MXPA99001026A - Substituted bisindolylmaleimides for the inhibition of cell proliferation - Google Patents

Abstract

Compounds of formula (I), wherein R is alkyl, alkylthio or hydroxy, as well as, pharmaceutically acceptable salts of compounds of formula (I) are antiproliferative agents useful in the treatment of cancer.

Description

BISINDOLILMERMIMIDES SUBSTITUTED FOR THE INHIBITION OF CELLULAR PROLIFERATION The present invention relates to substituted pyrroles. More particularly, the invention relates to substituted pyrroles of the formula wherein R is alkyl, hydroxy or alkylthio, as well as pharmaceutically acceptable precursors or pharmaceutically acceptable salts of the compounds of the formula I. The compounds of the formula I and their pharmaceutically acceptable salts are anti-pro-active agents for the cancer treatment or control, in particular for the treatment or control of solid tumors. The compounds of the invention are particularly suitable for the treatment and control of breast or colon tumors. REF. : 29265 The compounds of formula I are published generically in the patent U3-5, 057, 614. For the purposes of this document, the term "alkyl", alone or in combination, means a straight or branched chain alkyl group, which contains at most 10, preferably at most 5 carbon atoms, for example methyl, ethyl, propyl, isopropyl and the like, which is unsubstituted or substituted by one or more substituents, chosen from the group consisting of hydroxy, akoxy, amino, halogen, cyano, thioalkyo, carboxy, carboxylic acid derivatives or alkylsuifinium. Preferably, alkyl is an unsubstituted alkyl, especially methyl. The term "hydroxy protecting group" means any conventional hydroxy protecting group, for example methylsulfanium, acetyl, triacylsilyl, benzyl. The hydroxy protecting group is preferably metisucifanium. The term "pharmaceutically acceptable pre-medicament products" means a compound which under physiological conditions or by solvolysis can be converted into a compound of formula I or a pharmaceutically acceptable salt thereof. In the above formula I, K is preferably CH 3, OH or SCH- The compounds of the formula I as well as the pharmaceutically acceptable salts of the compounds of the formula I are obtained according to the following reaction schemes 1 and 2. F. OUE A 1 wherein R has the above defined meaning and R 'is alkyl, aikyiote or OX, X being a hydroxy protecting group.

Tai as set forth in scheme 1, the compound of formula II, a known compound or a compound prepared by known methods, is reacted with a base of the type of sodium hydride (NaH) or with an alkylating agent such as methyl iodide (CH3I) in a solvent such as N, N-dimethylformartamide (DMF) or tetrahydrofuran (TKF), at a temperature between 0 and 25 ° C, to obtain the corresponding compound of formula III.

A compound of the formula III is reacted with a mixture of toluene-4-isocyanide isocyanide (TosMIC) and potassium tert-butoxide in a solvent, for example a glycol dimethyl ether (DME), at a temperature e -30 ° C and -60 ° C, then treated with methanol at a temperature of 65 ° C to obtain the corresponding compound of formula IV.

A compound of formula IV is reacted with gas HCl in isopropanol at a temperature of 0 ° C to obtain the corresponding compound of formula V.

A compound of formula V is reacted with oxo-acetylchloride of (l-methyl-iH-indol-3-yl) and triethylamine (Et3N), in a solvent such as methylene chloride, at a temperature comprised between 0 and 25 ° C. The resulting product is then treated with paratoluenesulfonic acid (pTsOH) in a solvent, for example to toluene, at a temperature of 25 ° C to obtain the corresponding compound of the formula la.

The compound of the formula la, wherein R 'is OX, is converted into a compound of the formula I, wherein R is hydroxy, by removal of the hydroxy protecting group by conventional methods, for example by treatment with a base , such as sodium hydroxide, in an aqueous / alcoholic solution.

Alternatively, a compound of the formula I is prepared as outlined in scheme 2.

