MXPA99001027A - 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, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulphonylaminoalkyl, arylsulphonyl-aminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulphinyl;R 4, R 5, R 6, R 7, R 4', R 5', R 6'and R 7'each independently are hydrogen, formula (II), CO 2R 9, CH 2OR 10, CHO, CH 2NR 11R 12, CON(R 13) 2, halogen, cyano, aryl, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, aralkyloxy, acylamino, monoalkylamino, dialkylamino, thio, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, azide, phosphate or phosphonate provided that at least one of R 4, R 5, R 6 and R 7 and at least one of R 4', R 5', R 6'and R 7'are other than hydrogen, with the proviso that when R 6 is methoxy, R 5 or R 5'are not methoxy;R 8 is alkyl or aryl;R 9 is alkyl or aryl;R 10 is hydrogen, alkyl 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 therefor or pharmaceutically acceptable salts of acidic compounds of formula (I) with basis or basic compounds of formula (I) with acids are antiproliferative agents useful in the treatment of cancer.

Description

BISINDOLILMERMIMIDES SUBSTITUTED FOR THE INHIBITION OF CELLULAR 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 R2 are independently hydrogen or alkyl; R4, R5, R6, R7, R4 ', R5', R6 'and Rr each independently are hydrogen, CH2OCR8, C02R9, CH2OR10, CHO, CH2NRnR12, CON (R13) 2; halogen, cyano, aryl, aralkyloxy, alkyl, Ref. 29267 hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, aralkyloxy, acylamino, monoalkylamino, dialkylamino, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, azide, phosphate or phosphonate, with the proviso that at least one of R4 , R, R6 and R7 and at least one of R, R5, R6 and R7 is other than hydrogen; R8 is alkyl or aryl; R is alkyl or aryl; R10 is hydrogen, alkyl 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); with the proviso that when R6 is methoxy, then R5 or R5 are not methoxy, as well as 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. The compounds of the invention 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. 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, selected from the group consisting of hydroxy, alkoxy, amino, halogen, thioalkyl or alkylsulfinyl. The term "alkoxy" denotes a group in which the alkyl moiety is defined as above, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, 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 or butyryl or of an aromatic carboxylic acid, for example benzoyl. Examples of the alkanoic acid substituents include one or more of the following: hydroxy, alkoxy, amino, halogen, thioalkyl, 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 of which are halogen, alkyl, hydroxy, benzyloxy, alkoxy, haloalkyl, nitro, amino and cyano. The term "halogen" means fluorine, chlorine, bromine or iodine. The term "amino" alone or in combination, means an amino group unsubstituted or substituted by one or more substituents, selected from the group consisting of alkyl, aryl, acyl, alkylsulfonyl or arylsulfonyl. 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 group, of 2 to 5 carbon atoms, which have at least one triple bond. Groups of 3 to 5 carbon atoms are preferred. The term "amino protecting group" means a conventional protecting group of the amino group, such as alkyl, preferably methyl, substituted alkyl, such as trityl and trialkylsilylethyl, acyl, and the like. 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 formula I or a pharmaceutically acceptable salt thereof. In formula I above, R and R are preferably alkyl. In an especially preferred embodiment, R1 and R1 are preferably methyl. R2 and R2 are preferably hydrogen. At least one of R4, R5, R6 and R7 and at least one of R4, R5, R6 and R7 is preferably nitro, alkoxy, O alkyl, halogen, cyano, CH2OCR8, C02R9, CH2OR10, CH2NRpR12, CHO, CON (R13) 2; alkylthio or aralkyloxy. In a preferred embodiment, at least one of R4, O R5, R6 and R7 and one of R4 ', R5', R6 'and R7' is cyano, CH2OCR8, C02R9, CH2OR10, CH2NRUR12, CHO or CON (R13) 2. In an especially preferred embodiment, one of R4, R5, R6 and R7 and one of R4 ', R5', R6 'and R7' is nitro, alkoxy, O II alkyl, halogen, cyano, CH2OCR8, C02R9, CH2OR10, CH2NRUR12, CHO, CON (R13) 2; alkylthio or aralkyloxy and the others are hydrogen. In an especially preferred embodiment, R and R are independently nitro, alkoxy, alkyl, halogen, O cyano, CH2OCR8, C02R9, CH2OR10, CH2NRpR12, alkylthio, aralkyloxy, CHO or CON (R13) 2, and R4, R5, R7 and R4 ', R5' and R7 'are hydrogen. R8 and R9 independently are preferably alkyl, especially preferably methyl, R10 is hydrogen or alkyl, preferably methyl, R11 and R12 are hydrogen or alkyl and R13 is hydrogen or alkyl. Preferred compounds of the formula I are those in which R1 and R1 are alkyl; R2 and R2 are hydrogen and at least one of R4, R5, R6 and R7 and at least one of R4, R5, R6 and R7 are nitro, alkoxy, alkyl, halogen, OR II cyano, CH2OCR8, C02R9, CH2OR10, CH2NRUR12, CHO or CON (R13) 2, alkylthio or aralkyloxy and R8 and R9 are alkyl; R10 is alkyl; Ru and R12 are alkyl; and R13 is alkyl. In an especially preferred embodiment, R1 and R9 * 4 f * 7 are methyl; R and R are hydrogen, one of R, R, R, R and one R, R, R6 and R7 are nitro, alkoxy, alkyl, halogen, 0 cyano, CH20CR, C02R, CH20R, alkylthio, aralkyloxy, CH2NRnR12, CHO or CON (R13) 2, and the others are hydrogen; R8 and 9 10 11 17 n R are methyl; R is methyl; R and R are methyl; and R is methyl. In another preferred embodiment, R1 and R are alkyl; R2 and R2 are hydrogen; and at least one of R4, R5, R6 and R7 is amino, acylamino, monoalkylamino or dialkylamino. In an especially preferred embodiment, R1 and 'R1 are alkyl; R and R are hydrogen; R is amino, acylamino, monoalkylamino or dialkylamino and at least O, one of R4, R5, and R6 is CH2OCR8, C02R9, CH2OR10, CHO, CH2NRnR12, CON (R13) 2, halogen, cyano, aryl, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, aralkyloxy, acylamino, monoalkylamino, dialkylamino, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, azide, phosphate or phosphonate. In a more preferred embodiment form, R1 and R1 are alkyl; R 9 and R 9 'are hydrogen, R (α is amino, acylamino, O II monoalkylamino or dialkylamino and R6 is CH2OCR8, C02R9, CH2OR10, CHO, CH2NRpR12, CON (R13) 2, halogen, cyano, aryl, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, aralkyloxy, acylamino, monoalkylamino, dialkylamino , thio, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, azide, phosphate or phosphonate; R6 is preferably alkoxy, halogen, cyano, alkylthio, alkyl, nitro or acylamino. The compounds of formula I, wherein X and Y mean both 0, are prepared in accordance with the following Schemes 1-3.

SCHEME 1 II wherein R1, R2, R4, R5, R6 and R7 have the meaning described above; with the proviso that when any of R,? - R are substituents that react with acid chlorides, for example when any of R -R is a hydroxy, hydroxyalkyl, amino, monoalkylamino or aminoalkyl group, then such a substituent will be protected with a conventional protective group. As explained in Scheme I, a compound of formula II, a known compound or a compound synthesized by known methods, is reacted by conventional methods with NaH and CH3I in an inert organic solvent, for example N, N- dimethylformamide or tetrahydrofuran, at a temperature between 0 ° C and 25 ° C, to obtain the corresponding compound of formula III. The compound of formula III is reacted with oxalyl chloride in a solvent such as diethyl ether (Et2?) Or dichloromethane (CH2Cl2) at a temperature comprised between 0 and 25 ° C, to obtain the corresponding compound of the formula IV.

