MXPA01001683A - New use of taxoid derivatives - Google Patents

Abstract

The present invention relates to a new use of taxoid derivatives. It relates more precisely to a method for treating abnormal cell proliferation in the brain of mammals including men by administrating a taxoid derivative.

Description

NEW USE OF TAXOID DERIVATIVES DESCRIPTION OF THE INVENTION The present invention relates to a new use of taxoid derivatives. It relates more precisely to a method for treating abnormal cell proliferation in the brain of mammals, including man, by administering the compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof: wherein: Z represents a hydrogen atom or a radical of the general formula: R, NH O (II) OH in which: Ri represents a benzoyl radical optionally substituted with one or more identical or different atoms or radicals chosen Ref: 126588 The halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms or trifluoromethyl radicals, a tenoyl or furoyl radical or a radical R2-0- CO- in which R2 represents: - an alkyl radical containing from 1 to 8 carbon atoms, - an alkenyl radical containing from 2 to 8 carbon atoms, 0 - an alkynyl radical containing from 3 to 8 carbon atoms - a cycloalkyl radical containing from 3 to 6 carbon atoms, - a cycloalkenyl radical containing from 4 to 6 carbon atoms or - a bicycloalkyl radical containing from 7 to 10 carbon atoms, these radicals being optionally substituted with one or more substituents chosen from halogen atoms and 0 hydroxyl radicals, alkoxy radicals containing from 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains from 1 to 4 carbon atoms, piperidino or morpho radicals flax, 1-piperazinyl radicals (optionally substituted in the 4-position with an alkyl radical containing from 1 to 4 carbon atoms or with a ^ ^ ^ ^ ^ ^ ^ ^, .., .., ---- gftff ^ f ^^ radical phenyl alkyl in which the alkyl portion contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing from 4 to 6 carbon atoms, 5 phenyl radicals (optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing from 1 to 4 carbon atoms or alkoxy radicals containing from 1 to 4 carbon atoms), cyano or carboxyl radicals or alkoxycarbonyl radicals in which the alkyl portion contains from 1 to 4 carbon atoms. - a phenyl radical or a- or β-naphthyl optionally substituted with one or more atoms selected from halogen atoms and alkyl radicals containing from 1 to 4 carbon atoms or alkoxy radicals containing from 1 to 4 carbon atoms Carbon, or - a 5-membered aromatic heterocyclic radical preferably chosen from furyl and thienyl radicals, - or a saturated heterocyclic radical containing from 4 to 6 carbon atoms, optionally substituted with one or more alkyl radicals containing from 1 to 4 carbon atoms, R3 represents an unbranched or branched alkyl radical containing from 1 to 8 carbon atoms, ** * *** ^^ ^ u "tí ** ** * * * * ¡¡¡¡¡¡¡jg¡í &faith a branched or unbranched alkenyl radical containing 2 to 8 carbon atoms, an unbranched alkynyl radical or branched containing from 2 to 8 carbon atoms, a cycloalkyl radical containing from 3 to 6 carbon atoms, a phenyl radical or α- or β-naphthyl optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkyloxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aralkylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl , cyano, nitro and trifluoromethyl, or a 5-membered aromatic heterocycle containing one or more identical and different heteroatoms chosen from nitrogen, oxygen and sulfur atoms and optionally substituted with one or more identical substituents or di selected atoms of halogen atoms and alkyl radicals, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or alkoxycarbonyl, with the understanding that, in the substituents of phenyl, a- or b-naphthyl and aromatic heterocyclic radicals , the alkyl radicals and the alkyl portions of the other radicals contain from 1 to 4 carbon atoms, and 5 that the alkenyl and alkynyl radicals contain from 2 to 8 carbon atoms, and that the aryl radicals are phenyl or a-or radicals. β-naphthyl, R 4 represents an alkoxy radical containing from 1 to 6 carbon atoms in an unbranched or branched chain, an alkenyloxy radical containing from 3 to 6 carbon atoms in an unbranched or branched chain, an alkynyloxy radical which contains from 3 to 6 carbon atoms in an unbranched or branched chain, a cycloalkyloxy radical containing from 3 to 6 carbon atoms or a cycloalkenyloxy radical containing 4 to 6 carbon atoms, these radicals being optionally substituted with one or more halogen atoms or with an alkoxy radical containing from 1 to 4 carbon atoms, an alkylthio radical containing from 1 to 4 carbon atoms or a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains from 1 to 4 carbon atoms, a cyano radical or carbamoyl or an N-alkylcarbamoyl or N, N-dialkylcarbamoyl radical in which each alkyl portion contains from 1 to 4 carbon atoms or, with the nitrogen atom to which it is attached, forms a saturated 5- or 6-membered heterocyclic radical, which optionally contains a second hetero atom chosen from oxygen, sulfur or nitrogen atoms, optionally substituted with an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical in which the alkyl portion contains from 1 to 4 carbon atoms, R5 represents an alkoxy radical containing from 1 to 6 carbon atoms in an unbranched or branched chain, an alkenyloxy radical containing from 3 to 6 carbon atoms, an alkynyloxy radical containing from 3 to 6 carbon atoms. carbon, a cycloalkyloxy radical containing from 3 to 6 carbon atoms, a cycloalkenyloxy radical containing from 3 to 6 carbon atoms, those radicals being optionally substituted with one or more halogen atoms or with an alkoxy radical containing from 1 to 4 carbon atoms, an alkylthio radical containing from 2 to 4 carbon atoms or a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains 1 to 4 carbon atoms, a cyano or carbamoyl radical or an N-alkylcarbamoyl or N, N-dialkylcarbamoyl radical in which each alkyl portion contains from 1 to 4 carbon atoms or, with the nitrogen atom to which it is attached, forms a saturated 5- or 6-membered heterocyclic radical, optionally containing a second heteroatom chosen from oxygen, sulfur or nitrogen atoms, optionally substituted with an alkyl radical containing from 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical wherein the alkyl portion contains from 1 to 4 carbon atoms. Preferably, the aryl radicals which may be represented by R 3 are phenyl or α- or β-naphthyl radicals optionally substituted with one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl radicals, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aralkylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carbonyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl, with understanding that the alkyl radicals and the alkyl portions of the other radicals . "•. ::,» teat «¿Hiá'á.