SCHEME 2 where R and R have the meaning defined above. As set forth in scheme 2, a compound of formula VI, a known compound or a compound synthesized by known methods is reacted with NaH and CK3I, in a solvent such as DMF or THF, to form the corresponding compound of formula VII. The compound of formula VII is reacted with oxaiyl chloride, in a solvent such as diethyl ether (Et20) or dichloromethane (CH2C12), to form the corresponding compound of formula VIII. A compound of formula VIII is reacted with a compound of formula IX, a known compound or a compound synthesized by known methods, and pTsOH in CH 2 Cl 2 at a temperature between 0 and -25 ° C, then reacted with Et 3 N in solvent, for example toluene, around 25 ° C to obtain the corresponding compound of the formula la. The compound of formula la, wherein R 'means OX, is converted into the compound of formula I, wherein R is hydroxy, eliminating the hydroxy protecting group by conventional methods, such as NaOH treatment at , aqueous / alcoholic solvent mixtures.

The compounds of the formula I and their pharmaceutically acceptable salts inhibit cellular processes, for example cell proliferation and are therefore useful for the treatment or control of cancer, of inflammatory diseases, of immunological and broncho-pulmonary and cardiovascular disorders and for the application afterwards. of organ transplants. The antiproliferative activity of the compounds of the invention are illustrated below. These effects indicate that the compounds are useful for the treatment of cancer. The breast epithelial carcinoma cell line, MDA-MB435, and the colon carcinoma cell line, SW480, were received from the ATCC (American Type Culture Collection) and multiplied in culture medium, as recommended by the ATCC . To analyze the effect of various compounds on the growth of these cells, the cells are plated at a concentration of 1500 cells / well, in a 96-well historic culture plate ("test plate"). The day after starting the culture, the compounds to be analyzed are dissolved in 100% DMSO (dimethyl sulfoxide) to obtain a standard solution of 10 mM concentration. Each compound was dissolved in H20 to obtain a concentration of lmM and was added to pits in triplicate in the first row of the reference plate, provided with 96 holes, containing medium to obtain a final concentration of 40 μM. The compounds are then dissolved in the medium, forming series in the "reference plate". The diluted compounds are then transferred to the test plates containing cells. A row of "control cells" receives DMSO. The final concentration of DMSO in each hole is 0.1%. After 5 days of the drug addition, the plate containing MDAMB435 cells is analyzed as follows. Plates containing 3W480 cells are analyzed after 7 days of drug addition as follows. MTT ([3- (4,5-dimethytiazoi-2-ii) -2,5-diphenyl-2H-tetrazoyl] bromide, cysozoin blue) is added to each well to obtain a final concentration of 1 mg / ml. The plate is then incubated at 37 ° C for 2.5-3 hours. The medium containing the MTT is removed and 50 μi of 100% ethanoi is added to each well to dissolve the formazan. The absorbances are read using an automated plate reader (Bio-te microplate reader). The IC50's are calculated using the equation of Reed 'and Munsch, see Am. J. Hygiene, voi, 27, pp. 493-497, 1938.

The results are shown in the following table Table 1 Antiproiiferative activity in Ceiuiares lines * Average of two experiments separately. Compound A is 3- (i, 6-dimethyl-iH-indoi-3-yl) _4_. { l-methyl-IH-indoi-3-ii) -pyrroi-2,5-dione. Compound B is 3- (β-methylisuiphanyl-1-methyl-iH-indoi-3-yl) -4- (1-methyl-1H-indoi-3-ii) -pyrroi-2,5-dione. Compound C is ia 3- (6-hydroxy-i-methyl-iH-indol-3-ii) -4- (i-methyl-iH-indol-3-yl) -pyrrole-2, 5-dione. Compound D is ia 3- (6-etii-l-methyl-lH-indol-3-yl) -4- (i-methy-lH-indol-3-yl) -pyrrole-2, 5-dione.

