MXPA99000961A - Substituted bisindolylmaleimides for the inhibition of cell proliferation - Google Patents

Abstract

Compounds of formula (I) wherein R 1 and R 1'are independently alkyl, aryl, alkenyl or alkynyl;R 2 and R 2'are independently hydrogen or alkyl;R 4, R 5, R 6 and R 7 each independently are (a), CO 2R 9, CH 2OR 10, CHO, CH 2NR 11R 12, CON(R 13) 2, hydrogen, halogen, cyano, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino, aralkyloxy, monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl or alkylsulphonyl, provided that at least one of R 4, R 5, R 6 or R 7 is cyano, (a), CO 2R 9, CH 2OR 10, CH 2NR 11R 12, CHO or CON(R 13) 2;R 8 is alkyl, aralkyl or aryl;R 9 is alkyl, aralkyl or aryl;R 10 is hydrogen, alkyl, aralkyl or aryl;R 11 and R 12 are independently hydrogen, alkyl, aryl, aralkyl or acyl;R 13 is hydrogen, alkyl, aryl or aralkyl;and one of X and Y signifies O and the other signifies O, S, (H,OH) or (H,H);as well as pharmaceutically acceptable prodrugs or salts of acidic compounds of formula (I) with bases and or basic compounds of formula (I) with acids are antiproliferative agents useful in the treatment of cancer.

Description

- - BISINDOLILMERMIMIDES SUBSTITUTED FOR THE INHIBITION OF CELL PROLIFERATION DESCRIPTION OF THE INVENTION The present invention relates to substituted pyrroles. More particularly, the invention relates to substituted pyrroles of the formula wherein R1 and R1 are independently alkyl, aryl, alkenyl or alkynyl; R2 and R are independently hydrogen or alkyl; R4, R5, R6 and R7 each independently are CH2OC (0) R8, CH2OR10, CHO, CH2NRUR12, hydrogen, halogen, cyano, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, Rßf. 29266 - - nitro, amino, acylamino, aralkyloxy, monoalkylamino, dialkylamino, alkylthio, alkylsulfinyl or alkylsulfonyl, with the proviso that at least one of R4, R5, R6 or R7 is cyano, CH2OC (0) R8, CH2OR10, CH2NRUR12 eight; R8 is alkyl, aralkyl or aryl; R9 is alkyl, aralkyl or aryl; R10 is hydrogen, alkyl, aralkyl or aryl; Ru and R 12 are independently hydrogen, alkyl, aryl, aralkyl or acyl; R 13 is hydrogen, alkyl, aryl or aralkyl; and one of X and Y means O and the other means O, S, (H, OH) or (H, H); as well as the pharmaceutically acceptable precursors thereof or the pharmaceutically acceptable salts of the acidic compounds of the formula I with bases and / or the basic compounds of the formula I with acids. The compounds of the formula I and their pharmaceutically acceptable salts are anti-proliferative agents useful for the treatment or control of cancer, in particular for the treatment or control of solid tumors. The compounds of the invention are especially indicated for the treatment or control of breast tumors and colon tumors.

As used in the invention, the term "alkyl", alone or in combination with others, means a saturated hydrocarbon group, linear or branched, containing a maximum of 10, preferably a maximum of 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl , sec-butyl, t-butyl and pentyl, which is unsubstituted or substituted by one or more substituents, chosen from the group consisting of hydroxy, alkoxy, amino, halogen, thioalkyl, cyano, carboxy, carboxylic acid derivatives and alkylsulfinyl . The term "alkoxy" denotes a group in which the alkyl moiety is defined as above, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy or t-butoxy and the like. A haloalkyl group can carry one or more halogen atoms, examples of this group being chloromethyl and trifluoromethyl. The term "acyl", alone or in combination, means a group derived from an alkanoic acid, unsubstituted or substituted, with a maximum of 10, preferably with a maximum of 5 carbon atoms, for example acetyl, propionyl, butyryl , trifluoroacetyl, chloroacetyl, trichloroacetyl, aminoacetyl or 2-amino-propionyl and the like or of an unsubstituted or substituted aromatic carboxylic acid, for example benzoyl. Examples of the alkanoic acid substituents include one or more of the following: hydroxy, alkoxy, amino, halogen, thioalkyl, cyano, carboxy, carboxylic acid or alkylsulfinyl derivatives and the like. Examples of aromatic carboxylic acid substituents include one or more of the following: halogen, alkyl, hydroxy, benzyloxy, alkoxy, haloalkyl, nitro, amino, cyano, and the like. The term "aryl", alone or in combination, means an unsubstituted phenyl group or a phenyl group bearing one or more, preferably one to three substituents, examples being halogen, alkyl, hydroxy, benzyloxy, alkoxy, haloalkyl , nitro, amino and cyano. The term "halogen" means fluorine, chlorine, bromine or iodine. The term "carboxylic acid derivative" means an ester, amide, cyano, acid chloride and the like. The term "alkenyl" refers to straight or branched chain hydrocarbon groups, having 2 to 5 carbon atoms, having at least one double bond. Groups of 3 to 5 carbon atoms are preferred. The term "alkynyl" means straight or branched chain hydrocarbon groups, having 2 to 5 carbon atoms, having at least one triple bond. Groups of 3 to 5 carbon atoms are preferred. As used herein, the term "pharmaceutically acceptable pre-product" means a compound which, under physiological conditions or by solvolysis, can be converted into a compound of the Formula I or a pharmaceutically acceptable salt thereof.