SCHEME 2 wherein R1, R2, R4, R5, R6, R7, 'R1', R2 ', R4', R5 ', R .6"and R r are those described above; with the proviso that when any one of R-R7 or R1 -R7 'is a substituent that can react with acid chlorides, for example when any one of R ^ R7 or R1 -R7', is hydroxy, hydroxyalkyl, amino, monoalkylamino or aminoalkyl, then such a substituent will be protected with a conventional protecting group. As illustrated in Scheme 2, a compound of formula V, a known compound or a compound synthesized by known methods, is reacted with P0C13, in N, N-dimethylformamide (DMF), at a temperature between 0 and 60 ° C to obtain the corresponding compound of formula VI. A compound of the formula VI is reacted with NaH and CH3I in an inert solvent, for example dimethylformamide or THF, to obtain the corresponding compound of the formula VII. A compound of the formula VII is reacted with the potassium tert-butoxide (KOtBu) and with toluene-4-sulfonyl isocyanide (TosMIC) in a solvent, for example ethylene glycol dimethyl ether (DME) at a temperature between -30 and -60 ° C, then treated with methanol at a temperature of 65 ° C to obtain the corresponding compound of formula VIII. A compound of the formula VIII is reacted with gaseous HCl in isopropanol to obtain the corresponding compound of the formula IX. A compound of formula IX is reacted with a compound of formula IV and Et3N in a solvent, such as methylene chloride, at a temperature between 0 and 25 ° C. The resulting product is then treated with para-toluenesulfonic acid (pTsOH) in a solvent, for example toluene, at a temperature around 25 ° C to obtain the corresponding compound of formula I. If during the reaction of IX and IV a protective group has been used, then it will be removed by methods already known to the person skilled in the art. Alternatively and preferred, to prepare a compound of the formula I wherein R 4, R 5, R 6, R 7, R 4, R 5, R 6 and R 7 are amino, alkylamino, dialkylamino or acylamino, a pre-synthesis product of bis is reduced -indolylmaleimide of the formula I, in which R 4, R 5, R, R, R, R 5, R and R 7 are nitro, by methods known to those skilled in the art, to obtain the corresponding amino bis-indolylmaleimide. The amino group is then modified to obtain the alkylamino, dialkyl or acylamino derivative by methods known to those skilled in the art. The compounds of the formula I, wherein R 1, R 2, R 4, R 5, R 6 and R 7 are the same as R 1 ', R 2', R 4 ', R 5', R 6 'and R 7' respectively, are obtained in accordance with next Scheme 3. SCHEME 3 wherein R is an amino protecting group, W is halogen and R1, R2, R4, R5, R6 and R7 are the same as R1 ', R2', R4 ', R5', R and R respectively and have been described above.

As illustrated in Scheme 3, a compound of formula XI, a known compound or a compound prepared by known methods, is reacted with a compound of formula X, a known compound or a compound prepared by known methods, and a base such as methyl magnesium iodide and a base such as sodium hydride, in a solvent, for example toluene, at a temperature between 25 ° C and the reflux temperature of the solvent, to obtain the corresponding compound of the formula XII. A compound of formula XII is reacted with a base, for example potassium carbonate, and with an alkylating agent, such as CH3I, in a solvent, for example N-methylpyrrolidinone, at room temperature, to obtain the corresponding compound of the formula XIII. The protecting group R is removed to obtain the corresponding compound of the formula la by conventional methods, which may include the reaction of a compound of the formula XIII with potassium hydroxide in a solvent, for example ethanol, followed by treatment with a mixture of 1, 1, 1, 3, 3, 3-hexa-metildisilazane and methanol in a solvent, for example DMF, at room temperature. A compound of the formula I is obtained, wherein one of X and Y means O and the other one means S, by reaction of a compound of the formula I, wherein X and Y signify, both 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, the reagent of Lawesson [2,4-bis (4-methoxyphenyl) -1,2-dithioxo-l, 3,2,4-dithiaphosphetane: Bull. Soc. Chim. Belg. 87 (1978) 229-238] or the reagent of Davy [2,4-bis (ethylthio) -1,3,4,2,4-dithiadiphosphetane; Sulfur. Lett. 1983, 1, 167]. This 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. A compound of the formula la, wherein one of X and Y means 0 and the other means (H, OH), is prepared by reducing a compound of the formula I in which X and Y signify, 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 has been 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 dihydro-bis (2-methoxyethoxy) -aluminate sodium, 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 or 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 means (H, OH). For the catalytic hydrogenation conventional methods can be used, such as the protection and deprotection of the indole ring substituents according to known procedures. The catalytic hydrogenation can be carried out, for example, 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 atmospheric pressure. 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 by a known method. 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 by a known method." Suitable salts are those that are derived not only from inorganic acids, for example hydrochlorides, hydrobromides, phosphates or sulfates, but also 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 (MDAMB435) was received from the ATCC (American Type Culture Collection) and multiplies in culture in, 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 1 mM and 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" receive DMSO. The final concentration of DMSO in each hole is 0.1%. After 5 days of the drug addition, the plate is analyzed as follows. MTT (3- (4,5-methylthiazol-2-yl) -2,5-diphenyl-2H-tetrazolium bromide, thiazolyl blue) is added to each well to obtain a final concentration of 1 mg / ml. The plate is then incubated at 370 ° C for 2.5 - • 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 reported in the following Table refer to compounds of the formula la.

TABLE which R1 and R1 are methyl and Continuation 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, emulsion solutions 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, but normally they are needed 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 human persons, 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 as a single dose or divided into several doses. The following examples illustrate the invention.

Example 1 3- (6-methoxy-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione a) A solution of the known 6-nitro-lH-indole (5 g, 31 mM) in dimethylformamide (DMF) (50 ml) is cooled to 0 ° C and treated with NaH (1 g, 37 m). 0 ° C for two hours, CH3I (2.3 ml, 37 mM) is added and the reaction mixture is stirred overnight, allowing it to return to room temperature. The mixture is poured into H2O (500 ml), extracted with ethyl acetate (EtOAc, 200 ml, 4 times). The organic fractions are combined, dried over MgSO, filtered and concentrated by evaporation. Purification by flash column chromatography yields l-methyl-6-nitro-lH-indole (5.34 g, 97%). b) A stirred solution of l-methyl-6-nitro-1H-indole in diethyl ether (Et 2? 5 ml) is cooled to 0 ° C and treated with oxalyl chloride (0.15 ml, 1.7 mM). The mixture is stirred at room temperature overnight, the solids are collected, washed with ether and dried to obtain (255 mg, 96%) (l-methyl-6-nitro-1H-indol-3-yl) chloride. oxo-acetyl. c) A mixture of DMF (7 ml, 90 mM) and P0C13 (2.25 ml, 24.5 mMoles) is cooled to 5 ° C and treated with the known 6-methoxy-1H-indole. The mixture is stirred at room temperature for 1 hour, heated at 45 ° C for 1 hour and allowed to return to room temperature overnight. The reaction mixture was poured onto ice (100 ml) and stirred for 30 minutes, while a solution of KOH (9.6 g, 171 mM) in H20 was added dropwise. (20 ml). It is stirred for 30 minutes, heated at 60 ° C for 1 hour, the reaction mixture is cooled to 30 ° C and the pH is adjusted to 7 by the addition of 1N HCl. The mixture is extracted with EtOAc (50 ml, 3 times), the organic phases are combined, dried over MgSO, and concentrated by evaporation. The residue is purified by crystallization from methanol to obtain 6-methoxy-lH-indole-3-carboxaldehyde (1.65 g, 69%).

A solution of 6-methoxy-1H-indole-3-carboxaldehyde (1.65 g, 9.4 mMiM) in DMF (10 ml) is cooled to 0 ° C and treated with NaH (11.3 mM). The mixture is stirred at room temperature for 1 hour, cooled to 0 ° C, treated with CH3I (0.7 ml, 11.3 mM), then allowed to return to room temperature overnight. The mixture is poured into H2O (200 ml), acidified with HCl and extracted with EtOAc (100 ml, 2 times). The organic phases are combined and dried over MgSO4, filtered and concentrated by evaporation to obtain 6-methoxy-1-methyl-1H-indole-3-carboxaldehyde (1.78 g, 99%). e) A suspension of potassium tert-butoxide (KOtBu, 1.62 g, 14.4 mM) in dimethoxyethane is cooled (to -30 ° C).