The compound E is the. { l-methyl-3- [4- (1-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -lH-indole-6- il} -acetonitrile. The pyrroles of the formula I and their salts mentioned above can be used with medicaments, for example in the form of pharmaceutical preparations which are administered orally, for example in the form of tablets, coated tablets, dragees, hard or soft gelatine capsules, solutions, emulsions or suspensions. They can also be administered rectally, for example in the form of suppositories, or parenterally, for example in the form of injectable solutions. For the manufacture of the pharmaceutical preparations these compounds can be formulated together with inorganic or organic, therapeutically inert excipients. The excipients for tablets, coated tablets, dragees and hard gelatine capsules can be lactose, corn starch and derivatives thereof, talc, stearic acid and its salts. Suitable excipients for soft gelatine capsules are vegetable oils, waxes, fats, semi-solid or liquid polyols. Depending on the nature of the active ingredient, soft gelatine capsules normally do not require excipients. Suitable excipients for the manufacture of solutions and syrups are water, poiols, sucrose, invert sugar and glucose. Suitable excipients for injectable solutions are water, alcohols, poiols, glycerin and vegetable oils, waxes, fats and semi-liquid polyols. The pharmaceutical preparations may also contain preserving agents, solubilizing agents, stabilizing agents, humectants, sweeteners, colorants, flavors, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They may also contain other therapeutically active substances. As mentioned above, the pyrroles of the formula I and their salts mentioned above can be used for the treatment or control of oncological, inflammatory, immunogenic, bronchial and cardiovascular diseases. The dosage can vary within wide ranges and should logically be adjusted to the individual requirements of each patient. In general, in the case of oral administration to adult humans, a daily dose of 5 mg to 5000 mg should be adequate, and the upper limit may be exceeded if indicated by the physician. The daily dose can be administered as a single dose or divided into several doses.

The following examples illustrate the invention.

EXAMPLE 1 3- (1,6-dimethyl-lH-indol-3-yl) -4- (1-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione A 0 ° C is cooled to 0 ° C solution of the known 6-methyl-lH-indole-carboxaldehyde (5 g, 31 mM) in DMF (100 ml), treated with NaH (38 mM) and stirred at 0 ° C for 3 hours. After treatment with CH3I (2.35 ml, 38 mM), the mixture is allowed to return to room temperature overnight. The mixture is then poured over H20 (500 ml) and extracted with ethyl acetate (EtOAc, 200 ml, 3 times). The organic phases are combined and dried over MgSO4, filter and concentrate by evaporation. Purify by flash column chromatography to obtain 1,6-dimethyl-lH-indole-3-carboxaldehyde (5.2 g, 97%). A suspension of potassium tert-butoxide (KO-t-Bu), 2.21 g, 19.7 mM) in DME (30 ml) is cooled to -30 ° C and treated with a TosMIC solution (1, 97 g, 10.1 mM). After the addition is complete, the mixture is further cooled to -60 ° C, treated with 1,6-dimethyl-lH-indole-3-carboxaldehyde (5.8 mM) in DME (20 ml) and stirred thereto. temperature for 1.5 hours. Methanol (15 ml) is added to the cooled solution, then heated to reflux temperature for 15 minutes and the solvent is evaporated. The residue is treated with H20 (20 ml) containing acetic acid (HOAc, 0.75 ml), then extracted with CH2Cl2 (50 ml, 3 times). The organic phases are combined and extracted with a saturated solution of NaHCO 3., they are dried over MgSO4, filtered and concentrated by evaporation. Purification is carried out by flash column chromatography to provide (1,6-dimethyl-1H-indol-3-yl) -acetonitrile (0.86 g, 81%). . Bubble for 3 hours HCl (gas) in a suspension of (1, 6-dimethyl-lH-indoI-3-yl) -acetonitrile (0.86 g, 4.7 mM) in isopropanol (iPrOH) (20 ml). ), which has cooled to 0 ° C. The solvent is evaporated, the residue is taken up in diethyl ether and concentrated by evaporation (Et20, 50 ml, 2 times) and then drying under high vacuum to obtain the hydrochloride of 2- (1,6-dimethyl-1H). -indoI-3-ii) -isopropyl acetimidate. To a suspension of the known (1-methyl-1H-indol-3-yl) -oxo-acetyl chloride (183 mg, 0.83 mM) and the hydrochloride of 2- (1, 6-dimethyl-1H-indoI- 3-ii) -isopropylacetimidate (233 mg, 0.83 mM) in CH2C12 (6 mL) which was previously cooled to 0 ° C, Et3N (0.46 mL, 3.3 mM) is added. The reaction mixture is allowed to warm to room temperature overnight, then diluted with CH2Cl2 (20 mL) and extracted with H20 (15 mL) and 0.5 N HCl (15 mL). The organic fraction is dried over MgSO4, filtered, concentrated by evaporation and the residue is taken up in toluene. (3 ml). After cooling to 0 ° C, para-toluenesulfonic acid (pTsOH, 174 mg, 0.91 mM) is added and the mixture is stirred at room temperature for 3 hours. The precipitated red solids are collected and partitioned in Ch 2 Cl 2 (50 ml) and H20 (25 ml). The organic fraction is washed with a saturated solution of NaHCO 3 (25 ml), dried over MgSO 4, filtered and concentrated by evaporation. The residue is washed with cold Ch 2 Cl 2, obtaining 3- (1,6-dimethyl-lH-indol-3-yl) -4- (l-methyl-lH-indol-3-yl) -pyrrole-2,5-dione.; p.f. 264-266 ° C.

