MXPA00008923A - Substituted bisindolymaleimides for the inhibition of cell proliferation - Google Patents

Abstract

Substituted pyrroles of formula (I) wherein R1 is hydrogen and R2 is methyl or R1 is methyl and R2 is hydrogen or R1 is hydroxymethyl and R2 is methyl as well as pharmaceutically acceptable prodrugs or pharmaceutically acceptable salts thereof are antiproliferative agents useful in the treatment of cancer.

Description

BISINDOLIMALEIMIDAS SUBSTITUIDAS FOR THE INHIBITION OF CELL PROLIFERATION.

FIELD OF THE INVENTION The present invention relates to pyrrole: substituted of formula: wherein R ~ is hydrogen and R ~ is methyl or R "is methyl and R" is hydrogen or R "is hydroxymethyl and R" is methyl as well as pharmaceutically acceptable precursors or pharmaceutically acceptable salts thereof.

The compounds of formula I possess anriprol i ferat i va activity; specifically and inhibit REF. : 122706 division of the G2 / M phase of the cell cycle and are referred to as inhibitors of "G2 / M phase of the cell cycle".

- The compounds of formula I are protected by formula I of U.S.F. 5,057,614, without being specifically described as a group or individually. Additionally, the aforementioned activity of the compounds of the present invention has not been described anywhere or evidenced as obvious in U.S.F. 5,057,614, and therefore-- it is surprising.

Formula I above comprises the following three compounds: The term "pharmaceutically acceptable prodrugs" means a compound that can be converted to physiological conditions or by solvolysis in any of the compounds of formula I or in a pharmaceutically acceptable salt of said compounds.

The compounds of Formula I, as well as the pharmaceutically acceptable salts of said compounds, are prepared by reactions depicted in the following Schemes. The synthesis of each of these compounds is also described in Examples 1-3.

Compound 1-1 can be prepared by reacting (l-methyl-6-ni tro-lH-indol-3-yl) -oxo-acetyl (3") chloride with 1-methyl-ethyl-ethyl acid hydrochloride ter [ 1- (2, 2-dimethyl-propionyl) -lH-indol-3-yl] -3-ethanimidic acid (7) and treating the reaction product with a base.

Compound 1-2 can be prepared by reacting (1-methyl-1H-indol-3-yl) -oxo-acetyl chloride (17) with 1-methyl-ethyl ester hydrochloride [1- (2, 2- dimethyl-propionyl) -6-nitro-lH-indol-3-ii] -3-ethanimidic acid (19) and treating the reaction product with a base.

Compound 1-3 can be prepared by reacting (1-methoxymethyl-1H-indol-3-yl) -oxo-acetyl chloride (10) with 1-methyl ester hydrochloride of (1-methyl-6-yl) -IH-indol-3-yl) -3-ethanimide (15) and treating the reaction product with an acid.

SCHEME 1 SCHEME 2 SCHEME 3 The antiproliferative activity of the compounds of the invention is demonstrated below: These effects indicate that the compounds are useful in the treatment of cancer, particularly in solid tumors.