In formula I above, R1 and R1 are preferably I rent. In an especially preferred embodiment, R1 and R1 are preferably methyl.

Preferably, one of R4, R, R6 and R7 is cyano, 0 || CH2OCR8, C02R9, CH2OR10, CH2NRnR12, CHO or CON (R13) 2; and the others are hydrogen.

In a particularly preferred embodiment, R6 is O || cyano, CH2OCR8, C02R9, CH2ORi0, CH2NRUR12, CHO or CON (R13) 2; Y R4, R5 and R7 are hydrogen.

They are particularly preferred compounds of the Formula I those in which R1 is methyl, R2 is hydrogen, Rl is methyl, R2 is hydrogen, R4, R5, R7 are hydrogen and R6 is cyano, CH2OCR8, OR C02R9, CH2OR10, CH2NRUR12, CON (R13) 2 or CHO.

In the especially preferred compounds, R1 is methyl, R2 is hydrogen, R1 is methyl, R2 is hydrogen, R4, R5, R7 are hydrogen and R6 is cyano, CH2OCR8, II 0 C02R9, CH2OR10, CH2NRUR12, CON (R13) 2 and CHO where R8 and R9 are alkyl, preferably methyl , R10 is alkyl, preferably methyl or hydrogen and R11, R12 and R13 are hydrogen. The compounds of the formula I in which X and Y signify, both 0, are prepared according to Scheme I below.

Scheme I wherein R1, R1 'R2, R2', R4, R5, R6 and R7 have the meaning described above; with the proviso that when any of R1, R1 'R2, R2', R4, R5, R6 or R7 is a substituent that reacts with acid chlorides, for example when any of R1, R1 'R2, R2', R4, R5, R6 or R7 is a hydroxy, hydroxyalkyl, amino, monoalkylamino or aminoalkyl group, then such a substituent will be protected with a conventional protecting group. As explained in Scheme I, a compound of the formula II, a known compound or a compound synthesized by known methods, is reacted by conventional methods with oxalyl chloride in an inert organic solvent, for example a halogenated aliphatic hydrocarbon, at a temperature between 0 ° C to the reflux temperature of the solvent, to obtain the corresponding compound of the formula III. The compound of the formula III is reacted with a compound of the formula IV, a known compound or a compound synthesized by known methods, and triethylamine in a solvent such as dichloromethane, at a temperature comprised between 0 to 25 ° C, then treat with para-toluenesulfonic acid in a solvent such as toluene, at a temperature around 25 ° C, to obtain the corresponding compound of the formula la. If a protecting group is used during the reaction of a compound of formula III with a compound of formula IV, it is removed at this point using known methods.

A compound of formula I, wherein one of X e Y means O and the other means (H, OH), is prepared by reducing a compound of the formula I in which X and Y mean, both O (formula la) with a metal hydride complex. The reduction can take place by a known method, including the protection of the indole ring substituents before carrying out the reduction and deprotection thereof once the reduction is carried out according to known methods. Preference is given to using an alkali metal hydride and aluminum, such as lithium aluminum hydride, although other hydrides, such as diisobutylaluminium hydride and sodium dihydro-bis (2-methoxyethoxy) aluminate, can also be used. Suitable inert organic solvents, in which reduction can be effected, include aliphatic and cyclic ethers, such as diethyl ether or tetrahydrofuran (THF) and hydrocarbons such as hexane, benzene and toluene. Conveniently, the reduction takes place around the ambient temperature. A compound of formula I can be prepared, wherein one of X and Y means O and the other means (H, H), by catalytic hydrogenation of a compound of formula I wherein X and Y mean O and the other - -signifies (H, OH). For the catalytic hydrogenation, conventional methods can be used, including the protection and deprotection of the indole ring substituents according to the known procedures.

Thus, the catalytic hydrogenation can be carried out in the presence of a noble metal catalyst, such as palladium or platinum, for example palladium on carbon (Pd / C) and an inert organic solvent, such as an alkanol (for example methanol). or ethanol). The catalytic hydrogenation is conveniently carried out at room temperature and under atmospheric pressure. A compound of the formula I is prepared, in which one of X and Y means 0 and the other means S, by reacting a compound of the formula I in X and Y both mean 0 with a sulfurizing agent. Conventional methods can be used to carry out the sulfurization, which include the protection of the substituents before sulfurization and the deprotection after the sulfurization, as is known to those skilled in the art. The sulfurization is conveniently carried out using phosphorus pentasulfide, Lawesson's reagent [2,4-bis (4-methoxyphenyl) -1,2-dithioxo-1,3,2,4-dithiaphosphetane: Bull. Soc. Chim. Belg. 87 (1978) 229-238] or the reagent of Davy [2,4-bis (methylthio) -1,3,2,4-dithiadiphosphetane; Sulfur. Lett. 1983, 1, 167].