(DME, 25 ml) and a solution of toluene-4-sulfonylmethyl isocyanide (TosMIC, 1.45 g, 7.4 mM) in DME (15 ml) was added. The mixture is cooled to -60 ° C, a solution of 6-methoxy-1-methyl-1H-indole-3-carboxaldehyde (800 mg, 4.23 mM) is added slowly and the reaction mixture is stirred for 1.5 hours. The mixture is treated with methanol (11 ml), heated at reflux temperature for 15 minutes, then the solvent is evaporated. The residue is treated with H2O (15 ml) containing acetic acid (HOAc, 55 ml), then extracted with CH2CI2 (50 ml, 3 times). The organic layers are combined and washed with a saturated solution of NaHCO 3 (50 ml), dried over MgSO 3, filtered and concentrated by evaporation. Purification by flash column chromatography yields (6-methoxy-l-methyl-lH-indol-3-yl) -acetonitrile (0.6 g, 70%). f) Gaseous HCl is bubbled into a suspension of (6-methoxy-l-methyl-lH-indol-3-yl) -acetonitrile in isopropanol (25 ml) which is cooled to 0 ° C. After 3 hours the solvent is evaporated and the residue is taken up in diethyl ether (Et20, 50 ml, 2 times) and concentrated by evaporation. The residue is then dried with high vacuum to yield the hydrochloride of 2- (6-methoxy-l-methyl-lH-indol-3-yl) -isopropyl acetimidate (1.6 g, 82%).

A suspension of (1-methyl-6-nitro-1H-indol-3-yl) -oxo-acetyl chloride (251 mg, 0.94 mM) and 2- (6-isopropyl) isopropyl ester hydrochloride is cooled to 0 ° C. -methoxy-l-methyl-lH-indol-3-yl) -acetymidic (280 mg, 0.94 mM) in CH2C12 (25 ml), is treated with Et 3 N (0.53 ml, 3.7 mmol) and stir overnight, allowing it to return to room temperature.

The mixture is diluted with CH2Cl2 (25 mL), washed with H20 (20 mL) and 0.5 N HCl (20 mL). The organic phases are combined and dried over MgSO, filtered and concentrated by evaporation. The residue is taken up in toluene (4 ml), cooled to 0 ° C, treated with pTsOH (197 mg, 1 mM) and stirred for 3 hours. The precipitated red solids are collected and partitioned between CH2C12 (50 ml) and H20 (25 ml). The organic fraction is washed with a saturated solution of NaHCO 3 (25 ml), then dried over MgSO 3, filtered and concentrated by evaporation. The residue is rinsed with tetrahydrofuran (THF), obtaining3- (6-methoxy-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione, m.p. 308-310 ° C, in a yield of 31%.