Example 2 3- (6-Methylsulfanyl-1-methyl-1H-indol-3-yl) -4- (1-methyl-1H-indol-3-yl) -pyrrole-2, 5-dione a) A solution of 6-Methylsulfonyl-1H-indole (6.8 g, 42 mmol) in DMF (50 ml) is added at 0 ° C over a period of 10 minutes to a slurry or slurry of NaH (55 mmol) in DMF (10 ml) . It is stirred for 1 hour at 0 ° C, then Ch3I (4.0 ml, 64 mmol) is added and the mixture is stirred at 0 ° C for 30 minutes, then at room temperature for 1 hour, then poured on ice. H20 and extracted with EtOAc. The organic phase is washed with a saturated solution of NaCl, dried over MgSO 4, filtered and concentrated by evaporation to yield 6.7 g (91.0%) of 1-methyl-β-methylsulfanyl-1H-indole in the form of yellow oil, after having purified by flash column chromatography. b) To a solution of l-methyl-6-methylsulfonyl-lH-indole (658 mg, 3.71 mmol) in Et20 (7 ml) at 0 ° C is added oxalyl chloride (0.55 ml, 6.31 mmol) ). Stir for 3 hours, collect the orange liquid, wash with Et20 and dry to obtain (l-methyl-6-methylsulfanyl-lH-indol-3-yl) -oxo-acetyl chloride (819 mg, 66% ). c) To a solution of (l-methyl-6-methylsulfanyl-lH-indol-3-yl) -oxo-acetyl chloride (816 mg, 3.05 mmol) and 2- (1-methyl-lH-) hydrochloride indol-3-yl) -isopropyl acetimidate (815 mg, 3.06 mmol) in CH2C12 (40 mL) at 0 ° C is added Et3N (1.75 mL, 12.56 mmol). The mixture is stirred at the same temperature for 30 minutes, then the reaction mixture is stirred at room temperature for 3.5 hours and diluted with CH2C12. The organic phase is washed with H20, a 0.5 N HCl solution, a saturated NaCl solution, then dried over MgSO4 / filtered and concentrated by evaporation to yield an orange foam. This material is dissolved in toluene (24 ml) and treated with p-TsOH (613 mg, 3.23 mmol) at 0 ° C.