This reaction is conveniently carried out in an inert solvent, such as an aliphatic or cyclic ether (for example, dimethoxyethane) or an aromatic hydrocarbon which can be halogenated (for example, benzene, toluene or chlorobenzene) and at an elevated temperature, especially at the reflux temperature of the reaction mixture. If desired, an acidic compound of the formula I can be converted to a pharmaceutically acceptable salt with a base or a basic compound of the formula I can be converted to a pharmaceutically acceptable salt by reaction with an acid. The conversion of an acidic compound of formula I into a pharmaceutically acceptable salt can be carried out by treatment with a suitable base in a known manner. Suitable salts are those which are derived not only from inorganic bases, for example, sodium, potassium or calcium salts, but also from organic bases, such as ethylenediamine, monoethanolamine or diethanolamine. The conversion of a basic compound of the formula I into a pharmaceutically acceptable salt can take place by treatment with a suitable acid in a known manner. Suitable salts are those which are derived not only from inorganic acids, for example, hydrochlorides, hydrobromides, phosphates or sulfates, but also from organic acids, for example acetates, citrates, fumarates, tartrates, maleates, methanesulfonates or p-toluenesulfonates. The pyrroles of the formula I and their pharmaceutically acceptable salts inhibit cellular processes, for example cell proliferation and can be used for the treatment or control of inflammatory disorders such as arthritis, immunological diseases, related to organ transplants, and in oncology. The breast epithelial carcinoma cell line, MDAMB-435, and the colon carcinoma cell line, S 480, were received from the ATCC (American Type Cell Culture Collection) and multiply in culture medium, as recommended 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 1 mM 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 MDA-MB435 cells is analyzed as follows. Plates containing S 480 cells are analyzed after 7 days of drug addition as follows. MTT ([3- (4,5-methylthiazol-2-yl) -2,5-diphenyl-tetrazolium bromide, thiazolyl 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. - 3 hours. The medium containing the MTT is removed and 50 μl of 100% ethanol is added to each well to dissolve the formazan. The absorbances are read using an automated plate reader (Bio-tek microplate reader). IC50's are calculated using the Reed and Munsch equation, see Am. J. Hygiene, Vol. 27, pp. 493-497, 1938.

The results are provided in the following Table.

Antiproliferative Activity Table in the Cell Line * Average of two individual trials. The pyrroles of the formula I and their salts mentioned above can be used as 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 pharmaceutical preparations, these compounds can be formulated with inert or inert organic excipients. As excipients of this type for tablets, coated tablets, dragees and hard gelatine capsules, lactose, corn starch or derivatives thereof, stearic acid or its salts can be used. Suitable excipients for soft gelatine capsules are vegetable oils, waxes, fats, semi-solid or liquid polyols. Depending on the nature of the active substance, the excipient may be dispensed with, however, they are normally required in the case of soft gelatin capsules. Suitable excipients for the manufacture of solutions and syrups are water, polyols, sucrose, invert sugar and glucose. Suitable excipients for injectable solutions are water, alcohols, polyols, glycerin and vegetable oils. Suitable excipients for suppositories are natural and hydrogenated oils, waxes, fats and semi-solid polyols. The pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavors, salts for varying the osmotic pressure, buffers, coatings and antioxidants. They may also contain other therapeutically valuable 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, immunological, broncho-pulmonary 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 doctor. The daily dose can be administered in a single dose form or divided into several doses. The following examples illustrate the invention: EXAMPLE 1 1-methyl-3- [4- (1-methyl-1H-indol-3-yl) -2,5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl] -lH-indole 6-carbonitrile The l-methyl-lH-indole-6-carbonitrile (1.0 g, 6.4 mmol), a known compound, is dissolved in ethyl ether (Et2 ?, 25 ml), cooled in an ice bath and treated with oxalyl chloride (0.95 ml, 10.9 mmol, 1.7 equiv.). It is removed and immediately the yellow bath precipitates the ice bath. The mixture is stirred at room temperature overnight, the solids are collected and washed with ethyl ether and dried under vacuum for 30 minutes to obtain 1.53 g (96%) of (6-cyano-1-methyl-1H chloride. -indol-3-yl) -oxo-acetyl. This material (1.53 g, 6.2 mmol) together with 2- (l-methyl-lH-indol-3-yl) -acetymidic isopropyl ester hydrochloride (1.66 g, 6.2 mmol, 1 equiv.) Is suspended in CH2CI2 (100 ml) and cooled in an ice bath. The mixture is treated with Et3N (3.5 ml, 24.8 mmol, 4 equiv.), Stirred at 0 ° C for 30 minutes, then at room temperature for another 3 hours. The reaction mixture is then diluted with CH2Cl2 (150 ml), washed with H20 (50 ml) and then with 0.5 N HCl (50 ml). The organic fractions are dried over MgSO, filtered and evaporated to give a dark oil. The residue is taken up in toluene (30 ml), cooled in an ice bath, then treated with pTsOH (1.3 g, 6.8 mmol, 1.1 equiv.), Then stirred at room temperature for 2 hours. The precipitated red solids are collected, washed with a small volume of toluene, hexane, H 2 O, then divided between 500 ml of CH 2 Cl 2 and 75 ml of saturated NaHCO 3 solution. The organic layer is dried over MgSO 4, filtered and concentrated by evaporation to yield 2 g of a red solid. The solid is washed with CH2Cl2, cooled, recrystallized from acetone / hexane to give 938 mg of 1-methyl-3- [4- (1-methyl-lH-indol-3-yl) -2,5-dioxo-2. , 5-dihydro-lH-pyrrol-3-yl] -lH-indole-6-carbonitrile.