The negative epithelial breast carcinoma line for the estrogen receptor (MDA-MB-435) was purchased from the American Type Cell Culture Collec- tion (ATCC, Rockville, MD), and grown in the medium recommended by the ATCC. For the analysis of the effect of the compounds tested on the growth of said cells, the cells were plated at 2000 cells per well in a 96-well culture plate ("test plate"), and incubated overnight 37 ° C with C 0Z 5% The following day, the tested compounds were dissolved in dimethylsulfoxide (DM50) aL_ 1001 to yield a stock solution of 10 mM Each compound was diluted with sterile distilled water to 1 mM "and then added to wells in triplicate of a 96-well "master plate" containing medium in an amount sufficient to yield a final concentration of 40-μM. The compounds were serially diluted in the middle in the "master plate". A final volume of one quarter of the diluted compounds was transferred to "test plates" in duplicate. DMSO was added to a row of "control cells" so that the final concentration of DMSO in each well was 0.1%. The "test plates" were returned to the incubator and 3 days after. The addition of the test compound was tested on a "test plate" as described below. Similarly, 5 days after the addition of the test compound, the second "test plate" was also analyzed as described below.3- (4,5-Dimethyl-thiazol-2-yl) -2,5-di-phenyl-2H-t-tetrazolium bromide (thiazolyl blue, MTT) was added to each well to yield a final concentration of 1 mg / ml. The plate was then incubated at 37 ° C for 3 hours. The medium containing MTT was removed and 50 μl of 100% ethanol was added to each well to dissolve the resulting formazan metabolite. To ensure complete dissolution, the plates were shaken for 15 minutes at room temperature. The absorbances were read in a microtiter plate reader (Molecular Dynamics) at a wavelength of 570 nm with a reference of 650 nm. Percent inhibition was calculated by subtracting the blank from all wells, and then subtracting the average absorbance division given each test triplicate by the average of the 1.00 controls. The inhibitory concentrations (IC50 and CI90) were determined by linear regression from a graphical representation of the logarithm of the concentration with respect to percent inhibition.

The S 480 colon adenocarcinoma line and the HCT-116 colon carcinoma line from the ATCC were also obtained and tested according to the same protocol provided above with the following modifications. The S 480 cell line was plated at 1000 cells per well and analyzed 6 days after the addition of the test compound. The HCT-116 line was plated at 750 cells per well and analyzed at 4 days after the addition of the test compound. For the MIT analysis, the plates were centrifuged at 1000 rpm for 5 minutes before aspiration of the medium containing MTT, and 100 μl of 100% ethanol was used to dissolve the formazan. The results of the aforementioned in vitro tests are described in Tables I-III below.

TABLE I Antiproliferative Activity in the Cell Line MDA-MB-435 * An average of at least three separate experiments.

TABLE II Antiproliferative Activity on the HCT-116 Cell Line * An average of at least three separate experiments.

TABLE YOUR ACTIVITY Anriprol Activity on the S 480 Cell Line * An average of at least three separate experiments.

For the analysis of the effect of the compounds on La. cell cycle progression, MDA-MB-435 cells (ATCC, Rockville, MD) were plated at 1 x 10d cells / 10 ml per 10 cm plate in the following growth medium: RPMI 1640 + heat-inactivated fetal bovine serum 10%, 2 mM L-glutamine and 50 U / ml pen-strep (all from GIBCO / BRL, Gaithersburg, MD). The cells were incubated overnight at _37nC with CO_5%. The next day, 10 μl of each of the compounds to be tested was added to the individual plates in a 100% DMSO solution to obtain a final stock concentration of 1 / lOOOx. Additionally, 10 μl of 100% DMSO was added to a control plate. - The final concentration of DMSO in all the plates, including the control, was 0.1%. The plates were returned to the incubator.

Then, at certain temporary moments, the medium of each plate was transferred to a 50 ml centrifuge tube. The cell layer that remained on the plate was then washed with 5 ml of phosphate buffered saline (PBS, GIBCO / BRL). The PBS was removed and combined with the medium in the appropriate tube. The cells were trypsinized for 5 min at 37 ° C, and the solution was collected and combined with the medium and PBS in the appropriate tubes. The tubes were then centrifuged for 5 minutes at 1200 rpm.The cells were fixed by removing the supernatant, tapping the tube to dislodge the pellet, and then adding 5 ml of 70% cold ethanol, while stirring gently. they were then stored at -20 C for> 24 hours.

The tubes containing the cells were removed from the freezer and left at room temperature for 20 to 30 minutes. The tubes were then centrifuged at 3000 rpm for 5 minutes. The supernatant was removed, the pellets were washed with 5 ml of PBS and the tubes were centrifuged as above. The supernatant was then removed and the pellet suspended in 0.5 ml of PBS. Then 0.5 ml of RNAse A (1 mg / ml in PBS) was added to each tube, and the tubes were incubated at 37 ° C for 15 minutes. 100 μl of propidinium iodide (Sigma, St. Louis, MO) (1 mg / ml in 15 PBS) was added to each tube, and the tubes were then incubated at room temperature for 2 to 3 minutes.