EXAMPLE 2 In a manner similar to that described in example lg), the following compounds are obtained. The starting materials are synthesized by a method similar to that described in sections Ib) and lf). a) 3- (6-Benzyloxy-l-methyl-lH-indol-3-yl) -4- (1-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione , pf 160-165 ° C, is obtained from (6- benzyloxy-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-1-methyl) isopropyl ester hydrochloride 6-nitro-lH-indol-3-yl) -aceti idico. b) 3- (6-Chloro-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione , pf 300-302 ° C, is obtained from the chloride of (6-chloro-l-methyl-lH-indol-3-yl) -oxo-acetyl and the hydrochloride of the isopropyl ester of 2- (l-methyl-6) -nitro-lH-indol-3-yl) -acetymidic. c) 3- (1, 6-Dimethyl-lH-indol-3-yl) -4- (6-methoxy-l-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione, m.p. 240-245 ° C, is obtained from (6-methoxy-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1,6-dimethyl) isopropyl ester hydrochloride -lH- indol3-yl) -acetymidic. d) 3- (1, 6-Dimethyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2,5-dione, m.p. 268-272 ° C, is obtained from the chloride of (l-methyl-6-nitro-lH-indol-3-yl) -oxo-acetyl and of the hydrochloride of the isopropyl ester of 2- (1,6-dimethyl) -lH-indol3-yl) -acetymidic. e) 3, 4-bis- (6-methoxy-l-methyl-lH-indol-3-yl) -pyrrol-2,5-dione, m.p. 258-260 ° C, is obtained from (6-methoxy-1-methyl-1H-indol-3-yl) -oxoacetyl chloride and isopropyl 2- (6-methoxy-1) isopropyl ester hydrochloride -methyl-lH-indol-3-yl) -acetymidic. f) 3- (6-Fluoro-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione , pf 270-272 ° C, is obtained from the (6-fluoro-methyl-lH-indol-3-yl) -oxo-acetyl chloride and the hydrochloride of the 2- (l-methyl-6-isopropyl) isopropyl ester. -nitro-lH-indol-3-yl) -acetymidic. g) 3, 4-bis- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2,5-dione, m.p. > 360 ° C, is obtained from the chloride of (l-methyl-6-nitro-lH-indol-3-yl) -oxo-acetyl and the hydrochloride of the isopropyl ester of 2- (l-methyl-6-nitro) -lH-indol-3-yl) -acetymidic. h) 3- (6-Fluoro-l-methyl-lH-indol-3-yl) -4- (6-methoxy-l-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione , pf 255-257 ° C, is obtained from (6-fluoro-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (6-methoxy-1-methoxy-1) isopropyl ester hydrochloride - methyl-lH-indol-3-yl) -acetymidic. i) 3- (6-Chloro-1-methyl-1H-indol-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) -pyrrole-2, 5-dione , pf 283-285 ° C, is obtained from the chloride of (6-chloro-l-methyl-lH-indol-3-yl) -oxo-acetyl and the hydrochloride of the isopropyl ester of 2- (6-methoxy-l) - methyl-lH-indol-3-yl) -acetymidic. j) methyl ester of l-methyl-3- [4- (l-methyl-6-nitro-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol- acid methyl ester 3-yl] -lH-indole-6-carboxylic, mp 294-296 ° C, is obtained from (l-methyl-6-methoxycarbonyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-6-isopropyl) isopropyl ester hydrochloride -nitro-lH-indol-3-yl) -acetymidic. k) l-Methyl-3- [4- (l-methyl-6-nitro-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -lH-indole-6-carbonitrile, Pf 253-255 ° C (decomp.). is obtained from (6-cyano-l-methyl-lH-indol-3-yl) -oxo-acetyl chloride and 2- (l-methyl-6-nitro-lH-indole isopropyl) isopropyl ester hydrochloride - 3-yl) -acetymidic. 1) 3- [4- (1, 6-dimethyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -l-methyl-lH -indol-6- carbonitrile, mp 310-312 ° C, is obtained from the chloride of (6-cyano-l-methyl-lH-indol-3-yl) -oxo-acetyl and the hydrochloride of the isopropyl ester of 2- (1,6-dimethyl) -lH-indol-3-yl) -acetymidic. m) 3- [4- (6-methoxy-lH-indol-3-yl) -2,5-dioxo-2,5-dihydro-l-pyrrol-3-yl] -l-methyl-indole-6 -carbonitrile, mp 261-263 ° C, is obtained from the (6- cyano-l-methyl-lH-indol-3-yl) -oxo-acetyl chloride and the hydrochloride of the 2- (6-methoxy-1) isopropyl ester -methyl-lH-indol-3-yl) -acetymidic. n) 3- (l-Methyl-6-methylsulfanyl-lH-indol-3-yl) -4- (1-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione , pf 273-275 ° C is prepared from (1- methyl-6-methylsulfanyl-1H-indol-3-yl) -oxo-acetyl chloride and acetimidic hydrochloride 2- (1-methyl-6-nitroyl) -indol-3-yl) -acetymidic. o) 3- (6-Bromo-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione , pf 319-321 ° C, is obtained from the chloride of (6-bromo-l-methyl-lH-indol-3-yl) -oxo-acetyl and of the hydrochloride of the isopropyl ester of 2- (l-methyl-6) -nitro-lH-indol-3-yl) -acetymidic. p) 3- (6-Iodo-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione , Pf 317-321 ° C, is obtained from the chloride of (6-iodo-l-methyl-lH-indol-3-yl) -oxo-acetyl and the hydrochloride of the isopropyl ester of 2- (l-methyl-6) -nitro-lH-indol-3-yl) -acetymidic. q) 3- (6-Azido-l-methyl-lH-indol-3-yl) -4- (6-methoxy-l-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione is obtained from the chloride of (6-azido-l-methyl-lH-indol-3'-yl) -oxo-acetyl and the hydrochloride of the isopropyl ester of 2- (6-methoxy-l-methyl-lH- indol-3-yl) -acetymidic. r) 3- (4-methoxy-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione , pf 290-292 ° C, is obtained from (4-methoxy-l-methyl-lH-indol-3-yl) -oxo-acetyl chloride and 2- (l-methyl-6-isopropyl) isopropyl ester hydrochloride -nitro-lH-indol-3-yl) -acetymidic. s) 3- (6-methoxy-l-methyl-lH-indol-3-yl) -4- (4-methoxy-l-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione , pf 270-273 ° C, is obtained from (4-methoxy-methyl-1H-indol-3-yl) -oxo-acetyl chloride and isopropyl 2- (6-methoxy-1) isopropyl ester hydrochloride - methyl-IH-indol-3-yl) -acetymidic. t) 3- (4-Fluoro-l-methyl-lH-indol-3-yl) -4- (6-methoxy-l-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione , pf 283-285 ° C, is obtained from (4-fluoro-methyl-lH-indol-3-yl) -oxo-acetyl chloride and the hydrochloride of 2- (6-methoxy-1) isopropyl ester - methyl-lH-indol-3-yl) -acetymidic. u) 3- (4-Fluoro-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione is obtained from (4-fluoro-l-methyl-lH-indol-3-yl) -oxo-acetyl chloride and 2- (l-methyl-6-nitro-lH-indole isopropyl) isopropyl ester hydrochloride - 3-yl) -acetymidic. v) 3- [4- (5-methoxy-l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -l-methyl -indol-6- carbonitrile pf 326-328 ° C, is obtained from the chloride of (6-cyano-l-methyl-lH-indol-3-yl) -oxo-acetyl and the hydrochloride of the isopropyl ester of 2- (5-methoxy-1) -methyl-lH-indol-3-yl) -acetimide. w) 3- (6-Chloro-1-methyl-1H-indol-3-yl) -4- (5-methoxy-1-methyl-1H-indol-3-yl) -pyrrole-2, 5-dione , pf 289-292 ° C, is obtained from the chloride of (6-chloro-l-methyl-lH-indol-3-yl) -oxo-acetyl and the hydrochloride of the isopropyl ester of 2- (5-methoxy-l) - methyl-lH-indol-3-yl) -acetymidic. x) 3- (5-Methoxy-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-methylsulfanyl-1H-indol-3-yl) -pyrrole-2, 5-dione , Pf 261-264 ° C, is obtained from (1- methyl-6-methylsulfanyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (5-methoxy-1-methoxy-1) isopropyl ester hydrochloride -methyl-lH-indol-3-yl) -acetymidic. y) 3- (6-Ethoxy-1-methyl-1H-indol-3-yl) -4- (5-methoxy-1-methyl-1H-indol-3-yl) -pyrrole-2, 5-dione , pf 229-232 ° C, is obtained from (6-ethoxy-l-methyl-lH-indol-3-yl) -oxo-acetyl chloride and 2- (5-methoxy-1-methoxy-1) isopropyl ester hydrochloride - methyl-lH-indol-3-yl) -acetymidic. z) 3- (1, 6-Dimethyl-lH-indol-3-yl) -4- (1, 5-dimethyl-lH-indol-3-yl) -pyrrole-2,5-dione, m.p. 248-250 ° C, is obtained from the (1-6-dimethyl-lH-indol-3-yl) -oxo-acetyl chloride and the hydrochloride of the 2- (1,5-dimethyl-lH) isopropyl ester -indol-3- il) -acetymidic. aa) 3- (5-Chloro-1-methyl-1H-indol-3-yl) -4- (1, 6-dimethyl-1H-indol-3-yl) -pyrrole-2,5-dione, m.p. 247-249 ° C, is obtained from the chloride of (5-chloro-l-methyl-lH-indol-3-yl) -oxo-acetyl and the hydrochloride of the isopropyl ester of 2- (1,6-dimethyl) -IH-indol-3-yl) -acetymidic. bb) 3- [4- (1, 6-dimethyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -1-methyl-1H -indo1-5-carbonitrile, mp 269-271 ° C, is obtained from the chloride of (5-cyano-l-methyl-lH-indol-3-yl) -oxo-acetyl and of the hydrochloride of the isopropyl ester of 2- (1,6-dimethyl) -lH-indol-3-yl) -acetymidic. ce) 3- (1, 5-Dimethyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione, m.p. 248-250 ° C, is obtained from (1,5-dimethyl-lH-indol-3-yl) -oxo-acetyl chloride and 2- (l-methyl-6-nitro) isopropyl ester hydrochloride -IH-indol3-yl) -acetymidic. dd) l-Methyl-3- [4- (l-methyl-6-nitro-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -lH-indole-5-carbonitrile, mp 257-260 ° C, is obtained from the chloride of (5-cyano-l-methyl-lH-indol-3-yl) -oxo-acetyl and the hydrochloride of the isopropyl ester of 2- (l-methyl-6) -nitro-lH-indol-3-yl) -acetymidic. ee) 3- (5-Chloro-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2, 5 diona, pf 301-303 ° C, is obtained from the chloride of (5-chloro-l-methyl-lH-indol-3-yl) -oxo-acetyl and the hydrochloride of the isopropyl ester of 2- (l-methyl-6) -nitro- "lH-indol-3-yl) -acetymidic. ff) 3- (l-Methyl-5-nitro-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione , pf 270 ° C, is obtained from the chloride of (l-methyl-5-nitro-l-indol-3-yl) -oxo-acetyl and the hydrochloride of the isopropyl ester of 2- (l-methyl-6-nitro) -lH- indol3-yl) -acetymidic. gg) 3- (5-methoxy-l-methyl-lH-indol-3-yl) -4- (4-methoxy-l-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione , pf 250-254 ° C, is obtained from (4-methoxy-methyl-1H-indol-3-yl) -oxo-acetyl chloride and isopropyl 2- (5-methoxy-1) isopropyl ester hydrochloride - methyl-lH-indol-3-yl) -acetymidic. hh) 3, 4-bis- (5-methoxy-l-methyl-lH-indol-3-yl) -pyrrol-2,5-dione, m.p. 236-238 ° C, is obtained from (5-methoxy-l-methyl-lH-indol-3-yl) -oxoacetyl chloride and 2- (5-methoxy-1-methoxy-1) isopropyl ester hydrochloride -methyl-lH-indol-3-yl) -acetymidic. ii) 3- (1, 5-Dimethyl-lH-indol-3-yl) -4- (5-methoxy-l-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione, m.p. 217-220 ° C, is obtained from (1,5-dimethyl-lH-indol-3-yl) oxo-acetyl chloride and the hydrochloride of the 2- (5-methoxy-1-methyl-) isopropyl ester lH-indol-3-yl) -acetymidic. jj) 3- (5-Chloro-l-methyl-lH-indol-3-yl) -4- (5-methoxy-l-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione , pf 245-248 ° C, is obtained from the chloride of (5-chloro-l-methyl-lH-indol-3-yl) -oxo-acetyl and the hydrochloride of the isopropyl ester of 2- (5-methoxy-l) - methyl-lH-indol-3-yl) -acetymidic. kk) 3- [4- (5-methoxy-l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -l-methyl -indol-5- carbonitrile, mp 252-255 ° C, is obtained from (5-cyano-l-methyl-lH-indol-3-yl) -oxo-acetyl chloride and 2- (5-methoxy-l-methyl-lH hydrochloride - indol-3-yl) -acetymidic. 11) 3- (l-Methyl-6-nitro-lH-indol-3-yl) -4- (l-methyl-7- nitro-lH-indol-3-yl) -pyrrole-2, 5-dione is prepared from (l-methyl-6-nitro-lH-indol-3-yl) -oxo-acetyl chloride and 2- (l-methyl-7-nitro-lH-indole isopropyl) isopropyl ester hydrochloride - 3-yl) -acetymidic. mm) 3- (6-Fluoro-l-methyl-lH-indol-3-yl) -4- (l-methyl-7- nitro-lH-indol-3-yl) -pyrrole-2, 5-dione it is obtained from (6-fluoro-l-methyl-lH-indol-3-yl) -oxo-acetyl chloride and 2- (l-methyl-7-nitro-lH-indole) isopropyl ester hydrochloride - 3-yl) -acetymidic. nn) 3- (1, 6-Dimethyl-lH-indol-3-yl) -4- (l-methyl-7-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione, m.p. 259-261 ° C, is obtained from the chloride of (l-methyl-7-nitro-lH-indol-3-yl) -oxo-acetyl and the hydrochloride of the isopropyl ester of 2- (1,6-dimethyl) -IH-indol-3-yl) -acetymidic. oo) 3- (4-Fluoro-l-methyl-lH-indol-3-yl) -4- (6-ethoxy-l-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione , pf > 280 ° C, is obtained from the chloride of (4-fluoro-l-methyl-lH-indol-3-yl) -oxo-acetyl and the hydrochloride of the isopropyl ester of 2- (6-ethoxy-l-methyl) - lH-indol-3-yl) -acetymidic. pp) 3- (4-Bromo-l-methyl-lH-indol-3-yl) -4- (6-ethoxy-l-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione , pf > 266 ° C, is obtained from the chloride of (4-bromo-l-methyl-lH-indol-3-yl) -oxo-acetyl and the hydrochloride of the 2- (6-ethoxy-l-methyl) isopropyl ester -lH- indol-3-yl) -acetymidic. qq) 3- (6-Ethoxy-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2, 5-dione , pf 260 ° C, is obtained from (l-methyl-6-nitro-l-indol-3-yl) -oxo-acetyl chloride and 2- (6-ethoxy-l-methyl) isopropyl ester hydrochloride -lH- indol-3-yl) -acetymidic. rr) The 3-. { 6- [2- (2-Ethoxy-ethoxy) -ethoxyl-1-methyl-1H-indol-3-yl} -4- (1-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione, m.p. 124 ° C, is obtained from the chloride of. { 6- [2- (2-ethoxy-ethoxy) -ethoxy-1-methyl-1H-indol-3-yl} -oxo-acetyl and the hydrochloride of the isopropyl ester of 2- (l-methyl-6-nitro-lH-indol-3-yl) -acetimidic acid. ss) The N-. { l-methyl-3- [4- (l-methyl-6-nitro-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -lH- indole-3- il} -acetamide is obtained from (6- acetylamino-l-methyl-lH-indor-3-yl) -oxo-acetyl chloride and 2- (l-methyl-6-nitro-lH) isopropyl ester hydrochloride -indol-3-yl) -acetymidic.