EXAMPLE 2 1-methyl-3- [4- (1-methyl-1H-indol-3-yl) -2,5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl] -lH-indole 5-carbonitrile Dissolve l-methyl-lH-indole-5-carbonitrile, a known compound (0.4 g, 2.55 mmole), dissolve in ethyl ether (25 ml), cool in an ice bath and treat with ethyl chloride. oxalyl (0.35 ml, 4.0 mmol, 1.6 equiv.). This mixture is stirred at room temperature overnight, then the solvent is removed by evaporation and taken up in CH 2 Cl 2 and this solvent is evaporated. This residue is suspended together with the isopropyl ester hydrochloride 2- (1-methyl-1H-indol-3-yl) -acetymidic (0.68 g, 2.55 mmol, 1 equiv.) In CH 2 Cl 2 (50 ml) and cooled in bath of ice. The mixture is treated with triethylamine Et3N (1.4 ml, 10 mmol, 4 equiv.), Stirred at 0 ° C for 30 minutes, then at room temperature for 3 more hours. The reaction mixture was then diluted with CH2C12 (100 ml), washed with H20 (25 ml) and then with 0.5 N HCl (25 ml). The organic fractions are dried over MgSO, filtered and concentrated by evaporation to yield a dark oil. The residue is taken up in toluene (50 ml), cooled in an ice bath, then treated with pTsOH (0.53 g, 2.8 mmol, 1.1 equiv.), Then stirred at room temperature overnight. The toluene is evaporated and the residue is dissolved in CH2Cl2 (100 ml), then washed with saturated NaHCO3 solution (30 ml), H2O (30 ml) and brine (30 ml). The organic layer is dried over MgSO 3, filtered and concentrated by evaporation, then purified on flash column (10% ethyl acetate [EtOAc] in hexane). The product is then purified by washing with cold CH2Cl2 to give 0.43 g of 1- [4- (1-methyl-1H-indol-3-yl) -2,5-dioxo-2, 5-dihydro-1H-pyrrol- 3-yl] -lH-indole-5-carbonitrile.

EXAMPLE 3 1-Methyl-3- [4- (1-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrole-3-yl acetic acid methyl ester ] -lH-ind? l-6-yl a) Methyl ester of 1-methyl-1H-indol-6-yl acetic acid. NaH (8.2 mM) in N, N-dimethylformamide (DMF) (20 ml) is cooled to 0 ° C, then treated with - - a solution of the previously known lH-indol-6-methanol (1 g, 6. 8 mM) in DMF (8 ml). Then it is stirred for 1 hour at 0 ° C, methyl iodide (Mel, 0.51 ml, 8.2 mM) dissolved in DMF (2 ml) is added, and the mixture is stirred overnight at 0 ° C, then poured onto ice / H ?O (250 ml) and extracted with EtOAc (50 ml, 3 times). The organic phase is dried over MgSO 4, filtered, concentrated by evaporation and purified by flash column chromatography to yield 1-methyl-1H-indole-6-methanol (0.82 g, 75%). This product (l-methyl-lH-indole-6-methanol, 1 g, 6.2 mM) is dissolved in a mixture of pyridine (5 ml) and acetic anhydride (AC2O, 5 ml) and stirred at room temperature overnight . The solvent is evaporated and the residue is purified by flash column chromatography to yield 1.09 g of 1-methyl-1H-indol-6-yl acetic acid methyl ester. b) Dissolve the methyl ester of acetic acid of l-methyl-lH-indol-6-yl (1.09 g, 5.7 mM) in Et20 (30 mL), cool to 0 ° C, and treat with oxalyl chloride. (0.87 ml, 10 mm). The mixture is kept stirring overnight, allowing it to return to room temperature. The yellow precipitate is collected, washed with Et20 and dried to yield 1.5 g of glyoxalyl chloride adduct, 3-chlorocarboncarbonyl-1-methyl-1H-indol-6-yl acetic acid methyl ester. The glyoxalyl chloride adduct (1.5 g, 5 mM) and the 2- (l-methyl-lH-indol-3-yl) -ethanimide isopropyl ester hydrochloride (1.3 g, 5 mM) are combined with CH2C12 ( 30 ml), cooled to 0 ° C, and treated with Et3N (2.84 ml, 20 mM).