Each resulting solution was passed through a filter plug tube (Becton Dickinson, San Jose, CA, # 2235).

The samples were read in a. apparatus FACSort (Becton Dickinson) using the manufacturer's CellQUEST program, and analyzed with the manufacturer's MOdFIT software. This measurement provides an indication of the percentage of cells in each of the following ^ phases: G0 / G1 phases, DNA synthesis (S) and G2 / M.

The results of a cell cycle progression experiment analyzed on day 1 after the addition of the compounds to be tested 1-1, 1-2 and 1-3 are summarized below in Table IV.

TABLE IV Effect of the compounds to be tested in the cell cycle The results summarized in Tables I-IV above show that compounds 1-1, 1-2 and 1-3 have antipyretic activity, and specifically cause an accumulation of cells in the G2 / m phase of the cell cycle.

The pyrroles of formula I above and their mentioned salts can be used as medicaments, for example in the form of pharmaceutical preparations, which can be administered orally, for example, in the form of tablets, coated tablets, dragees, soft gelatine capsules or hard, solutions, emulsions or suspensions. They can also be administered rectally, for example, in the form of suppositories, or parenterally, for example in the form of injectable solutions.

For the manufacture of the pharmaceutical formulations said compounds can be formulated with inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, airtight acid or its salts for tablets, coated tablets, dragees and hard gelatine capsules can be used as said carriers.

Suitable vehicles for soft gelatine capsules are vegetable oils, waxes, fats, semi-solid or liquid polyols. Depending on the nature of the active substance, vehicles are generally not required in the case of soft gelatine capsules. The vehicles suitable for the manufacture of solutions and syrups are water, polyols, sucrose, invert sugar and glucose. Suitable vehicles for injection are water, alcohols, polyols, glycerin, vegetable oils, phospholipids and surfactants, suitable suppository vehicles are hardened natural oils, waxes, fats and semi-liquid polyols.

The pharmaceutical preparations may also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for modifying the osmotic pressure, buffers, coating agents or antioxidants. They may also contain other therapeutically valuable substances.

As mentioned above, the pyrroles of formula I and their salts mentioned can be used in the treatment or control of oncological disorders. The dose may vary within wide limits and will of course be adjusted to the individual requirements in each particular case. In general, in the case of oral or parenteral administration to adult humans with a weight of about 70 kg, a daily dose of from about 10 mg to about 10000 mg, preferably from about 200 mg to about 5000 mg, more preferably from about 1000 mg, should be adequate, although the upper limit can be exceeded when necessary. The daily dose may be administered in the form of a single dose or in divided doses, or for parenteral administration it may be administered in the form of continuous infusion.

The following examples illustrate the present invention.

EXAMPLE 1 Preparation of 3- (lH-indol-3-yl) -4- (1-meth i 1-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione (1-1) A. 1 -Methyl-6-nitro-lH-indole To a suspension of 0.33 g (8.3 mmol) of NaH (60% dispersion in oil) in 30 ml of dry dimethylformamide ("DMF"), 0.973 g (6.00 mmol) of commercially available 6-nitro-lH-indole (1) was added at 0-5nC over a period of 10 minutes. After 1 h of stirring at the same temperature, 0.75 ml (12.1 mmol) of methyl iodide was added and the mixture was stirred at the same temperature for 30 minutes, and then at room temperature for 1 h, poured on ice and water and extracted with ethyl acetate. The organic phase was washed with saiin solution, dried over MgSO4 and concentrated to yield 0.814 g. (77.5%) of 1-met il-6-ni tro-H-indole (2) as a yellow solid. This material was used in the subsequent processes without purification. - B. (l-Methyl-6-nitro-l-indol-3-yl) -oxoacetyl chloride (3) To a solution of 1.33 g (7.55 mmol) of 1-methyl-6-nitro-lH-indole (2) ) in 1.5 ml of ether was added 1.5 ml (? 7.2 mmol) of oxalyl chloride at 0-5 ° C under argon atmosphere. A precipitate formed. After 3 h of stirring, the resulting solid was filtered, washed with a small amount of ether and dried to a yield of 1.9 g (95%) of (1-methyl-6-nitro-1H-indole) chloride. 3-yl) -oxo-acetyl (3) as a yellow solid. This material was used without purification.

