -OH), 4.11 (s, 5H, Cp), 4.08 (m, 2H, (t, 2H, J = 6.0 Hz, N-CH2), 2.49 (masked by the DMSO signal, 2H, -CH2 -CH3), 2.23 (s, 6H, NMe2), 0.98 (t, 3H, J = 7.3 Hz, -CH2-CH3) 2.3 Melting points The melting points of the "trans" and "cis" isomers are determined With the help of a Kofler bank, they are respectively 93-94 ° C for the "trans" isomer and 181 ° C for the "cis" isomer. "EXAMPLE 3: Cytotoxic activity of the" trans "and" cis "isomers of 1- [4 - (2-dimethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2-ferrocenyl-1-butene The evaluation of the cytotoxicity of the isomers"trans" and "cis" of 1- [4- (2-dimethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2-ferrocer.-1-butene was the subject of tests on human cell lines derived from a pleural effusion of a mammary adenocarcinoma (line MCF-7 ATCC HTB) as well as one of its variants (line MCF-7P). These cells are previously cultured in a mediumDulbecco MEM added 10 percent fetal calf serum and in a humid atmosphere (90 percent humidity)'relative) comprising 5 percent C02. In exponential phase of growth, these cells are trypsinized and replicated in 24-well plates of 1 milliliter at the rate of 2xl05 cells per well. After 3 days of incubation, the compounds to be tested are added at the appropriate doses and the plates are incubated for 5 days. As a result of this incubation, the cell viability of the cultures was determined with the help of the test called "MTT" which consists in adding in each well 20 μl of a solution containing 5 milligrams of (dimethyl-4, 5-bromide. thiazol-2-yl) diphenyl-2,5-tetrazolium (MTT) in 1 milliliter of phosphate buffering saline (PBS), and allowing the plates to incubate for 1 hour at 37 ° C under atmospheric conditions identical to those defined previously in the present. MTT is metabolized in living cells in an insoluble blue compound (formazan). As a result of this incubation, the wells are washed with the aid of phosphate buffer to remove the MTT and the residual formazan crystals are put back into 1 milliliter of DMSO. Concentration in formazan for each well is read by photometry at a wavelength of 550 nm and compared to a control corresponding to a medium incubated in the presence of MTT but in the absence of cells. Figures 1A and IB show the results of cytotoxicity tests performed respectively with the "cis" isomer (Figure 1A) and the "trans" isomer (Figure IB) of 1- [4- (2-dimethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2-ferrocenyl-1-butene on the two cell lines indicated hereinabove. These results are expressed in surviving cell fractions as a function of dose of the tested compound. By way of comparison, Figure 2 shows the results obtained by performing the same tests and under the same conditions with tamoxifen. Table 1 below presents the inhibitory doses 50 (IC 50) expressed in μmoles and calculated on the points of Figures 1A, IB and 2 comprised between 5xl0"7 and 10" 5 moles / liter. TABLE IFurther the inhibitory dose 50 is weak, more the cytotoxic activity is high and the results expressed in Table 1 show that the "cis" and "trans" isomers of 1- [4- (2-dimethylaminoethoxy) phenyl] -1- ( 4-hydroxyphenyl) -2-ferrocenyl-1-butene have, on the two cell lines tested, a cytotoxic activity superior to that of tamoxifen. As a result of the foregoing, the invention is not limited solely to these embodiments and application which are described more explicitly; it covers, on the contrary, all the variants that could occur to a person skilled in the art, without departing from the scope or scope of the present invention.