Then it is allowed to return to room temperature overnight, the reaction mixture is diluted with CH2Cl2, extracted with H20 (50 ml), and with 0.5M HCl (50 ml). The organic phase is washed dry over MgSO, filtered and concentrated by evaporation to obtain a red solid. This material is combined with toluene (70 ml) and treated with para-toluenesulfonic acid (pTsOH, 1 g, 5.5 mM), then stirred for three hours. It is filtered, the insoluble material is washed with toluene and then dissolved with CH2Cl2 (250 ml) and extracted with NaHCO3. (2 times, 200 ml each time). The organic layer is dried over MgSO, filtered and concentrated by evaporation to yield a red residue. The residue is purified by washing with EtOAc and cold acetone, obtaining the methyl ester of acetic acid of 1-methyl-3- [4- (1-methyl-lH-indol-3-yl) -2,5-dioxo-2. , 5-dihydro-lH-pyrrol-3-yl] -1H-indol-6-yl; p.f. 271 ° C.

EXAMPLE 4 The following compounds are prepared in a manner similar to that of Example 3b. a) 1-Methyl-3- [4- (1-methyl-lH-indol-3-yl] -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] methyl ester 1H-indole-6-carboxylic acid, mp 245 ° C, from the methyl ester of l-methyl-lH-indole-6-carboxylic acid. b) l-Methyl-3- [4- (l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -lH-indole 6-carboxaldehyde, mp 241 ° C, from l-methyl-lH-indole-6-carboxaldehyde. c) 3- (6-Methoxymethyl-1-methyl-1H-indol-3-yl) -4- (1-methyl-1H-indol-3-yl) -pyrrole-2, 5-dione, m.p. 216-17 ° C, from 6-methoxymethyl-1-methyl-1H-indole. The 6-methoxymethyl-1-methyl-1H-indole is prepared according to the following procedure: A solution of the known lH-indol-6-methanol (0.5 g, 3.4 mM) in DMF (30 ml) is treated with NaH ( 8.16 mM) at 0 ° C. It is stirred for 1 hour and the mixture is treated with a Mel solution (0.5 ml, 8.1 M) in DMF (2 ml). The mixture is allowed to return to room temperature overnight, then poured into H20 (150 ml). and extracted - with CH2C12 (50 ml, 3 times). The organic layer is dried over MgSO, filtered and concentrated by evaporation. It is purified by flash column chromatography, obtaining 0. 28 g of 6-methoxymethyl-1-methyl-1H-indole.

EXAMPLE 5 3- (6-Hydroxymethyl-1-methyl-1H-indol-3-yl) -4- (1-methyl-1H-indol-3-yl) -pyrrole-2, 5-dione The methyl ester is combined of the acetic acid of 1-methyl-3- [4- (l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -lH- indol-6-yl (0.87 g, 2 mM) with a solution of Et3N / H20 / methanol (MeOH) (5: 4: 1) and heat to ~50 ° C until thin layer chromatography indicates that the material of departure has completely disappeared. The solvent is evaporated, the residue is dissolved in CH2C12 (150 ml) and extracted with H20 (50 ml), 0.05 M HCl (50 ml) and saturated NaHCO3 solution (50 ml). The organic layer is dried over MgSO, filtered and concentrated by evaporation. Crystallization from EtOAc yields 0.35 g of 3- (6-hydroxymethyl-1-methyl-1H-indol-3-yl) -4- (1-methyl-1H-indol-3-yl) -pyrrole-2, 5- diona; p.f. 245- - - EXAMPLE 6 Amide of 1-methyl-3- [4- (l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrole-3-acid il] -lH-indole-6-carboxylic A mixture of 0.7 g (1.84 mmol) of 1-methyl-3- [4- (l-methyl-1H-indole) is heated at 50 ° C under argon for 2 days. -3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -lH-indole-6-carbonitrile, 2.4 g (15.6 mmol) of sodium perborate tetrahydrate in 15 ml of water and 250 ml of methanol. The majority of the solvent is removed in vacuo, the residue is dissolved with water and extracted with ethyl acetate. The organic phase is washed with brine, dried over MgSO4 and concentrated to give 0.6 g of a red solid material, which is refluxed in ethyl acetate. The suspension is placed in a freezer and the red solid is collected by filtration, obtaining 154.3 mg (21%) of pure amide of 1-methyl-3- [4- (l-methyl-lH-indol-3-yl)] -2, 5-dioxo-2, 5-dihydro-3-yl] -lH-indole-6-carboxylic acid, mp 176-182 ° C (decomp.).