It is stirred for 3 hours at room temperature, then the reaction mixture is extracted with CH2C12. The organic phase is washed with a saturated solution of NaHCO 3, with a saturated solution of NaCl, then dried over MgSO 3, filtered and concentrated by evaporation. Purification by flash column chromatography provides 3- (6-methylsulfanyl-1-methyl-1H-indol-3-yl) -pyrrole-2, 5-dione (435.8 mg, 35.5%); p.f. 24ß-251 ° C. The 6-methylsulfanyl-1H-indole is prepared as follows: To a solution of sodium methoxide, prepared with Na metal (8.65 mg, 0.38 M) in methanol (200 ml) between 0 and 5 ° C is added a solution of 4- (methylthio) -benzaldehyde (12.6 mL, 94.7 mmol) and methyl azidoacetate (44 g, 0.382 mol) in methanol (30 mL). It is stirred at room temperature for 3 hours, then the suspension is diluted with H20 (300 ml). The solids are filtered, washed with water and dried under vacuum to obtain 19.4 g (82.0%) of the methyl 2-azido-3- (4-methylthiophenyl) -propenoate as a yellow solid. A solution of methyl 2-azido-3- (4-methylthiophenyl) -propenoate (20.6 g, 83 mmol) in xylene (200 ml) over boiling xylene (250 ml) is added dropwise over a period of 2 hours. ). The reaction mixture is heated to boiling under reflux for a further 2 hours, then cooled slowly and placed in the freezer overnight. The solids are filtered, washed with a small amount of CH2Cl2 / hexane (1: 3) and dried to yield 11.2 g (61.0%) of methyl 6-methylsulfanyl-lH-indole-2-carboxylate. A mixture of methyl 6-methyl-6-methylsulfanyl-1H-indole-2-carboxylate (11) is heated at reflux temperature for 30 minutes., 2 g, 51 mmol) and 2N NaOH (125 mL). The clear solution is cooled and extracted with EtOAc. The aqueous fraction is acidified with concentrated HCl until pH = 1, a precipitate is formed which is filtered and dried to yield 6-methylsulfanyl-1H-indole-2-carboxylic acid (9.6 g, 91.0%). A mixture of 6-methyl-6-methylsulfanyl-1H-indole-2-carboxylic acid (9.6 g, 46 mmol), Cu powder (2.1 g, 33 mmol) and quinoline (100 ml) is heated to 215 ° C for 3 hours. The mixture is cooled to room temperature, filtered through celite and the filtrate is diluted with H20 (500 ml). The cooled mixture is acidified with concentrated HCl (pH = 1) and extracted with EtOAc. The organic fraction is washed with a saturated solution of NaCl, dried over MgSO 4, filtered and concentrated by evaporation to yield 6-methylsulfanyl-1H-indole (6.8 g, 90%) after having purified by Flash column chromatography.

Example 3 3- (6-Hydroxy-1-methyl-1H-indol-3-yl) -4- (1-methyl-1H-indol-3-yl) -pyrrole-2, 5-dione The benzenesulfonate of l-methyl-lH-indol-6-yl from the already known 1-H-indol-6-yl benzenesulfonate by the process described above for the synthesis of l-methyl-6-methylsulfanyl-lH-indole from 6-methylsulfanyl-lH-indole. The 3-chlorocarbononocarbonyl-1-methyl-1H-indol-6-yl benzenesulfonate is prepared from the benzenesulfonate of 1-methyl-1H-indol-6-yl according to the procedure described above for the synthesis of the -methyl-6-methylsulfanyl-lH-indol-3-yl) -oxo-acetyl. The benzenesulfonate of l-methyl-3- [4- (1-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -lH-indole -6-yl is prepared from the benzenesulfonate of 3-chlorocarbononocarbonyl-l-methyl-lH-indol-6-yl and the hydrochloride of isopropyl 2- (l-methyl-lH-indol-3-yl) -acetimidate with according to the procedure described above for the synthesis of 3- (6-methyl-sulfanyl-l-methyl-lH-indol-3-yl) -4- (l-methyl-lH-indol-3-yl) -pyrrol- 2, 5-dione. 3- (6-Hydroxy-l-methyl-lH-indol-3-yl) -4- (1-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione is prepared by treating the benzene sulfonate of l-methyl-3- [4- (l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -lH-indole-6- ilo (141 mg, 0.28 mmol) with 4N NaOH (0.5 mL, 2 mmol) and CH3OH (4 mL) and heating at reflux temperature for 6 hours. The reaction mixture was cooled to room temperature, diluted with H20, acidified with 2N HCl and extracted with EtOAc. The organic phase is washed with a saturated solution of NaCl, dried over MgSO 4, filtered, concentrated by evaporation and purified by flash column chromatography to obtain 3- (6-hydroxy-1-methyl-1H-indole). 3-yl) -4- (l-methyl-lH-indol-3-yl) -pyrrole-2,5-dione (15 mg); p.f. 279-282 ° C.