- atfiria ,,,. they contain from 1 to 4 carbon atoms, that the alkenyl and alkynyl radicals contain from 2 to 8 carbon atoms and that the aryl radicals are phenyl or α- or β-naphthyl radicals. Preferably, the heterocyclic radicals which can be represented by R3 are 5-membered heterocyclic radicals containing one or more identical or different atoms chosen from nitrogen, oxygen and sulfur atoms, optionally substituted with one or more identical or different substituents selected from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl radicals containing from 1 to 4 carbon atoms, aryl radicals containing from 6 to 10 carbon atoms, alkoxy radicals containing from 1 to 4 carbon atoms, radicals aryloxy containing from 6 to 10 carbon atoms, amino radicals, alkylamino radicals containing from 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains from 1 to 4 carbon atoms, acylamino radicals in which the . acyl contains from 1 to 4 carbon atoms, alkoxycarbonylamino radicals containing from 1 to 4 carbon atoms, acyl radicals containing e from 1 to 4 carbon atoms, arylcarbonyl radicals in which the aryl portion contains from 6 to 10 carbon atoms, cyano, carboxyl or carbamoyl radicals, alkylcarbamoyl radicals in which the alkyl portion contains from 1 to 4 carbon atoms, dialkylcarbamoyl radicals in which each alkyl portion contains from 1 to 4 carbon atoms or alkoxycarbonyl radicals in which the alkoxy portion contains from 1 to 4 carbon atoms. Preferably, the radicals R4 and R5, which may be identical or different, represent unbranched or branched alkoxy radicals containing from 1 to 6 carbon atoms, optionally substituted with a methoxy, ethoxy, ethylthio, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano radical , carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-pyrrolidinocarbonyl or N-piperidinocarbonyl. More specifically, the present invention relates to the products of general formula (I) in which Z represents a hydrogen atom or a radical of the general formula (II) in which Ri represents a benzoyl radical or a radical R2 -0-C0- in which R2 represents a tert-butyl radical and R3 represents an alkyl radical containing from 1 to 6 carbon atoms, an alkenyl radical containing from 2 to 6 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a phenyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms (fluorine, chlorine) and alkyl (methyl), alkoxy (methoxy), dialkylamino radicals ¿¿Ljjt¿? Á £ a u¿t ÍMlie¿tt.? ^ "..a ....." = ^ I & fe ^^^^^^^^^^^ (dimethylamino), acylamino (acetylamino), alkoxycarbonylamino (tert-butoxycarbonylamino) or trifluoromethyl, or 2- or 2- radicals. 3-furyl, 2- or 3-thienyl or 2-, 4- or 5-thiazolyl, and R4 and R5, which may be identical or different, each represent an unbranched or branched alkoxy radical containing from 1 to 6. carbon atoms. Even more preferably, the present invention relates to the products of general formula (I) in which Z represents a hydrogen atom or a radical of general formula (II) in which Ri represents a benzoyl radical or a radical R2 -0-C0- in which R2 represents a tert-butyl radical and R3 represents an isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-thiazolyl radical, 4-thiazolyl- or 5-thiazolyl, and R 4 and R 5, which may be identical or different, each represent a methoxy, ethoxy or propoxy radical. Of even more special interest are the products of the general formula (I) in which R3 represents a phenyl radical and Ri represents a tert-butoxycarbonyl radical, R4 and R5, which may be identical or different, represent a methoxy, ethoxy or propoxy radical. With even greater interest, the present invention relates to (2R, 3S) -3ter-butoxycarbonylamino-2-hydroxy- 3-phenylpropionate of 4a-acetoxy-2a-benzoyloxy-5β, 20-epoxy-l-hydroxy-7β, 10β-dimethoxy-9-oxo-l-taxen-13a-yl of formula da) It is known from WO 96/30355 how to prepare a derivative according to the present invention by two processes. According to a first multi-step process, starting with the 10-desacet? Lbaccatma III formula: OCOCc 6H5R is selectively protected at positions 7 and 13, for example in the form of a silyl ether, followed by the action of a product of the general formula: R-X (IV) wherein R represents a radical as defined above and X represents a reactive ester residue such as a sulfuric or sulfonic ester residue or a halogen atom, to give a product containing an -OR unit at position 10 and groups silyl at positions 7 and 13. Then, the silyl protecting groups are replaced with hydrogen atoms to give a compound that still contains the -OR group at position 10 and OH groups at positions 7 and 13. The last derivative is selectively etherified in the 7-position by the reaction with the derivative of the formula IV to give the derivative of the formula (I) in which Z is equal to hydrogen. The final step consists of esterifying in position 13, according to a process which is known per se, the derivatives of formula (la), in which Z represents hydrogen, in the presence of a β-lactam according to, for example , the process described in EP 617,018, or in the presence of an oxazolidine as described, for example, in WO 96/30355 mentioned above. After deprotection of the protecting groups at positions 7 and 10, an ester of the formula (la) is obtained in which Z is different from hydrogen and R represents hydrogen. The next step is to react in positions 7 and 10 simultaneously by the action of a reagent formed in itself of a sulfoxide of formula (V) and acetic anhydride (Pum erer type reaction), R-SO-R (V) wherein R has the same meaning as above, to form an intermediate of the alkylthioalkyloxy type at positions 7 and 10. The final step, which allows the desired compound of formula (la) to be obtained, is carried out on the intermediate compound obtained above, by the action of activated Raney nickel. In general, the action of the reagent formed m if you from the sulfoxide of general formula (V), preferably dimethyl sulfoxide and acetic anhydride, is carried out in the presence of acetic acid or an acetic acid derivative such as haloacetic acid, at a temperature between 0 and 50 ° C.