EXAMPLE 7 1-Methyl-3- [4- (1-methyl-lH-indol-3-yl) -2,5-dioxo-2,5-dihydro-lH-pyrrol-3-yl] ethyl ester - 1H-indo-1-6-carboxylic a) The l-methyl-6-cyanoindole is heated to reflux (3.12 g, 21.9 mmol) in 180 ml of ethanol / water (8: 1) containing 15 g of potassium hydroxide, to yield 3.0 g of l-methyl-lH-indole-6-carboxylic acid as a white solid . b) A solution of 1.05 g (6.0 mmol) of 1-methyl-1H-indole-6-carboxylic acid in 15 ml of methylene chloride is added with stirring at room temperature to a solution of 1,905 g (10 mmol) of hydrochloride of 1-ethyl-3- (3-dimethyl-aminopropyl) -carbodiimide, 1.20 g (10 mmol) of 4-dimethylaminopyridine in 20 ml of methylene chloride. Ethanol is added and the reaction mixture is stirred for 15 h. The reaction mixture is extracted with ethyl acetate, the organic phase is washed with brine and dried over anhydrous magnesium sulfate. Chromatographic purification of this material yields 1.08 g (89%) of the l-methyl-1H-indole-6-carboxylic acid ethyl ester, in the form of a pale yellow oil. c) The ethyl ester of 1-methyl-3- [4- (1-methyl-lH-indol-3-yl) -2,5-dioxo-2,5-dihydro-lH-pyrrol-3-yl] -1H-Indole-6-carboxylic, mp 215-216 ° C, is prepared from the ethyl ester of l-methyl-lH-indole-6-carboxylic acid, using a procedure similar to that described in Example 3b.

EXAMPLE 8 3- [1- (2-Propyl) -6-methoxymethyl-lH-indol-3-yl] -4- (1-methyl-lH-indo-3-yl) -pyrrole-2, 5-dione a) 10 g (55.2 mmoles) of 4-methyl-3-nitro-benzoic acid, 16.8 ml (126.96 mmoles) of N, N-dimethylformamide dimethylacetal in N are heated at 140 ° C under argon for 17 hours. -dimethylformamide anhydrous (50 ml). The reaction mixture was cooled to room temperature and concentrated by evaporation to obtain a dark red residue, which was dissolved in 70 ml of hot methanol, kept at 25 ° C for 3 h and at 4 ° C overnight. The crystalline product is filtered and the crystals are washed with ice-cooled methanol, then hexane. Dry with high vacuum to obtain 10.6 g (76.9%) of 4- (2-dimethylamino-vinyl) -3-nitro-benzoic acid methyl ester. b) A solution of 4- (2-dimethylamino-vinyl) -3-nitro-benzoic acid methyl ester (10.4 g, 41.5 mmol) in 160 ml of methanol is stirred under an argon atmosphere and 12.9 ml are added dropwise ( 101.92 mmole) of chlorotrimethylsilane. The resulting red solution is boiled with reflux for 18 h and thin layer chromatography in hexane / ethyl acetate (65:35) will indicate when the reaction is complete (absence of the starting products). The reaction mixture is concentrated by evaporation and the oily residue is redissolved in 100 ml of ethyl acetate, extracted with saturated sodium bicarbonate solution and saturated sodium chloride solution, the organic layer is dried over magnesium sulfate and concentrated to obtain a residue in the form of oil. Crystallization from 30 ml of anhydrous ether yields 10.8 g of 4-carbomethoxy-2-nitrophenyl-acetaldehyde dimethylacetal. c) The 4-carbomethoxy-2-nitrophenyl-acetaldehyde dimethylacetal (8.75 g, 41.43 mmol) is reduced under hydrogen atmosphere (50 psi, 0.45 g of 10% Pd / C) in 170 ml of methanol for 2.5 h. The solution is filtered over celite and concentrated by evaporation to obtain an oil. It is recrystallized from ether and hexane to yield 6.16 g of 2-amino-4-carbomethoxy-phenylacetaldehyde dimethylacetal. d) A solution of 5.9 g (24.66 mmoles) of 2-amino-4-carbomethoxy-phenylacetaldehyde dimethylacetal in 160 ml of acetic acid and 4.8 ml (65.12 mmoles) of acetone is stirred under argon for 10 minutes. anhydrous sodium sulfate (46.24 g, 325.6 mmol). During a period of 2 min. Sodium triacetoxyborohydride (20.7 g, 97.68 mmol) is added and the reaction mixture is stirred at 250 ° C for 20 min. The reaction mixture is slowly poured into 490 ml of a saturated solution of sodium bicarbonate and extracted with ethyl acetate.