Example 4 { l-methyl-3- [4- (l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -lH-indole-6- il} -acetonitrile a) To a solution of 3.7 g (23.8 mmol) of l-methyl-6-cyanoindole, known compound, in 110 ml of methylene chloride is treated at room temperature with 22.6 ml of a solution 3M of diisobutyl-aluminum hydride (DIBAL) in hexane. The mixture is stirred at 25 ° C for 3 h, added to a mixture of 120 ml of 2N hydrochloric acid and 120 ml of methylene chloride and kept under stirring for 17 h at room temperature. The organic layer is separated, washed with water, dried over magnesium sulfate and chromatographed through a column of silica gel, obtaining 2.26 g (60%) of l-methyl-lH-indole-6-carboxaldehyde. in the form of a white solid. b) A solution of 0.900 g (5.65 mmol) of 1-methyl-lH-indole-6-carboxaldehyde is added at -50 ° C, with stirring, to a solution of 2.0 g (10.5 mmol) of isocyanide of toluene-4-sulfonylmethyl and 20 ml of a 1M solution of potassium t-butoxide in 15 ml of tetrahydrofuran. The reaction mixture is stirred at -30 ° C for 2 h, treated with 20 ml of methanol and the new mixture is stirred for an additional 1 hour between 45 and 50 ° C, poured onto ice-water and extracted with ethyl acetate. ethyl. The organic phase is dried over magnesium sulfate and concentrated to yield (1-methyl-1H-indolyl-6-yl) -acetonitrile. c) The { l-methyl-3- [4- (l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -lH-indole-6- il} -acetonitrile, m.p. 225-226.5 ° C, is prepared from (1-methyl-lH-indolyl-6-yl) -acetonitrile, similarly to example 2b and 2c.

Example 5 3- (6-Ethyl-l-methyl-lH-indol-3-yl) -4- (1-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione a) Stir at room temperature for 2 days a mixture of 6.0 of 6-chloroacetyl-l-pivaloylindole (K. Teranishi et al., Synthesis 1994, 1018), 5.75 ml of 58% hydroiodic acid in 35 ml of acetic acid. The reaction mixture is poured into water and the product is extracted with ethyl acetate, washed with a solution of 5% sodium bicarbonate and with water. The organic phase is dried over magnesium sulfate and concentrated to obtain a dark oil. By purification of this material on silica gel column 3 are obtained, 9 g of l- (6-acetyl-indol-1-yl) -2, 2-dimethylpropan-l-one. b) 3.9 g of 1- (6-acetyl-indol-1-yl) -2,2-dimethylpropan-1-one, dissolved in 50 ml of methanol, are treated with a solution of sodium methoxide (0.84). g of sodium metal in 20 ml of methanol). The reaction is stirred at room temperature for 1 h, poured onto 2N hydrochloric acid / ice and extracted with ethyl acetate. The organic extracts are dried over magnesium sulfate and concentrated to yield 1.3 g of 5-acetylindole after having been purified by chromatography. c) To a 0.26 g (6.55 mmol) of NaH slurry (60% oil dispersion) in 10 ml of dry N, N-dimethylformamide, a solution of 6-acetylindole (1.04 g, 6.55 mmoles) of 5 ml of N is added between 0 and 4 ° C, Dry N-dimethylformamide. Stir at the same temperature for 15 min. and 1.45 g (10.1 mmol) of methyl iodide are added. The new mixture is stirred at the same temperature for 1 hour, poured onto ice and water and extracted with ethyl acetate. The organic phase is washed with brine, dried over magnesium sulfate and concentrated to give 1- (1-methyl-1H-indol-6-yl) -etonone, after having been purified by silica gel column chromatography. d) A mixture of 0.226 g of 1- (1-methyl-1H-indol-6-yl) -ethanone, 1.35 ml of 85% hydrazine hydrate, 0.88 is stirred at 62 ° C overnight. g of potassium hydroxide in 15 ml of diethylene glycol. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated to obtain 0.200 g of 6-ethyl-1-methylindole as a colorless oil, after purification by silica gel column chromatography. e) 3- (6-ethyl-l-methyl-lH-indol-3-yl) -4- (1-methyl-lH-indol-3-yl) -pyrrole-2,5-dione, m.p. 247-248 ° C, is synthesized from 6-ethyl-1-methylindol, similarly to example 2b and 2c.