C. [1- (2, 2-Dimethyl-propionyl) -lH-indol-3-yl] -acetonitrile (6) Using the procedure of sub-section A above, the N-alkylation reaction of 10.2 g (6 ~ 5 mmol) of (1H-indol-3-yl) -acetonitrile (5) commercially available with 8.7 ml (71 mmol) of trimethylacetyl chloride and 3.4 g (85 mmol) of NaH (60% dispersion in oil) as a base in 115 ml of DMF yielded 6.6 g (38.7%) of [l- (2,2-dimethyl-propionyl) -lH-indol-3-yl] -acetoni tryl (6) in the form of a yellow oil after chromatographic purification.

D. 1 - (2,2-Dimethyl-propionyl) -lH-indol-3-yl] -3-ethanimidic acid hydrochloride '1-methyl ester (7) To a suspension of 6.6 g (27.5 mmol) of [1 (2,2-dimethyl-l-propionyl) -lH-indol-3-yl] -acetonitrile (6) from Step C above in 105 ml of 2-propanol , 40 ml (0.563 mmol) of acetyl chloride was added dropwise at 0-5 ° C over a period of 20 minutes. The reaction mixture was stirred at room temperature overnight, concentrated, and the residue was diluted with about 75 ml of ethyl acetate, heated for 15 minutes in a steam bath, cooled and placed in a refrigerator. . The precipitate was filtered and dried to yield 6.0 g (65.0%) of the hydrochloride 1-methyl ester of [1- (2, 2-dimethyl-propisyl) -1H-indol-3-yl] -3-ethanimidic acid (7) hydrochloride in the form of a white solid.

E. 3- [1- (2, 2-Dimethyl-propionyl) -lH-indol-3-yl] -4- (1-methyl-6-nitro-l-indol-3-yl) -pyrrole-2, 5- dione (4) To a solution of 1.25 g (4.69 mmol) of (1-methyl-6-nitro-l-indol-3-yl) -oxo-acetyl (3) chloride from Step B above and 1.6 g (4.75 mmol) of the [1- (2, 2-dimethyl-propionyl) -lH-indol-3-yl] -3-ethanimide acid hydrochloride 1-methyl ester (7) from Step D above in 80 ml of sodium chloride methylene, 2.6 ml (18.65 mmol) of triethylamine was added at 0 ° C under an argon atmosphere. After stirring at the same temperature for 30 minutes, the reaction mixture was then stirred at the same temperature for 30 minutes, and then the reaction mixture was stirred at room temperature for 3 1/2 hours and diluted with more ethylene chloride. . The organic phase was washed with water, 0.5 N HCl solution, saline, dried over MgSO4 and concentrated to yield 3.01 g of a foam. This material was dissolved in 50 ml of toluene and treated with 987.9 mg (5.19 mmol) of p-toluenesulfenic acid at 0 ° C. After 3 hours of stirring at room temperature, the reaction mixture was extracted with methylene chloride. The organic phase was washed with a saturated solution of NaHC 3, saline, dried over MgSO 4 and concentrated to yield 3.9 g of crude material. Chromatographic purification on a silica gel column yielded 1.7 g (77%) of 3- [1- (2, 2-dimethyl-propionyl) -lH-indole-3-yl) -4- (1-met il- 6-Nitro-lH-indol-3-yl) -pyrrole-2, 5-dione (4) as an orange solid, m.p. > 146 ° C with decomposition. MS: (M +), m / z 470.