EXAMPLE 3 3- (l-Methyl-6-methylsulfanyl-lH-indol-3-yl) -4- (l-methyl-6-. Nitro-lH-indol-3-yl) -pyrrole-2, 5-dione a) To a solution of sodium methoxide, prepared from Na metal (8.65 g, 0.38 M) in methanol (200 ml) between 0 and 5 ° C, a solution of 4- (methylthio) -benzaldehyde (12.6 ml) is added. , 94.7 mM) and methyl azidoacetate (44 g, 0.382 M) in methane! (30 ml). Stir at the same temperature for 3 hours, then dilute the suspension with H2O (300 ml). The solids are filtered, washed with water and dried with vacuum, obtaining 19.4 g (82.0%) of the methyl 2-azido-3- (4-methylthio-phenyl) -propenoate, in the form of a yellow solid. A solution of methyl 2-azido-3- (4-methylthiophenyl) -propenoate (20.6 g, 83 mM) in xylene (200 ml) is added dropwise over boiling xylene (250 ml) over a period of 2 hours.

The reaction mixture is kept at the reflux temperature for a further 2 hours, then slowly cooled and placed in a 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-sulphanyl-1H-indol-2-carboxylate (11.2 g, 51 mM) and 2N NaOH (125 ml) is heated at reflux temperature for 30 minutes. The clear solution is cooled and extracted with EtOAc. The aqueous fraction is acidified with HCl to pH = 1 and the precipitate that forms is filtered and dried to yield 6-methylsulfanyl-1H-indole-2-carboxylic acid (9.6 g, 91.0%).

A mixture of 6-methylsulfanyl-1H-indole-2-carboxylic acid (9.6 g, 46 moles), Cu powder (2.1 g, 33 mM) and quinoline (100 ml) is heated at 215 ° C for 3 hours. The mixture is cooled to room temperature, filtered over celite and the filtrate is diluted with H 2 O (500 ml). The cold mixture is acidified with concentrated HCl (pH = 1) 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 obtain 6-methylsulfanyl-1H-indole (6.8 g, 90%) after purification by chromatography on Flash column.

In a similar manner to example lf), 2- (1-methyl-6-nitro-1H-indol-3-yl) -acetimidic acid isopropyl ester hydrochloride is prepared from (l-methyl-6-nitro-lH-indol-3-yl) -acetonitrile. c) Similarly to example lg), 3- (l-methyl-6-methylsulfanyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3 is prepared il) -pyrrole-2, 5-dione, mp 273-275 ° C, from (l-methyl-6-methylsulfanyl-1H-indol-3-yl) -oxo-acetyl chloride and 2- (1-methyl-6-nitro) isopropyl ester hydrochloride -lH-indol-3-yl) -acetymidic.

EXAMPLE 4 3, 4-bis- (6-methoxy-l-methyl-indol-3-yl) -pyrrole-2, 5-dione a) A solution of CH3MgI (15 mM, in Et2?) is treated with a solution of 6-methoxy-lH-indole (2.21 g, 15 mM) in toluene (20 ml). This suspension is stirred at room temperature for 3.5 hours and a solution of 3,4-dichloro-1-methylmaleimide (1.2 g, 6.5 mM) in toluene (20 ml) is added dropwise. Heat to reflux temperature and hold for 2 hours, cool the mixture to room temperature and treat with NaH (26 mM). The mixture is heated at reflux temperature for 15 hours, the mixture is poured into a solution of 20% citric acid in water and extracted with EtOAc (100 ml. 3 times) . The organic fractions are washed with H2O, with a saturated solution of NaCl and dried over MgSO4. They are filtered, the solvent is evaporated, the residue is purified by flash column chromatography and 3,4-bis- (6-methoxy-1H-indol-3-yl) -1-methylmaleimide (3.65 g, 70%) is obtained. ). b) A solution of 3,4-bis- (6-methoxy-lH-indol-3-yl) -1-methylmaleimide (0.97 g, 24 mMol) and N-methyl pyrrolidinone (25 ml) is treated with K2C03 (5.8) g, 42 mMoles) and CH3I (2.13 g, 15 mM). The mixture is stirred for 15 hours, the volatile liquids are removed and the product is precipitated by the addition of H20 (50 ml), collected and washed with H20 (20 ml) and hexane (10 ml) to yield the 3,4-bis. - (6-methoxy-l-methyl-indol-3-yl) -1-methylmaleimide (1 g, 96%). c) Treat a suspension of 3,4-bis- (6-methoxy-1-methyl-indol-3-yl) -1-methylmaleimide (0.96 g, 2.23 mM) in ethanol (30 ml) with 5N KOH (30 ml). ml) and heated to reflux temperature until thin layer chromatography indicates the disappearance of the starting material (approximately 22 hours). The majority of the ethanol is removed, the pH of the solution is adjusted to 2 by the addition of 2N HCl. The solids are collected from the filtrations and washed with H2O. This material (0.92 g) in DMF (16 ml) is treated with a pre-mixed solution of 1,1,1,3,3,3-hexamethyldisilazane (4 g, 25 mM) and CH 3 OH (4 g, 12.5 mMoles). The solution is stirred for 15 hours at room temperature, H20 (20 ml) is added and the precipitated solids are collected by filtration and washed with H20, providing 3,4-bis- (6-methoxy-1-methyl-indole). 3-yl) -pyrrole-2, 5-dione, mp > 350 ° C.