The organic layer is dried over magnesium sulfate. The filtered solution is concentrated and an oily residue (6 g) is obtained which is purified by flash chromatography (75% ethyl acetate in hexane) to yield 3.8 g of 4-carbomethoxy-2- (N-2-propylamino) -phenylacetaldehyde dimethylacetal. e) The 4-carbomethoxy-2- (N-2-propylamino) -phenylacetaldehyde dimethylacetal (3.7 g, 13.15 mmoles) is refluxed for 1 h. together with 100 ml of IN hydrochloric acid in methanol. The solution is concentrated and the residue is dissolved in 50 ml of ethyl acetate, washed with saturated sodium bicarbonate solution, the organic layer is dried over magnesium sulfate and concentrated by evaporation to yield 2.78 g of 6-carbomethoxy-l- (2-propyl) -indole. f) A solution of 0.250 g (1.15 mmol) of 6-carbomethoxy-1- (2-propyl) -indole in 2 ml of anhydrous tetrahydrofuran is added dropwise to a stirring slurry of lithium aluminum hydride (52.4 mg, 1.38 g). mmoles) in 7 ml of anhydrous tetrahydrofuran under an argon atmosphere at 0 ° C and then stirred at 25 ° C for 45 min. The solution is cooled to 0 ° C and 0.340 ml of methanol are added dropwise, then 0.58 ml of an IN sodium hydroxide solution. The roof is stirred at 25 ° C for 15 min. The white precipitate is filtered over celite and the solution is concentrated. The residue is suspended in 20 ml of ethyl acetate and 20 ml of water. The layers are separated. The aqueous layer is extracted with ethyl acetate and both layers of ethyl acetate are combined and dried over magnesium sulfate. Concentrate and obtain 6-hydroxymethyl-1- (2-propyl) -indole as an oil (214 mg). g) A solution of 6-hydroxymethyl-1- (2-propyl) -indole (0.214 g, 1.13 mmol) in 2 ml of anhydrous N, N-dimethylformamide is added dropwise to a slurry of 95% NaH. mg, 1.36 mmoles) in 6 ml of anhydrous N, N-dimethylformamide at 0 ° C under an argon atmosphere and the reaction mixture is stirred at 0 ° C for 1 h, then methyl iodide (84.7 ml, 1356 mmoles) is added. ). The reaction mixture was stirred at 20 ° C under an argon atmosphere for 17 h. It is poured onto ice-water (50 ml) and extracted with ethyl acetate. Dry the ethyl acetate layers over anhydrous magnesium sulfate and concentrate by evaporation. Purification by flash chromatography using ethyl acetate (2-5%) / hexane provides 107 mg of 6-methoxymethyl-1- (2-propyl) -indole. h) The 6-methoxymethyl-1- (2-propyl) -indole is reacted with oxalyl chloride and then with the hydrochloride of isopropyl 2- (1-methyl-1H-indol-3-yl) -ethanoimidate, as described in Example 3b to yield 3- [1- (2-propyl) -6-methoxymethyl-1H-indol-3-yl] -4- (1-methyl-1H-indol-3-yl) -pyrrole -2, 5-dione.

EXAMPLE 9 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 of Step 1 is granulated with a 20% solution of Povidone K30 (Element 4). 3 The granules of Step 2 are dried at 50 ° C. 4 The granulate of Step 3 is milled in a suitable mill. Element 5 is added to the ground granulate in the Step 4 and mix for 3 minutes. The granulate of Step 5 is pressed in a suitable press.

EXAMPLE 10 FORMULATION OF CAPSULES - - Manufacturing procedure: 1. Mix Elements 1, 2 and 3 in a suitable mixer for 15 minutes. 2. Elements 4 & 5 and mix for 3 minutes. 3. It is packaged in the appropriate capsule.

EXAMPLE 11 PREPARATION OF THE INJECTABLE SOLUTION / EMULSION Element Ingredient mg / 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 1 ml Manufacturing procedure: 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 1 is added to the mixture of Step 2 and homogenized until a translucent dispersion is obtained.

- -. It is filtered under sterile conditions through a 0.2 um filter and packed in vials.

EXAMPLE 12 PREPARATION OF INJECTABLE SOLUTION / EMULSION Element Ingredient mg / ml 1 Compound A 1 mg 2 Glycofurol 10-50 mg 3 Lecithin 20-50 mg 4 Soybean Oil 1-5 mg Glycerin 8-12 mg Water to complete 1 ml Manufacturing procedure: 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 1 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 0.2 um filter and packed in vials.

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

Claims (25)