In general, the action of the Raney nickel activated in the presence of an aliphatic alcohol or an ether is carried out at a temperature between -10 and 60 ° C. In the application FR 97-14442 an additional process has been described. This invention allows, in a single step, the direct, selective and simultaneous alkylation of the two hydroxyl functions at positions 7 and 10 of the derivatives of 10-deacetylbaccatin or derivatives thereof esterified at position 13, of formula (VI) ) wherein A represents a hydrogen or a side chain of formula (lia) below: in which G represents a protective group for the hydroxyl function, Ri and R3 have the same meaning as in the formula (II) g ^^ H ^ jjJH & g ^^^ g ^^ jggÉj ^^^ or an oxazolidine unit of formula (Id) wherein Ri and R3 have the same meaning as in formula (II), Ra and Rb, which may be identical or different, represent hydrogen or alkyl, aryl, halo, alkoxy, arylalkyl, alkoxyaryl, haloalkyl, haloaryl, it is possible for the substituents to optionally form a 4 to 7 membered ring. It is preferred to use 10-desacetylbaccatine as a raw material, ie the product of formula (III), which allows an appreciable economy in regard to the process and also avoids the steps of protection and intermediate deprotection in the old processes. Among the groups G for protecting the hydroxyl function of formula (lia), it is generally preferred to choose all protecting groups described in texts such as Greene and Wuts, Protective Groups in Organic Synthesis, 1991, John Wiley & Sons, and MacOmie, Protective Groups in Organic Chemistry, 1975, Plenum Press, and that are unprotected under * - ^ a ^? ik- ^ r ^^^ aá _ ^. ^ a¿ »a ..._, __ ^ s .-, ._ ,. J? _ - conditions which degrade the rest of the molecule little or not at all, such as, for example: ethers, preferably ethers such as methoxymethyl ether, 1-ethoxyethyl ether, benzyloxymethyl ether, p-5-methoxybenzyloxymethyl ether, benzyl ethers optionally substituted with one or more groups such as methoxy, chloro, nitro, 1-methyl-l-methoxyethyl ether, 2- (trimethylsilyl) ethoxymethyl ether, tetrahydropyranyl ether and silyl ethers such as trialkylsilyl ethers, carbonates such as trichloroethyl carbonates. More particularly, radicals Ra and R of general formula (11b) are chosen from those described in patent WO 94/07878 and the derivatives particularly more Preferred are those in which Ra is hydrogen and R is a p-methoxyphenyl radical. The alkylating agent is chosen from: • alkyl halides, and preferably gives alkyl (Rl) iodides • alkyl sulfates such as methyl sulfate • oxoniums such as the trialkyloxonium boron salts, in particular trimethyloxonium tetrafluoroborate ( Me3OBF4).

Preferably, methyl iodide is used. The alkylating agent is used in the presence of an anionization agent such as one or more strong bases, in anhydrous medium. Among the bases that can be used in anhydrous medium, mention may be made of: • alkali metal hydrides such as sodium or potassium hydride • alkali metal alkoxides such as potassium tert-butoxide • silver oxide, Ag20 • 1, 8-bis (dimethylamino) naphthalene • mixtures of mono- or dimethalic bases such as those described, for example, in publications such as P. Caubére Chem. Rev. 1993, 93, 2317-2334 or M. Schlosser Mod. Synth. Methods (1992), 6, 227-271; in particular alkali metal t-butoxide / alkali or combinations of alkali metal amide / alkali metal t-butoxide are preferred. One of the two bases can be generated "in situ". Among all possible combinations of the alkylating agent and the anionization agent, it is preferred to use methyl iodide in the presence of potassium hydride. jy j feÉ | faith | The reaction is preferably carried out in an organic medium which is inert under the reaction conditions. Among the solvents, it is preferred to use: • ethers such as tetrahydrofuran or dimethoxyethane • when using silver oxide, it is preferred to use polar aprotic solvents such as dimethylformamide, or aromatic solvents such as toluene • when 1,8-bis (dimethylamino) is used ) naphthalene, it is preferred to use alkyl esters such as ethyl acetate. For the best implementation of the invention it is preferred to use a molar ratio between the anionization agent and the substrate greater than 2 and preferably between 2 and 20. It is also preferred to use a molar ratio between the alkylating agent and the substrate greater than 2. and preferably between 2 and 40. It is preferred to use a reaction temperature between -30 ° C and 80 ° C. The reaction time fluctuates advantageously between a few and 48 hours depending on the reagents chosen.