Example 6 FORMULATION OF TABLETS * Compound A means a compound of the invention. Manufacturing procedure: 1. Mix elements 1, 2 and 3 in an appropriate mixer for 15 minutes. 2. The powder mixture from stage 1 is granulated with a 20% solution of Povidone K30 (item 4). 3. The granules of stage 2 are dried at 50 ° C. 4. The granulate of stage 3 is milled in a suitable mill. 5. The ground granulated element 5 ai is added in step 4 and mixed for 3 minutes. 6. The granulate is pressed in step 5 in a suitable press. Example 7 FORMULATION OF CAPSULES Manufacturing procedure: 1. Mix elements 1, 2 and 3 in a suitable mixer for 15 minutes. 2. Items 4 and 5 are added and mixed for 3 minutes. 3. It is packaged in the appropriate capsule.

Example 8 PREPARATION OF THE INJECTABLE SOLUTION / EMULSION Ingredient Ingredient ftis / ml 1 compound A 1 mg 2 polyethylene glycol 400 10-50 mg 3 lecithin 20-50 mg 4 soybean oil 1-5 mg glycerin 8-12 mg 6 water to complete l ml Manufacturing procedure: i. The element i is dissolved in element 2. 2. Elements 3, 4 and 5 are added to element 6 and ground until a dispersion is obtained, then homogenized. 3. Add the solution from stage 1 to the mixture of stage 2 and homogenize until a translucent dispersion is obtained. 4. It is filtered under sterile conditions through a 0.2μ filter and packed in vials.

Example 9 PREPARATION OF INJECTABLE SOLUTION / EMULSION mg / ml 1 compound A l g 2 glycofurol 10-50 mg 3 lecithin 20-50 mg 4 soybean oil 1-5 mg glycerin 8 - 12 mg 6 water to complete 1 mi Fragmenting the raopcation: 1. Element 1 is dissolved in element 2. 2. Elements 3, 4 and 5 are added to element 6 and ground to a dispersion, then homogenized. 3. The solution of step i is added to the mixture of step 2 and homogenized until a translucent dispersion is obtained. 4. It is filtered under sterile conditions through a 0.2μm filter and packed in vials.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention is the conventional one for the manufacture of the objects to which it refers.

Having described the invention as above, property is claimed as contained in the following:

Claims (11)

RE I V I ND I C AC I ONE S

1. A compound of the formula characterized in that R is alkyl, alkylthio or hydroxy or the pharmaceutically acceptable salts of the compounds of the formula I.

2. A compound according to claim 1, characterized in that R is alkyl.

3 A compound according to claim 1, characterized in that it is unsubstituted alkyl.

4. A compound according to claim 1, characterized in that R is methyl.

5. A compound according to claim 1, characterized in that R is hydroxy.

6. A compound according to claim 1, characterized in that R is alkylthio.

7. A compound according to claim 1, characterized in that R is methylthio.

8. A compound according to claim 1, characterized in that R is alkyl substituted by one or more of hydroxy, alkoxy, amino, halogen, thioalkyl, carboxy, carboxylic acid derivatives, cyano or alkylsulfinyl.

9. A compound according to claim 1, characterized in that R is alkyl substituted by cyano.

10. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, as claimed in any of claims 1 to 9 and an inert excipient.

11. Use of a compound as claimed in any one of claims 1 to 9 to inhibit cell proliferation or to prepare the corresponding medicaments.