- - CLAIMS
1. A compound of the formula characterized in that R1 and R1 are independently alkyl, aryl, alkenyl or alkynyl; R2 and R2 are independently hydrogen or alkyl; R4, R5, R6 and R7 each independently are CH2? C (0) R8, CH2OR10, CHO, CH2NRnR12, hydrogen, halogen, cyano, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino, aralkyloxy, monoalkylamino , dialkylamino, alkylthio, alkylsulfinyl or alkylsulfonyl, with the proviso that at least one of R4, R5, R6 or R7 is cyano, CH2OC (0) R8, CH2OR10, CH2NRUR12 or CHO; R is alkyl, aralkyl or aryl; R9 is alkyl, aralkyl or aryl; R10 is hydrogen, alkyl, aralkyl or aryl; - R 11 and R 12 are independently hydrogen, alkyl, aryl, aralkyl or acyl; R 13 is hydrogen, alkyl, aryl or aralkyl; and one of X and Y means O and the other means O, S, (H, OH) or (H, H); and the pharmaceutically acceptable precursors thereof or the pharmaceutically acceptable salts of the acidic compounds of the formula I with bases or the basic compounds of the formula I with acids.
2. 2. A compound according to claim 1, characterized in that R1 is alkyl.
3. 3. A compound according to claim 2, characterized in that R1 is methyl.
4. 4. A compound according to claim 1, characterized in that R2 is hydrogen.
5. 5. A compound according to claim 1, characterized in that R1 is alkyl and R2 is hydrogen.
6. 6. A compound according to claim 5, characterized in that R1 is methyl.
7. 7. A compound according to claim 1, characterized in that one of R4, R5, R6 and R7 is cyano, CH2OC (0) R8, CH2OR10, CH2NRUR12 or CHO and the others are hydrogen.
8. 8. A compound according to claim 7, characterized in that R6 is cyano, CH2OC (0) R8, CH2OR10, CH2NRUR12 or CHO and R4, R5 and R7 are hydrogen.
9. 9. A compound according to claim 8, characterized in that R8 is alkyl, R9 is alkyl, R10 is hydrogen or alkyl and R11, R12 and R13 are hydrogen.
10. 10. A compound according to claim 8, characterized in that R6 is cyano, CH2OC (0) R8 or CH2OR10.
11. 11. A compound according to claim 10, characterized in that R is alkyl, R9 is alkyl, R10 is hydrogen or alkyl and R13 is hydrogen.
12. 12. A compound according to claim 11, characterized in that R8 is methyl, R9 is methyl and R10 is hydrogen or methyl.
13. 13. A compound according to claim 1, characterized in that R1 is alkyl, R2 is hydrogen, R1 is alkyl, R2 is hydrogen, R4, R5, R7 are hydrogen and R6 is cyano CH2OC (0) R8, C02OR9, CH2OR10, CH2NRUR12, CHO, CON (R13) 2.
14. 14. A compound according to claim 13, characterized in that R8 is alkyl, R9 is alkyl, R10 is hydrogen or alkyl and R11, R12 and R13 are hydrogen.
15. 15. A compound according to claim 14, characterized in that R8, R9 are methyl and R10 is hydrogen or methyl.
16. 16. The compound according to claim 1, characterized in that it is l-methyl-3- [4- (l-methyl-lH-indol-3-yl) -2,5-dioxo-2,5-dihydro-lH- pyrrol-3-yl] -lH-indole-6-carbonitrile.
17. 17. The compound according to claim 1, characterized in that it is l-methyl-3- [4- (l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH- pyrrol-3-yl] -IH-indole-5-carbonitrile.
18. 18. The compound according to claim 1, characterized in that it is the methyl ester of acetic acid of 1-methyl-3- [4- (1-methyl-lH-indol-3-yl] -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -1H-indol-6-yl.
19. 19. The compound according to claim 1, characterized in that it is l-methyl-3- [4- (l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH- pyrrol-3-yl] -lH-indole-6-carboxaldehyde.
20. 20. The compound according to claim 1, characterized in that it is 3- (6-methoxymethyl-l-methyl-lH-indol-3-yl) -4- (l-methyl-lH-indol-3-yl) -pyrrole -2, 5-dione.
21. 21. The compound of claim 1, characterized in that it is 3- (6-hydroxymethyl-1-methyl-1H-indol-3-yl) -4- (1-methyl-1H-indol-3-yl) -pyrrole-2. , 5-dione.
22. 22. A pharmaceutical composition comprising a compound of the formula I or a pharmaceutically acceptable precursor thereof or a pharmaceutically acceptable salt of an acid compound of the formula I with a base or a basic compound of the formula I with an acid, such as it is claimed in any of claims 1-21 and of an inert excipient.
23. 23. The pharmaceutical composition according to claim 22, characterized in that R1 and R1 are independently alkyl and R2 and R are hydrogen.
24. 24. The pharmaceutical composition according to claim 23, characterized in that R4, R5, R7 are hydrogen and R6 is cyano, CH2OC (0) R8, CH2OR10, CHNRnR12 or CHO.
25. 25. The use of a compound, as claimed in any of claims 1-21, for the inhibition of cell proliferation or for the preparation of the corresponding medicaments. SUMMARY OF THE INVENTION The compounds of the formula in which R1 and R1 are independently alkyl, aryl, alkenyl or alkynyl; R2 and R2 are independently hydrogen or alkyl; OR II R4, R5, R6 and R7 each independently are CH2OCR8, C02R9, CH2OR10, CHO, CH2NRpR12, CON (R13) 2, hydrogen, halogen, cyano, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino, aralkyloxy, monoalkylamino, dialkylamino, alkylthio, alkylsulfinyl or alkylsulfonyl, with condition that at least one of R4, R5, R6 or R is O II cyano, CH2OCR8, C02R9, CH2OR10, CH2NRUR12, CHO or CON (R13) 2, R8 is alkyl, aralkyl or aryl; R is alkyl, aralkyl or aryl; R10 is hydrogen, alkyl, aralkyl or aryl; R11 and R12 are independently hydrogen, alkyl, aryl, aralkyl or acyl; R 13 is hydrogen, alkyl, aryl or aralkyl; and one of X and Y means O and the other means O, S, (H, OH) or (H, H); as well as the pharmaceutically acceptable precursors thereof or the pharmaceutically acceptable salts of the acidic compounds of the formula I with bases and / or the basic compounds of the formula I with acids are antiproliferative agents useful for the treatment of cancer.