After the alkylation step, when the latter is carried out in 10-desacetylbaccatine, the process then proceeds, in a known manner, to the esterification step according to, for example, the processes described in EP 617,018 or WO 96 / 30355 mentioned above. In this way, according to a first 3-step process, the procedure first begins with the dialkylation of 10-desacetylbaccatin, using an alkylating agent in the presence of a strong base, in a second step, the 10-deacetylbaccatin is coupled with dietherification in positions 7 and 10, in position 13, with a ß-lactam adequately protected in the presence of an activating agent chosen from tertiary amines and metal bases which ensures the formation of an alkoxide in position 13. The deprotection of the side chain is then achieved by an action of an inorganic or organic acid. In this way, according to a second process of 3 passes the procedure will begin first with the dialkylation of 10-desacetylbaccatin, using an alkylating agent in the presence of a strong base, in a second step, the 10-deacetylbaccatin is coupled dieterified in positions 7 and 10, at position 13, with an oxazolidine in the presence of a coupling agent such as diimides in the presence of an activating agent such as dialkylaminopyridines. The opening of the oxazolidine is achieved by the action of an inorganic or organic acid. According to a third process, the procedure begins with the esterification at position 13 of the baccatina adequately protected at positions 7 and , with a β-lactam or an oxazolidine in the presence of a coupling agent and / or an activating agent as described in the two above processes. After deprotection at positions 7 and 10, the dieterification is carried out at 0 positions 7 and 10 by means of an alkylating agent in the presence of a strong base. The deprotection of the side chain is then achieved by the action of an inorganic or organic acid. The products of general formula (I) have 5 remarkable biological properties. The measurement of the biological activity m vi tro was carried out on the tubulin extracted from the pig brain by the method of M.L. Shelanski et al., Proc. Nati Acad. Sci. USA, 7_0, 765-768 (1973). The study of the depolymerization of microtubules in tubulin was carried out according to the method of G. Chauviére et al., C.R. Acad. Sci. 293, series II, 501-503 (1981). In vivo, the products of general formula (I) proved to be active in rats grafted with melanoma B16 ji ^ g 5gg ^ a ^ a dose of between 1 and 50 mg / kg intraperitoneally, as well as other liquid or solid tumors. The compounds have antitumor properties, more particularly, activity against tumors which are resistant to Taxol® and Taxotere®. Such tumors include, for example, brain tumors which have a high expression of the mdr 1 gene (multidrug resistance gene). Multidrug resistance is the usual term that is related to the resistance of a tumor against several compounds that have different structures and mechanisms of action. It is generally known that taxoids are highly recognized by experimental tumors such as P388 / DOX, a P388 murine leukemia cell line selected for its resistance to Doxorubicin (DOX) which expresses mdr 1. The compounds according to the present invention are less recognized by P388 / DOX. More particularly, the compounds are less recognized than Taxotere® by the mdr 1. The compounds of formula (I) are used mainly to prepare a medicine to treat the abnormal proliferation of cells in the brain. The compound and especially the compound of formula (I) wherein R4 and R5 are each methoxy has a property of crossing the blood brain barrier. This is active compared to the other known taxoids such as Taxol® or Taxotere® to treat brain cancer. The product of formula (I) can be used concurrently with at least or not therapeutic treatment. This is more preferably used with other therapeutic treatments comprising antineoplastic drugs, monoclonal antibodies, immunotherapies, radiotherapies, or biological response modifiers. Among the modifiers of biological responses, lymphokines and cytokines, interleukins, a, β, or d interferons and TNF are preferably used. The product of formula (I) is preferably administered by parenteral administration such as intravenous, intraperitoneal, intramuscular or subcutaneous administration.

Example 1 1. INTRODUCTION The product of formula (la) is a potent anti-cancer agent in preclinical models. The analytical results obtained from a single bolus pharmacokinetic study i.v. in the mouse. ^^^ gg ^^^. ^^^. ^ .. ^. ^^^^^ .. ^^^^^^^ fe Groups of female C3H / HeN mice received the product by the intravenous route as a bolus at a dose level of 40 rng.kg "1 equivalent to 120 mg.rrf2 Blood and brain samples were obtained from all 5 dosed animals slaughtered at intervals of up to 72 hours per dose.The corresponding brain and plasma samples had have been tested to determine the product content by an LC-MS / MS assay. 2. METHODS Formulation: 2.25 mg.ml "1 of solution containing 5% Polysorbate 80, 5% ethanol and 90% aqueous 5% glucose solution, Fifty six female C3H / HeN mice, each 15 with a weight of 20 g were administered to each product II formulated by means of an iv bolus via the tail vein at an injection volume of 0.4 ml to give a total dose of 40 mg.kg "1.

Blood and Tissue Sample Intakes Sampling: Blood by cardiac puncture and liver and brain by dissection after sacrifice with C02. &; H H f f f Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie Tie , 45 minutes, 1, 2, 4, 6, 8, 14, 24, 48 and 72 hours after the dose. Whole blood was collected in heparinized tubes and the corresponding plasma samples were obtained by centrifugation and immediately frozen at -20 ° C. The tissues were removed, weighed and frozen immediately at -20 ° C. All samples were dispatched frozen for analysis. After the reception, the samples were stored frozen at approximately -18 ° C waiting for analysis.

LC-MS / MS Analysis of Brain and Plasma Samples Detection: LC-MS / MS (Sciex API III) in ion turbo-ion mode The following MS conditions were applied: Auxiliary gas flow 6 L.min " Nebulizer gas flow 0.6 L.min " Turbo temperature 450 ° C CGT 300 Gas curtain flow 0.6 L.rnin "Scan time ¡¡¡¡¡¡¡^ ^ ^^^^^^^^^^^^^^^^^^^^^^^ exploration / sec Ratio of 1:10 separation of the eluent Column: ABZ plus Supercosyl (3 μm) of 75 x 4.6 mm.

Mobile phase: Acetonitrile / methanol / ammonium acetate (10 mM); 40/25/25 volume / volume / volume.

Flow rate: 1 ml.min -i Room temperature.

Extraction: plasma: Add 100 μl of acetonitrile to the sample (50 μl), vortex, centrifuge, remove the supernatant, add 100 μl of mobile phase and inject 150 μl.

Brain: Add 100 μl of acetonitrile to the homogenized sample (100 mg of a brain homogenate with water 1: 1 w / w) and stir vortexically. Add 1 ml of diethyl ether, vortex, centrifuge, remove the organic layer and dry under N2. Reconstitute in 200 μl of mobile phase and inject 150 μl.

Calibration Standards: Plasma: Nine at concentrations of , 10, 20, 50, 100, 200, 300, 400 and 500 ng. 1 (product) Prepared by adding suitable aliquots of the product (concentrations = 0.1, 1 or 10 μg.l-) in ethanol to aliquots of 0.5 ml of mouse plasma, each sample vortexed after the addition of the drug, then a 50 μl aliquot was removed for the assay.