EXAMPLE 5 The following three procedures illustrate the methodology for reducing nitro-bis-indolmaleimides to amino bis-indolmaleimides. a) 3- [4- (6-amino-1-methyl-1H-indol-3-yl) -2,5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl] -l-methyl- lH-Indole-6-carbonitrile The 3- (6-cyano-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) - is suspended. pyrrole-2, 5-dione (9.0 g, 21 mM) in ethanol (1.8 1) and treated with tin chloride (II) dihydrate (35 g, 156 mM). It is stirred mechanically at reflux temperature for 16 h. The reaction mixture is cooled and reduced to the volume of 1 liter.

- This is poured over a mixture of ethyl acetate (2 liters) and a saturated solution of sodium bicarbonate (1 liter) and mix well. The organic phase is decanted and washed with a saturated solution of sodium bicarbonate, dried over magnesium sulfate, filtered, concentrated by evaporation and further purified by crystallization from tetrahydrofuran / hexane to yield 6. 5 g of 3- [4- (6-amino-1-methyl-1H-indol-3-yl) -2,5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl] -l-methyl -lH-indole-6-carbonitrile; p.f. 255-260 ° C. b) 3, 4-bis- (6-amino-lH-indol-3-yl) -pyrrole-2, 5-dione. 3,4-bis- (l-methyl-6-nitro-lH-indole) is dissolved. 3-yl) -pyrrole-2, 5-dione (50 mg, 0.11 mM), prepared according to Example 29, in N, N-dimethylformamide (10 ml), a catalytic amount of activated Raney nickel is added and stirred the reaction mixture in a Parr hydrogenator at 45 psi for 20 hours. The reaction mixture was filtered through a pad of celite with ethyl acetate and concentrated. The product is purified by recrystallization from acetone and hexane to give 3, 4-bis- (1-methyl-6-amino-1H-indol-3-yl) -pyrrole-2, 5-dione (35 mg). c) 3- (6-amino-l-methyl-lH-indol-3-yl) -4- (6-fluoro-1-methyl- - lH-indol-3-yl) -pyrrole-2, 5- dione To a suspension of 1.0 g (2.39 mMoles) of 3- (6-fluoro-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indole-3-yl ) -pyrrole-2, 5-dione in 20 ml of ethanol and 10 ml of tetrahydrofuran is added 0.55 g of 10% Pd / C and 0. 54 ml of 5% hydrochloric acid. The mixture is cooled in an ice bath and added by dripping for 5 min. 0.54 ml (14.34 mmoles) of hydrazine hydrate (85%). The reaction mixture is allowed to return to room temperature while stirring for two hours. The catalyst is removed by filtration over Celite. The filtrate is concentrated by evaporation and the residue is crystallized from ethyl acetate / tetrahydrofuran to yield 708 mg (76%) of 3- (6-amino-1-methyl-1H-indol-3-yl) -4- (6-fluoro-1-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione.

EXAMPLE 6 Following the general procedure described in Example 5, the following compounds are synthesized: a) 3- (6-amino-l-methyl-lH-indol-3-yl) -4- (6-chloro-l-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione is obtained from 3- (6-chloro-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione using the - -procedure c) of Example 5. b) 3- (6-amino-l-methyl-lH-indol-3-yl) -4- (6-bromo-1-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione it is obtained from 3- (6-bromo-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione using procedure a) of Example 5. c) 3- [4- (6-Amino-l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] methyl ester -1-methyl-lH-indole-6-carboxylic acid is prepared from 3- [4- (l-methyl-6-nitro-lH-indol-3-yl) -2,5-dioxo- acid methyl ester 2,5-dihydro-lH-pyrrol-3-yl] -1-methyl-lH-indole-6-carboxylic acid using procedure a) of Example 5. d) 3- (6-amino-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-methylsulfanyl-lH-indol-3-yl) -pyrrole-2, 5-dione is obtained from 3- (1-methyl-6-methylsulfanyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2, 5-dione using procedure a) of Example 5. e) The 3- (6-amino-1-methyl-1H-indol-3-yl) -4- (1, 6-dimethyl-1H-indol-3-yl) -pyrrole-2, 5-dione is obtained from 3- (1, 6-dimethyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione using procedure c) of Example 5. f) 3- (6-amino-l-methyl-lH-indol-3-yl) -4- (6-methoxy-l-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione is obtained from 3- (6-methoxy-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione using procedure b) of Example 5.

EXAMPLE 7 General procedure for obtaining amino-bis-indolylmaleimide hydrochloride salts: 3- (6-Amino-l-methyl-lH-indol-3-yl) -4- (6-fluoro-l-methyl-lH-indol-3-yl) -pyrrole-2, 5- hydrochloride salt dione To a mixture of 75 mg (0.193 M) of 3- (6-amino-l-methyl-lH-indol-3-yl) -4- (6-fluoro-l-methyl-lH-indol-3-yl ) -pyrrole-2, 5-dione in 2 ml of acetonitrile is added 10 ml of water, precipitating a solid. To this mixture 0.64 ml (0.772 mM) of 1.2 M hydrochloric acid are added, forming a clear solution. After 10 min. The mixture is concentrated to dryness. The residue is dissolved in 4 ml of water and lyophilized overnight to give 80 mg (97%) of the hydrochloride salt of 3- (6-amino-1-methyl-1H-indol-3-yl) -4 - (6-fluoro-1-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione. Similarly, the hydrochloride salts of other amines are prepared.