F_. 3- (1H-Indol-3-yl) -4- (1-methyl-6-ni troH-indol-3-yl) -pyrrole-2, 5-dione (1-1) 1.7 g were treated ( 3.61 mmol) of 3- [1 - (2, 2-dimethyl-3-pyrrolyl) -1H-indol-3-ü] -4 - (1-phenyl-6-nitro-1H-indol-3-yl) -pyrrole -2, 5-dione (4) from Stage E above in 60 ml of methanol with 5.6 ml (8.96 mmol) of a 1.6 mmolar solution of NaOCH3 in methanol. The reaction was stirred at room temperature for 1 hour, poured into 2N-HCl / ice and extracted with ethyl acetate. The organic extracts were dried over anhydrous MgSO 4 and concentrated to yield, after the chromatographic purification, 394.7 mg (28%) of 3- (1H-indol-3-yl) -4- (1-methyl-6-nitroyl) -indol-3-ii) -pyrrole-2, 5-dione (1-1) in the form of a red solid, mp > 280? CMS: M +), m / z 386 EXAMPLE 2 Preparation of 3- (1-hydroxymethyl) -1H-indo1-3-yl) -4- (l-methyl-6-nitro-lH-indol-3-yl) -pyrol 1-2, 5-dione ( 1-3) A. 1-Methoxymethyl-1H-indole (9!) Using the procedure of Example 1, Step A, the N-alkylation reaction of 1.17 g (10 mmol) of indole (8) commercially available with 1 ml (13.1 mmoi) of chloromethyl ether _ and 0.48 g (12 mmol) of NaH (60% dispersion in oil) as a base in 22 ml 'of DMF yielded 1.4 g "10 (86.9%) of 1-me toxymethyl-LH-indole (9) in the form of a colorless oil after chromatographic purification.

B Chloride of (1-me toxymethyl-lH-indol-3-yl) -oxoacetyl (10) Using the procedure of Example 1, Step B, the reaction of 0.23 g. (1.43 mmol) of 1-me toxymethyl-lH-indole (9) from Step A above with 0.25 ml (2.66 mmol) of oxalyl chloride in 3.5 ml of ether yielded 0.174 g (46.5%) of sodium chloride. -methoxymethyl-lH-indol-3-yl) -oxo-acetyl (10) as a yellow solid. This material was used without purification.

C. (6-Nitro-lH-indol-3-yl) -acetonitrile (13) To a stirred solution of 44.27 g (0.204 mmol) of 6-ni trogramin (12) [Jackson B. Hester, J.-Org. Chem., 29: 1158 (1964)] in 450 ml of acetonitrile were added 44.59 g (0.31 mmol) of methyl iodide at 0-5 ° C for a period of one hour. The reaction mixture was stirred at room temperature for three hours, and then a solution of 26.6 g (0.543 mmol) of sodium cyanide in 225 ml of water was added at once. The reaction mixture was heated at 32 ° C overnight, cooled to room temperature and the product was extracted three times with a total of 800 ml of ethyl acetate and 300 ml of water. The combined extracts were washed with water, IN HCl solution, a saturated solution of sodium bicarbonate, dried over Mg5d and the solvent was evaporated in vacuo. The orange-brown residue (41.3 g) was dissolved in 200 ml of hot ethyl acetate and passed through a small silica gel filter to yield 28.9 g (70.4%) of (6-nitro-1H-indolyl). 3-yl) -acetonitrile (13) as a yellow solid after evaporation of the solvent.

D. (1-methyl-6-nitro-1H-indo-3-yl) -acetonitrile (14) 65.5 g (0.474 mmol) of powdered potassium carbonate was added to a solution of 28.9 g (0.143 mmol) of (6-) Nitro-lH-indolyl-3-yl) -acetonitrile (13) from Step C above in 230 ml of dimethylformamide at room temperature. The suspension was stirred for 40 minutes, and then 25.48 g (0.179 mmol) of methyl iodide was added dropwise over 65 minutes.