Brain: Eleven at concentrations of 10, 20, 30, 100, 200, 300, 400, 500, 1000, 2500 and 5000 ng.g "1 in brain of homogenized mouse (brain with water 1: 1 weight / weight). by adding suitable aliquots of the product (concentrations = 1, 10 or 100 μg.ml "1) in ethanol to 0.5, 1, 3 or 4 g of homogenized mouse brain. Each sample vortexed after the addition of the drug and then a 100 mg aliquot was removed for the assay.

Retention times: Drug; product la: -2.3 min Efficiency of extraction: Plasma: ca. 58% at 200 ng.ml-i Brain: ca.41% at 500 ng.g "1 and 39% at 1000 ng.g-1, RESULTS 3.1 Plasma Levels The following table contains the plasma levels of the product observed after i.v. of the product at a dose level of 40 mg.kg-1 to the mouse.

Table 1 Preliminary plasma concentrations of the product after dosing i.v. at a level of 40 mg. kg "1 to the mouse ^ U ^ c ^^^^ »^^^^^^^ ^^^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ of the iv dosage at a level of 40 mg.kg "1 to the mouse (continued) Time after Concentration of the product in the plasma (ng.ml) of the dose (h) IV1 IV2 IV3 IV4 MEDIA ± s.d. lh 6017 7423 6693 6079 6553 655 4633 4337 4600 3564 4283 498 10 4h 1072 1110 835 830 962 150 ßh 449 316 346 336 362 59 204 199 195 154 188 23 14h 65 56 50 52 56 24 18 (blq) 15 (blq) 15 (blq) 16 (blq) 16 48 4 (blq) n.d. n.d. 4 (blq) 72 n.d. n.d. n.d. n.d n.a. n.a .: not applicable n.d .: was not detected (< I. o.d. of 4 ng.ml "1) blq: Below the limit of the exact quantification (20 ng.ml-1).

The following table contains the levels of the product in the whole brain observed after the IV administration. of the product at a dose level of 40 mg.kg-1 to the mouse.

Table 2 Preliminary concentration of the product in the brain after dosing i.v. at a level of 40 mg.kg "1 to the mouse 10 Time after Concentration of the product in the brain (ng.ml" 1) of the dose (h) IV1 IV2 IV3 IV4 MEDIA ± s.d. 2 m 6962 8817 8147 7630 7889 786 5 min 8344 8473 7762 8091 8167 313 m 5809 7100 7641 6481 6758 791 0. 5h 7262 6788 8317 6894 7315 698 0.75h 7675 8086 7513 7272 7637 342 lh 6424 8964 1747 7489 6156 3118 2h 7956 8418 6966 7017 7589 716 4h 7909 6939 6712 5459 6755 1008 Table 2 Preliminary concentration of the product in the brain after dosing i.v. at a level of 40 mg.kg "1 to the mouse (continued) n.d. was not detected (< I. o.d. of 92 ng.g "1) n.a .: not applicable 3. 3 Pharmacokinetic Parameters The following table contains the preliminary pharmacokinetic parameters for the derivative product after i.v. administration. to the mouse at 40 mg.kg "1 calculated using the average level data in plasma and brain. _S? _a_fea Table 3 Preliminary average pharmacokinetic data + calculated from the values > I. o.d. of 4 ng.ml #calculated values > b.l.q. of 20 ng.ml-1 * the corresponding AUC0-72h = 549.7 h.μg.g-1 A biexponential equation was fitted to the profiles using an interactive linear least squares algorithm as part of the SIPHAR package. The AUC was calculated by the trapezoidal rule of time 0 for both the time and the last value that was equal to or greater than Iod + (4 ng.ml-1) or Ioq * (20 ng.ml-1) for the plasma and up to 72 h per dose to the brain, and then extrapolated to infinity.

Key : AUCo-o .: Area under the concentration curve in plasma or brain against time from t = 0 (start of infusion) to infinity.

T? / 2 Initial: Average life (distribution) initial.

T1 2 Terminal: Terminal life time (elimination) (should be considered as an estimate that depends only on the sampling frequency in the terminal phase and the sensitivity of the test).

Clp Elimination of total plasma Vdss: Stationary distribution volume, n. a Not applicable 4. CONCLUSIONS • The product levels were high as would be expected after an IV dose. of 40 mg.kg-1 but declined rapidly from the peak at 2 minutes (mean 46.9 μg.ml "1) to less than 1 μg.ml-1 within 4 h (initial half-life of <0.7h). however, the levels persisted above the exact limit of quantification (20 ng.ml-1) until 14h after of the dose and consistently above the limit of detection (4 ng.ml "1) up to 24 h after the dose • A terminal half-life of 6.2 h of the detectable plasma levels (> 4 ng.ml- 1) .However, it should be noted that the terminal half-life largely depends on the sensitivity of the assay in this case and if the levels above the exact quantification limit (20 ng.ml-1) are used to calculate the pharmacokinetic parameters instead, then the terminal half-life falls to 2. Oh. It was determined that the elimination of the average total plasma is 1.3 l.h-1.kg-1 which represents a significant fraction of the average plasma flow in the liver (based on an average blood flow in the liver of ca 5.2 l.h-1.kg-1). • In this species after administration? .v, the product seems to easily penetrate the blood brain barrier. High levels were detected at the first sampling time (7.9 μg g-1 to 2 minutes) indicating a rapid absorption into the tissue. Although the peak level of 9.1 μg.g "1 was observed at 14h, the high concentrations were maintained until the last sampling time (5.3 μg.g-1 at 72h). Not surprisingly, the product was slowly removed from the brain with an average life of 31.4h.

The values of AUCo-8 (788 h.μg. "1 against 30 h.μg.ml" 1), the product levels in the brain were approximately twenty times those in the plasma.