EXAMPLE 8 3- (6-Amino-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione a) 5.29 g of l-methyl-6-nitroindole and 7.5 g of 10% Pd / C in 400 ml of ethanol are treated at 0 ° C with 30 ml of 2N hydrochloric acid and 2.04 ml of 85% hydrazine hydrate . It is stirred at room temperature and treated in portions with 1 ml of hydrazine hydrate. The mixture is filtered through a pad of celite and washed with ethanol. The filtered liquid is concentrated to 50 ml and cooled to 0 ° C for 1 hour. The crystals of hydrazine hydrochloride are filtered in the form of fine needles. The filtered liquid is concentrated to 25 ml, it is refrigerated and filtered to eliminate more secondary product. The filtered liquid is treated in portions with cold 6N hydrochloric acid and concentrated to 25 ml, cooled and crystals of bronze-colored product are collected. The filtered liquid is again concentrated to 10 ml and treated again with cold 6N hydrochloric acid, concentrated and redissolved in 5 ml of ethanol and hexane to continue the crystallization of the product. The bronze-colored crystals are collected and the overall yield was 2.80 g of 6-amino-1-methylindol hydrochloride. b) 2.5 g of 6-amino-1-methylindole hydrochloride are collected in 30 ml of dry pyridine and treated with 1.93 ml of trifluoroacetic anhydride at 0 ° C. It is stored in the refrigerant overnight. Collect in cold water and extract with ethyl acetate and wash with cold 5% phosphoric acid and 5% brine. The organic extracts are dried over magnesium sulfate and the concentrated crude product is purified by flash column chromatography on silica gel. The product is crystallized from methylene chloride / hexane to yield 1.1 g of 1-methyl-6-trifluoroacetylaminoindole. c) Collect 200 mg of l-methyl-6-trifluoroacetylaminoindole in 5 ml of ether and cool to 0 ° C. They are treated with 0.485 ml of oxalyl chloride 2. OM / methylene dichloride and stirred at 0 ° C for 2 h. The yellow crystals are collected and washed with ether and dried under vacuum to yield 240 mg of (6-trifluoroacetylamino-l-methyl-lH-i-ndol-3-yl) -oxoacetyl chloride. d) 240 mg of (6-trifluoroacetylamino-1-methyl-1H-indol-3-yl) -oxo-acetyl chloride and 181 mg of isopropyl ester hydrochloride are stirred in methylene chloride at 0 ° C for 2 hours. 2- (l-Methyl-6-nitro-lH-indol-3-yl) -acetymidic acid together with 494 mg of triethylamine, then at room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with 0.5N hydrochloric acid and with 5% brine.

It is again extracted with methylene chloride and the organic extracts are filtered through magnesium sulfate and concentrated. The crude residue is taken up in methylene chloride and treated at room temperature with 244 mg of p-toluenesulfonic acid for 5 hours. It is diluted with methylene chloride and a few drops of methanol are added to solubilize. It is washed with a 10% sodium bicarbonate solution and with water and reextracted with methylene chloride. The organic extracts are dried over magnesium sulfate and concentrated. The raw material is still purified by preparative LC (20% ethyl acetate in methylene chloride) to yield 48 mg of N-. { l-methyl-3- [4- (l-methyl-6-nitro-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -1H- indole-3-il} -trifluoracetamide in the form of a red-orange solid. e) 120 mg of N- are collected. { l-methyl-3- [4- (l-methyl-6-nitro-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -lH- indole-3-il} -trifluoracetamide in 8 ml of water / methanol (1/1), treated with 240 mg of potassium carbonate and heated to 450 ° C, maintained at this temperature for 5 hours. It is cooled to room temperature, taken up in methylene chloride, washed with water and extracted again with methylene chloride. The organic extracts are dried over magnesium sulfate, filtered and concentrated to near dryness. 25 ml of acetonitrile are added and concentrated to 5 ml, diluted with 25 ml of acetonitrile / water (1/1) and acidified with 0.25 ml of 1.0N hydrochloric acid. Concentrate to remove the acetonitrile and lyophilize to yield 50 mg of 3- (6-amino-1-methyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3 -yl) -pyrrole-2, 5-dione as an orange-red solid.

EXAMPLE 9 N-. { l-Methyl-3- [4- (l-methyl-6-nitro-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -lH- indole-3-il} -acetamide The (6-acetylamino-l-methyl-lH-indol-3-yl) -oxo-acetyl chloride is prepared from 6-amino-1-methyl-1H-indole using procedures similar to those described in Example 8b) and c). This chloride becomes the N-. { l-methyl-3- [4- (l-methyl-6-nitro-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -lH- indole-3-il} -acetamide applying a procedure similar to that described in Example 8d).

EXAMPLE 10 3- (6-Amino-l-methyl-lH-indol-3-yl) -4- (6- [4-azido-3-iodo-phenyl) -2-oxo-butyl] -l-methyl- lH-indol-3-yl) -pyrrole-2, 5-dione 3, 4-bis- (l-methyl-6-amino-lH-indol-3-yl) -pyrrole-2, 5-dione is dissolved (40 mg, 0.1 mM) in tetrahydrofuran (3 ml) and cooled to 0 ° C. 3- (4-Azido-3-iodo-phenyl) -propionic acid (29.6 mg, 0.09 mM) and then N-hydroxybenzotriazole (16 mg, 0.1 mmM) and diisopropylcarbodiimide (16 μl, 0.1 mM) are added. The reaction mixture was stirred at 0 ° C for 5 hours, then it was concentrated and purified by column chromatography, using 3% methanol in methylene chloride as eluent to obtain 3- (6-amino-1-methyl-1H). -indol-3-yl) -4- (6- [4-azido-3-iodo-phenyl) -2-oxo-butyl] -1-methyl-lH-indol-3-yl) -pyrrole-2, 5 -dione (18.7 mg, 29%).

EXAMPLE 11 In a manner similar to that described in Example 10, the following compounds are synthesized: a) 3- (6-Fluoro-l-methyl-lH-indol-3-yl) -4- (6- [4-azido-3-iodo-phenyl) -2-oxo-butyl] -l-methyl -lH-indol-3-yl) -pyrrole-2,5-dione is obtained from 3- (6-fluoro-1-methyl-lH-indol-3-yl) -4- (l-methyl- 6-amino-lH-indol-3-yl) -pyrrole-2, 5-dione. b) 3- (6-methoxy-l-methyl-lH-indol-3-yl) -4- (6- [4-azido-3-iodo-phenyl) -2-oxo-butyl] -l-methyl -lH-indol-3-yl) -pyrrole-2,5-dione is obtained from 3- (6-methoxy-l-methyl-lH-indol-3-yl) -4- (l-methyl- 6-amino-lH-indol-3-yl) -pyrrole-2,5-dione.

The N-. { 3- [4- (6-formylamino-l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -1-methyl-lH- indole-6-il} -formamide is obtained from 3,4-bis- (1-methyl-6-amino-1H-indol-3-yl) -pyrrole-2, 5-dione and formic acid. d) The N-. { 3- [4- (6-methoxy-l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] .- l-methyl-lH -indol-6-il} -formamide is obtained from 3- (6-methoxy-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-amino-lH-indol-3-yl) -pyrrole-2, 5-dione and formic acid.

EXAMPLE 12 N-. { 3- [4- (6-Acetylamino-l-methyl-lH-indol-3-yl) -2,5-dioxo-2,5-dihydro-lH-pyrrol-3-yl] -l-methyl-lH- indole-6-il} -acetamide 3, 4-bis- (1-methyl-6-amino-1H-indol-3-yl) -pyrrole-2, 5-dione (50 mg, 0.13 mmol) is dissolved in tetrahydrofuran (2.5 ml) and it is cooled to 0 ° C. Triethylamine (38.5 μL, 0.27 mM) and then acetyl chloride (19.4 μL, 0.27 mM) are added. The reaction mixture was stirred for 30 min, then concentrated. The reaction mixture was dissolved in chloroform, washed with 0.1N hydrochloric acid and the organic layer was dried over magnesium sulfate, filtered and concentrated. The product is purified by column chromatography, using as eluent 5% methanol in ethyl acetate, to yield the N-. { 3- [4- (6-acetylamino-l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -1-methyl-lH- indole-6-il} -acetamide (14 mg, 23%).

EXAMPLE 13 N-. { 3- [4- (6-Methoxy-l-methyl-lH-indo-l-3-yl) -2,5-dioxo-2,5-dihydro-lH-pyrrol-3-yl] -1-methy1- 1H-indol-6-yl} -acetamide In a manner similar to that described in Example 12, the N-. { 3- [4- (6-methoxy-l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -l-methyl-lH- indole-6-il} -acetamide is obtained from 3- (6-methoxy-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-amino-lH-indol-3-yl) -pyrrol- 2,5-dione.