Example 2 Evaluation of the product (IA) for its anti-tumor activity against human glioblastomas U251 and SF-295 implanted intracranially in mice NCr-nu. Four studies were initiated to evaluate the response of glioblastomas U251 and SF-295 for the treatment with the product (la). In both studies, glioblastomas U251 and SF-295 were initiated from cells implanted intracranially at a volume of 106 cells per mouse. The treatment program of the U251 glioblastoma cells implanted intracranially was iv, once a day, every six days for three treatments (qdd x 3), beginning at day four post-implant. The treatment program of SF-295 glioblastoma cells implanted intracranially was iv, once a day, every four days for three treatments (q4d x 3), starting on day two after implantation. For studies implanted intracranially, the compounds were evaluated based on their ability to increase the life span of the animals.

The positive control used for both of these tumor models was nitrous urea. The objective of this experimentation was to evaluate the product (la) by the antitumor effect against tumor models of human glioblastoma. In those experiments, the general DCTD, NCI techniques and procedures for in vivo efficacy studies were modified for their special application (In Vivo Cancer Models, NIH Publication No. 84-2635, 1984). These studies were conducted at approved facilities (AAALAC Registration No. 000643, AALAS Member No. 840723001, USDA Registration No. 64-R-001, OPPR, PHS, NIH, AWA, Insurance No. A3046-01). These facilities are certified by ISO 9001. The supervisory committee was the Southern Institutional Animal Care and Use Committee; the protocol used was IACUC No. 96-8-50.

Dilutions: The product was prepared in 5% ethanol, 5% tween 80, 90% D5W. The nitrosourea was prepared in 2% ethanol, 98% physiological saline.

M_É ~ 1 '"Js-« t __ »-. - -« SláÉ ^ S? ßa_d _____ 3_í ,, Dosage Preparation: All dosing solutions were prepared at the Research Institute of the South.

Administration of the Compound: The product (la) was administered in 0.4 ml / mouse based on the average total body weight. The nitrosourea was administered 0.1 ml / 10 g of body weight.

Stability of the compound: The product was kept on ice and was administered within 20 minutes of the preparation. The nitrosourea was kept on ice and was administered within 45 minutes of preparation.

Storage Conditions: All the compounds were stored in refrigerated dryers.

Management Precautions: The compounds were managed according to the procedures required by the safety committee of the Southern Research Institute. All the technicians were fully dressed and gloved, with facial masks and safety glasses during the administration of the compound.

Any animal implanted intracranially that appeared to be very serious was subjected to euthanasia for purposes of humanity. Since efficacy falls within this category of basic research, the completion of the experiment was based on the results that were determined to be optimal.

Species: Atomic NCr-nu female mice of six to eight weeks of age were used for the U251 trials implanted intracranially. Male atomic NCr-nu mice of six to eight weeks of age were used for the SF-295 trials implanted intracranially.

Justification: Immunodeficient mice are necessary for the propagation of human tumor xenografts, which was the target tissue for the compounds that were being developed.

Source: FCRDC (Animal Production Area), Frederick, MD for the trial of SF-295 implanted intracranially; Taconic Animal Farms, Germanto n, NY for the U251 trials implanted intracranially. -a ^ a &^ ¡í? ^ M ^ ¡^ Number and Sex: A total of 160 males were used in the SF-295 trials implanted intracranially; a total of 154 females were used in the U251 trials implanted intracranially.

Weight and age: Average weights were taken at the time that each trial began. The average weight of the mice implanted intracranially with glioblastoma U251 was 21 to 22 g. The average weight of the mice implanted intracranially with glioblastoma SF-295 was 24 to 26 g.

Animal Identification: Standard marks on the ear.

Quarantine: All animals were kept in a seven day observation period before being tested.

Accommodation and Sanitary Conditions: The animals were housed in insulated cages covered with a filter, five per cage. The cages and beds were changed twice weekly.

Food and Water: Ad libi tum Diet for Teklad Sterilizable Mouse 8656 (Harían Teklad) was given. Filtered tap water ad libi tum was provided.

Environmental Conditions: They were maintained according to the SRI standard operating procedures approved by the IACUC committee. Two experiments were implicated in this study (RP-36 and RP-38). As mentioned above, this experiment was designed to evaluate the activity of the product (the) against glioblastomas U251 and SF-295 intracranially in athermic MCr-nu mice. The doses for the product (la) were 30, 20 and 13.4 mg / kg / dose. For the two experiments implanted intracranially, the cells were prepared at a concentration of 3.33 x 107 cells per ml of media and injected at a volume of 0.03 ml per mouse. The cells were injected into the brain to the right of the midline with a 3/8 inch (0.9525 cm), .25 gauge stainless steel needle. The cultured cells were used for the experiment with U251 (RP-36). The programmed treatment was qdd x 3, iv, starting on day four, after the implant. Tumor tissue, made by a solid tumor, was used for the experiment with SF- ^^^^^^^^^^^^^^^^^^^^^^^^ j ^^^^^^^^^^^^^^^^^^^^^^^ g ^^^^^^^^^ 295 (RP-38). The scheduled treatment was q4d x 3, iv, beginning on day four, after implantation. Nitrosourea was given in each experiment for comparison purposes due to its known activity against tumors of the Central Nervous System (CNS). The doses were 27, 28 and 12 mg / kg / dose and the treatment program was the same as the treatment program for the product (la) in each experiment. In the first experiment (RP-36), each compound was effective in the treatment of glialblastoma U251 implanted intracranially. The treatment with product (la) resulted in five of ten, four of ten and three of ten survivors at 122 days and an ILS of 176%, 202% and 144% respectively, for the dose groups of 30, 20 (BAT) and 13.4 mg / kg / dose. Treatment with nitrosourea resulted in an ILS of 205% and 51% in the dose groups of 18 and 12 mg / kg / dose, respectively. There were ten out of seventeen out of ten survivors at 122 days in the dose group of 27 (BAT) and 18 mg / kg / dose. In the second experiment (RP-38), each compound was effective in the treatment of glioblastoma SF-295 implanted intracranially. The treatment with the product (a)? 30, 20 and 13.4 (BAT) mg / kg / dose resulted in an ILS of -9%, 94% and 81%, respectively. There was some toxicity at dose levels of 30 and 20 mg / kg / dose of | * T ** * * * ~ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^, according to the evidence of a respective average weight loss of 7 g and 6 g throughout the treatment period. There was a survivor of ten animals at 68 days in the dose group of 13.4 mg / kg / dose. The nitrosourea was toxic 5 at the higher dose level of 27 mg / kg / dose as evidenced by an average weight loss of 7 g throughout the treatment period. Treatment with nitrosourea at doses of 27, 18 and 12 mg / kg / dose resulted in an ILS of 50%, 131% and 106%, respectively. There were two survivors of ten animals at 68 days at the dose level of 27 (MTD) mg / kg / dose, and there was a survivor of ten animals at 68 days at the dose level of 18 mg / kg / dose. In summary, the product was tested against glialblastomas U251 and SF-295 implanted intracranially.

This compound was very active against these two tumor lines at both implant sites. ^ fl * -___.__ »* __ ^ ¿¡?? ^^^? ^ - ¡^ _i_ £ .. -2 < & . .__. ^ r. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ t RESPONSE OF THE IMPLANTED IC25 GLIOBLASTOMA IC TO PRODUCT TREATMENT (la) (continued) Treatment Group: IV, Q6D X Days of death survivors Day% of # 3 (4) at 122 average ILS days / death total 13.4 69 69 83 83 83 83 122 3/10 83.0 + 144 JE *. LO S S 14 Nitrosourea 27.0 10/10 ~ ~ 18.0 94 104 104 7/10 104.0 +205 16 12.0 41 45 49 49 49 54 66 69 69 80 0/10 51.5 + 51 S Gioblastoma U251; tumor source: cell culture; implanted: 04/17/98; Evaluation date: 08/17/98; Atomic NCr-nu female mice - taconic farms Control, 2% EtOH / saline; injection volume = 0.1 cc / lOg of body weight Product I (a), lot BFC611, prepared from batch no. 1 in 5% EtOH / 5% tween 80/90% D5W (soluble); injection volume = 0.4 ce • * -. ? Nitrosourea prepared from lot no. 2 in 2% EtOH / saline (soluble;); injection volume = 0.1 cc / lOg of body weight Note 1) Survivors at day 122 were not used in the calculations. The means were calculated using all deaths 2) S = moribund, slaughtered animal (used in the calculations).

RESPONSE OF THE IMPLEMENTED GLIOBLASTOMA SF-295 IC TO THE TREATMENT WITH PRODUCT (la) RESPONSE OF THE IMPLEMENTED GLIOBLASTOMA SF-295 IC TO THE PRODUCT TREATMENT (la) (continued) C? Gioblastoma SF-295; tumor source: 01 / A / 05F3T8; implanted: 08/26/98; MCr-Nu Male Atomic mice - Frederick Cancer Research Development Center Control, 2% EtOH / saline; injection volume = 0.1 cc / lOg of body weight Product I (a), lot BFC611, prepared from lot no. 1 in 5% EtOH / 5% Tween 80/90% of D5W (soluble); injection volume = 0.4 ce Nitrosourea, Bristol-Myers lot LAH84, prepared from the SRI lot No. 2-4 in 2% of EtOH / Saline solution (soluble); injection volume = 0.1 cc / lOg of body weight Note 1) Survivors at day 68 were not used in the calculations. The means were calculated using all deaths 2) S = moribund, slaughtered animal (used in the calculations).