EXAMPLE 14 3- (6-Methoxy-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-methyl-amino-lH-indol-3-yl) -pyrrole-2, 5- diona a) 6-aminoindole is prepared from 6-nitroindole in a manner similar to that described in Example 5b. b) N-methyl- (1-methyl-1H-indol-6-yl) -amine is synthesized from 6-amino-indole in a manner similar to that described in Example la. c) Methyl- (1-methyl-1H-indol-6-yl) amine (50 mg, 0.31 mM) is dissolved in methylene chloride (2 ml) and cooled to 0 ° C. Triethylamine (55 μl, 0.39 mM) and then benzyl chloroformate (52 μl, 0.39 mM) are added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was washed with 0.1 N hydrochloric acid and the organic phase was dried over magnesium sulfate, filtered and concentrated. The product is purified by column chromatography using 25% ethyl acetate in hexane as eluent to yield the methyl- (1-methyl-1H-indol-6-yl) -carbamic acid benzyl ester (67 mg, 73%). . d) The (3-chloroxalyl-1-methyl-1H-indol-6-yl) -methyl-carbamic acid benzyl ester is prepared from the benzyl ester of methyl- (1-methyl-1H-indol-6) il) -carbamic by a procedure similar to that described in Example Ib. e) The hydrochloride of 2- (6-methoxy-1-methyl-1H-indol-3-yl) -acetylimidic acid isopropyl ester, synthesized according to Example lf, and the benzyl ester of the acid (3- chlorocarbonocarbonyl-l-methyl-lH-indol-6-yl) -methylcarbamic acid in a similar manner to that described in example lg to obtain the benzyl ester of the acid. { 3- [4- (6-methoxy-l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -l-methyl-lH- indole-6-il} -methyl-carbamic. f) The benzyl ester of the acid is dissolved. { 3- [4- (6-methoxy-l-methyl-lH-indol-3-yl) -2,5-dioxo-2, 5-dihydro-lH-pyrrol-3-yl] -1-methyl-lH- indole-6-il} -methylcarbamic acid (26 mg, 0.048 mM) in toluene (4 ml). Pd / C (10 mg at 10%, 0.009 mM) is added and the reaction mixture is stirred in a Parr Hydrogenator at 50 psi for 13 h. The crude reaction mixture is filtered through a pad of celite and concentrated to obtain 3- (6-methoxy-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-methylamino -IH-indol-3-yl) -pyrrole-2, 5-dione (16 mg, 8%).

EXAMPLE 15 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 ground in a suitable mill. 5. Element 5 is added to the ground granulate in Step 4 and mixed for 3 minutes. 6. The granulate of Step 5 is pressed in a suitable press.

EXAMPLE 16 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 17 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 has; ta complfstar 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 μm filter and packed in vials.

EXAMPLE 18 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 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. 4. It is filtered under sterile conditions through a 0.2 μm 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)

1. A compound of the formula characterized because R1 and R1 are independently alkyl R6 amino, acylamino, monoalkylamino or dialkylamino and O II R6 is CH2OCR8, C02R9, CH2OR10, CHO, CH2NRHR12, CON (R13) 2, halogen, cyano, aryl, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, aralkyloxy, acylamino, monoalkylamino, dialkylamino, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, azide, phosphate or phosphonate, R8 is alkyl or aryl; R9 is alkyl or aryl; R is hydrogen, alkyl or aryl; Ru and R 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. A compound according to claim 1, characterized in that R6 is alkoxy, halogen, cyano, alkylthio, alkyl, nitro or acylamino.

3. A compound according to claim 1, characterized in that X and Y are both O.

4. The compound according to claim 1, characterized in that it is 3- (6-amino-l-methyl-lH-indol-3-yl) -4- (6-fluoro-l-methyl-lH-indol-3- il) -pyrrole-2, 5-dione.

5. The compound according to claim 1, characterized in that it is 3- (6-amino-l-methyl-lH-indol-3-yl) -4- (6-bromo-l-methyl-lH-indindo-3) -yl) -pyrrole-2, 5-dione.

6. The compound according to claim 1, characterized in that it is 3- (6-amino-l-methyl-lH-indol-3-yl) -4- (6-methoxy-l-methyl-lH-indol-3- il) -pyrrole-2, 5-dione.

7. The compound according to claim 1, characterized in that it is 3- (6-amino-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indole-3-) il) -pyrrole-2, 5-dione.

8. The compound according to claim 1, characterized in that it is 3- [4- (6-amino-1-methyl-1H-indol-3-yl) -2,5-dioxo-2, 5-dihydro-1H- pyrrol-3-yl) -l-methyl-lH-indole-6-carbonitrile.

9. The compound according to claim 1, characterized in that it is 3- (6-methoxy-1-methyl-1H-indol-3-yl) -4- (1, 6-dimethyl-1H-indol-3-yl) -pyrrole-2, 5-dione.

10. The compound according to claim 1, characterized in that it is 3- (6-benzyloxy-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indole-3 -yl) -pyrrole-2, 5-dione.

11. The compound according to claim 1, characterized in that it is 3- (6-chloro-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indole-3-) il) -pyrrole-2, 5-dione.

12. The compound according to claim 1, characterized in that it is 3- (1,6-dimethyl-lH-indol-3-yl) -4- (6-methoxy-l-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione.

13. The compound according to claim 1, characterized in that it is 3- (1,6-dimethyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione.

14. The compound according to claim 1, characterized in that it is 3, 4-bis- (6-methoxy-l-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione.

15. The compound according to claim 1, characterized in that it is 3- (6-fluoro-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indole-3-) il) -pyrrole-2, 5-dione.

16. The compound according to claim 1, characterized in that it is 3, 4-bis- (1-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione.

17. The compound according to claim 1, characterized in that it is 3- (6-amino-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-methylsulfanyl-lH-indole-3- il) -pyrrole-2, 5-dione.

18. The compound according to claim 1, characterized in that it is 3- (6-amino-1-methyl-1H-indol-3-yl) -4- (1, 6-dimethyl-1H-indol-3-yl) -pyrrole-2, 5-dione.

19. The compound according to claim 1, characterized in that it is the N-. { 3- [4- (6-methoxy-l-methylthyl-indol-3-yl) -2,5-dioxo-2,5-dihydro-lH-pyrrol-3-yl] -1-methyl-1H-indole 6-i-1} -acetamide.

20. The compound according to claim 1, characterized in that it is 3- (6-methoxy-l-methyl-lH-indol-3-yl) -4- (l-methyl-6-methyl-amino-lH-indole- 3-yl) -pyrrole-2, 5-dione.

21. The compound according to claim 1, characterized in that it is 3- [4- (1,6-dimethyl-lH-indol-3-yl) -2,5-dioxo-2,5-dihydro-lH-pyrrol- 3-yl] -l-methyl-lH-indole-6-carbonitrile.

22. The compound according to claim 1, characterized in that it is 3- (l-methyl-6-methylsulfanyl-lH-indol-3-yl) -4- (l-methyl-6-nitro-lH-indole-3-) il) -pyrrole-2, 5-dione.

23. The compound according to claim 1, characterized in that it is 3-. { 6- [2- (2-Ethoxy-ethoxy) -ethoxy] -l-methyl-lH-indol-3-yl} -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2, 5-dione.

24. 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.

25. The use of a compound, as claimed in any of claims 1-23, for the inhibition of cell proliferation or for the preparation of the corresponding medicaments. SUMMARY 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; R and R are independently hydrogen or alkyl; R, R, R6, R7, R4, R, R6 and R7 each independently O II are hydrogen, CH2OCR8, C02R9, CH2OR10, CHO, CH2NRpR12, CON (R13) 2; halogen, cyano, aryl, aralkyloxy, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, aralkyloxy, acylamino, monoalkylamino, dialkylamino, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, azide, phosphate or phosphonate, with the proviso that at least one of R4, R5, R6 and R7 and at least one of R, R5, R6 and R7 is. other than hydrogen; R8 is alkyl or aryl; R9 is alkyl or aryl; R10 is hydrogen, alkyl or aryl; R1 and R 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.