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. ^ a¿aá ^ te_ifea¿ ^ í

Claims (5)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property. 1. The use of a compound of formula (I) to prepare a medicine for treating abnormal proliferation of cells in the brain, the use comprising administering to a mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate OCOCfiH5 in which: Z represents a hydrogen atom or a radical of the general formula: R, NH O (II) OH in which: Ri represents jjlftg a benzoyl radical optionally substituted with one or more atoms or identical or different radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms or trifluoromethyl radicals, one radical tenoil or furoyl or a radical R2-0-C0- in which R2 represents: - an alkyl radical containing from 1 to 8 carbon atoms, - an alkenyl radical containing from 2 to 8 carbon atoms, - a radical alkynyl containing from 3 to 8 carbon atoms, a cycloalkyl radical containing from 3 to 6 carbon atoms, a cycloalkenyl radical containing from 4 to 6 carbon atoms or a bicycloalkyl radical containing from 7 to 10 carbon atoms. carbon atoms, those radicals being optionally substituted with one or more substituents chosen from halogen atoms and hydroxyl radicals, alkoxy radicals containing from 1 to 4 carbon atoms, dialkylaryl radicals in which each alkyl portion contains 1 to 4 carbon atoms, piperidino or morpholino radicals, 1-piperacline radicals (optionally substituted in the 4-position with an alkyl radical containing 1 to 4 carbon atoms or with a phenyl alkyl radical in which the alkyl portion contains from 1 to 4 carbon atoms), cycloalkyl radicals containing from 3 to 6 carbon atoms, cycloalkenyl radicals containing from 4 to 6 carbon atoms, phenyl radicals ( optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing from 1 to 4 carbon atoms or alkoxy radicals containing from 1 to 4 carbon atoms), cyano or carboxyl radicals or alkoxycarbonyl radicals in which the alkyl portion contains from 1 to 4 carbon atoms. - a phenyl radical or α- or β-naphthyl optionally substituted with one or more atoms chosen from halogen atoms and alkyl radicals containing from 1 to 4 carbon atoms or alkoxy radicals containing from 1 to 4 carbon atoms, or - a 5-membered aromatic heterocyclic radical preferably chosen from the furyl and thienyl radicals, - or a saturated heterocyclic radical containing from 4 to 6 carbon atoms, optionally substituted with one or more alkyl radicals containing from 1 to 4 carbon atoms, R3 represents an unbranched or branched alkyl radical containing from 1 to 8 carbon atoms, an unbranched or branched alkenyl radical containing from 2 to 8 carbon atoms, an unbranched or branched alkynyl radical containing from 2 to 8 carbon atoms , a cycloalkyl radical containing 3 to 6 carbon atoms, a phenyl radical or a- or ß-naphthyl optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formilf, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl, or an aromatic heterocycle of 5 members containing one or more identical or different heteroatoms chosen from nitrogen, oxygen • and sulfur atoms and optionally substituted with one or more identical or different substituents chosen from halogen atoms and alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, There is no carbamoyl, alkylcarbamoyl, '*' dialkylcarbamoyl or alkoxycarbonyl, with the understanding that, in the substituents of the phenyl, a- or b-naphthyl radicals and aromatic heterocyclics, the alkyl radicals and the alkyl portions of the other radicals contain from 1 to 4 carbon atoms, and that the alkenyl and alkynyl radicals contain from 2 to 8 carbon atoms, and that the aryl radicals are phenyl radicals or - or β-naphthyl, R 4 represents an alkoxy radical containing from 1 to 6 carbon atoms in an unbranched or branched chain, an alkenyloxy radical containing from 3 to 6 carbon atoms in an unbranched or branched chain, a radical alkynyloxy containing from 3 to 6 carbon atoms in an unbranched or branched chain, a cycloalkyloxy radical containing from 3 to 6 carbon atoms or a cycloalkenyloxy radical containing from 4 to 6 carbon atoms, these radicals being optional substituted with one or more halogen atoms or with an alkoxy radical containing from 1 to 4 carbon atoms, an alkylthio radical containing from 1 to 4 carbon atoms or a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains from 1 to 4 carbon atoms, a cyano or carbamoyl radical or an N-alkylcarbamoyl or N, N-dialkylcarbamoyl radical in which each alkyl portion contains from 1 to 4 carbon atoms or , with the nitrogen atom to which it is bound, forms a saturated 5- or 6-membered heterocyclic radical, optionally containing a second heteroatom chosen from oxygen, sulfur or nitrogen atoms, optionally substituted with an alkyl radical containing from 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical in which the alkyl portion contains from 1 to 4 carbon atoms, Rs represents an alkoxy radical containing from 1 to 6 carbon atoms in an unbranched or branched chain, a radical alkenyloxy containing from 3 to 6 carbon atoms, an alkynyloxy radical containing from 3 to 6 carbon atoms, a cycloalkyloxy radical containing from 3 to 6 carbon atoms, cycloalkenyloxy radical containing from 3 to 6 carbon atoms, those radicals being optionally substituted with one or more halogen atoms or with an alkoxy radical containing from 1 to 4 carbon atoms, an alkylthio radical containing from 2 to 4 carbon atoms; carbon or a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains from 1 to 4 carbon atoms, a cyano or carbamoyl radical or an N-alkylcarbamoyl or N, N-dialkylcarbamoyl radical in which each alkyl portion contains 1 to 4 carbon atoms or, with the nitrogen atom to which it is attached, forms a saturated 5- or 6-membered heterocyclic radical, optionally containing a second heteroatom chosen from oxygen, sulfur or nitrogen atoms, optionally substituted with an alkyl radical containing from 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical in which the alkyl portion contains from 1 to 4 carbon atoms. 2. The use of the compound according to claim 1, wherein Z represents a hydrogen atom or a radical of the general formula (II) in which Ri represents a benzoyl radical or a radical R2-0-CO- in which R 2 represents a tert-butyl radical and R 3 represents an alkyl radical containing from 1 to 6 carbon atoms, an alkenyl radical containing from 2 to 6 carbon atoms, a cycloalkyl radical containing from 3 to 6 carbon atoms, an phenyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms and alkyl, alkoxy, dialkylamino, acylamino, alkoxycarbonylamino or trifluoromethyl radicals, or 2- or 3-furyl, 2- or 3-thienyl or 2-radicals -, 4- or 5-thiazolyl, and R 4 and R 5, which may be identical or different, each represent an unbranched or branched alkyloxy radical containing from 1 to 6 carbon atoms. 3. The use of a compound according to claim 2, wherein Z represents a hydrogen atom or
1. A radical of the general formula (II) in which Ri represents a benzoyl radical or a radical R2-0-CO- in which R2 represents a tert-butyl radical and R3 represents an isobutyl, isobutenyl, butenyl, cyclohexyl radical, phenyl,
2. 2-furyl,
3. 3-furyl, 2-t-enyl, 3-t-enyl, 2-thiazolyl,
4. 4-thiazolyl or
5. 5-thiazolyl, and R4 and R5, which may be identical or different, each represent a methoxy radical , ethoxy or propoxy. 4. The use of (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxyl-3-f-enylpropionate of 4a-acetoxy-2a-benzoyloxy-5β, 20- 20 epoxy-lβ-hydroxy-7β, 10β-dimethoxy? -9-oxo-11-taxen-13a-yl, to prepare a medicine to treat the abnormal proliferation of cells in the brain. ^^^^^^^^^^^^^^ £ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 5. The use of the compound according to claims 1 to 4, "wherein the abnormal proliferation of the cells is brain cancer 6. The use of the compound according to claim 5, wherein this use was carried out concurrently with at least other treatments The use of the compound according to claim 6, wherein the other therapeutic treatments comprise antineoplastic drugs, monoclonal antibodies, and monotherapies, immunotherapies, radiotherapies, or biological response modifiers 8. The use of the compound in accordance with claim 7, wherein the modifiers of the response comprise lymphokines and cytokines 9. The use of the compound according to claim 8, wherein the response modifiers comprise interleukins, α, β, β, interferons and TNF. compound according to claim 1, wherein the medicine is administered by palenteral administration. The use of the compound according to claim 10, wherein the compound of formula (I) is administered by intravenous, intraperitoneal, intramuscular or subcutaneous administration.