After stirring at room temperature overnight, the reaction mixture was cooled and poured into a total of 600 ml of water. The precipitate was filtered, washed with a little water and placed over phosphoric anhydride until a constant weight was reached. The procedure yielded 30.4 g (95.4%) of (l-methyl-6-nitro-lH-indol-3-yl) -acetonitrile (14), which was used without further purification. ~ ~ (1- Methyl-6-nitro-lH-indol-3-yl) -3-ethanimidic acid 1-methylhydrochloride (15) HCl gas was bubbled into a stirred suspension of 82 g (0.382 mmol) of (1-meth i 1-6-ni tro-lH-indol-3-yl) -acetonitrile (14) from Step D above, in 1000 ml of 2-propanol at 0-10 ° C. After adding about 350 g of HCl, ether was added to the reaction mixture to form a precipitate. The solid was collected, washed with ether and dried under vacuum to yield 102 g (87.5%) of the hydrochloride 1-methyl ester of (l-methyl-6-nitro-1H-indol-3-yl) -3-ethanimidic acid. (fifteen) .

F. 3- (1-Methoxymethyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2, 5-dione (11) Using the procedures of Example 1, Stage E, the condensation reaction of 1.3 g (5.17 mmol) of oxoacetyl chloride (10.) from step E above, with 1.7 g (5.45 mmol) of hydrochloride 1-methyl ester of (l-methyl-6-ni troyl-indol-3-yl) hydrochloride - 3-ethanimide (15) "from Stage E above in 95 ml of methylene chloride yielded 1.08 g (48.5%) of 3- (1-methoxymethyl-1H-indol-3-yl) -4- (1-methyl) - 6-Nitro-1H-indol-3-yl) -pyrrole-2, 5-dione (11) as an orange solid, mp> 250 ° C with dec MS: (M +), m / z 430.

G. 3- (1-Hydroxymethyl-1H-indol-3-yl) -4 -1-methyl-6-nitro-1H-indol-3-yl) -pyrrole-2, 5-dione (1-3) A solution of 727.5 mg of 3- (l-methoxymethyl-lH-indol-3-yl) -4- (1-methyl-6-nitro-lH-indol-3-yl) -pyrrole-2, 5-dione (11) from the above Step F in 65 ml of THF was treated with about 40 ml of 2N HCl. The reaction mixture was refluxed for 5 hours, cooled and the product extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvent was evaporated to yield an orange solid. Chromatographic purification of this material yielded 123.3 mg of 3- (1-hydroxymethyl-1H-indol-3-yl) -4- (1-methyl-6-nitro-1H-indol-3-yl) -pyrrol- 2, 5-diana (1-3) as a red solid, mp 210-213nc. MS: (M +), m / z 416.

E JEMPLO 3 Preparation of 3- (l-methyl-lH-indol-3-yl 6-nitro-1H-indol-3-yl) -pyrrole-2, 5-dione (1-2) A. (l-Methyl-lH-indol-3-yl) -oxo-acetyl chloride (17) Using the procedure of Example 1, Step B, the reaction of 6 ml (47 mmol) of 1-me 111- lH-indole (16) commercially available with 8 ml (92 mmol) of oxalyl chloride in IZO ml of ether yielded 7.6 g (73.2%) of (1-methyl-lH-indole-3-yl) -oxo chloride. -acetyl (17) as a yellow solid. This material was used without further purification.

B. [1 (2,2-Dimethyl-propionyl) -6-nitro-L-indol-3-yl] -acetonitrile (18) Using the procedure of Example 1, Step A, the N-alkylation reaction of 346.6 mg ( 1.72 mmol) of 6-nitro-1H-indolyl 1-3-acetonityl (13) from Example 2, Step C, with 0.3 ml (2.44 mmol) of t-rimetylacetyl chloride and 70.8 mg (1.77 mmol) NaH (60% dispersion in oil) as a base in 8 ml of DMF yielded 287.7 mg (43.2%) of [1- (2,2-dimethyl-propio-nil) -6-nitro-lH-indole- 3-yl] -acetonitrile (18) in the form of a yellow oil.

C. 1-Methyl ester of [1 (2,2-dimethylpropionyl) -6-nitro-lH-indol-3-yl] -3-ethanimide hydrochloride (19) _ A gas HCl jet was bubbled for 3 minutes into a suspension with constant stirring of 1.45 g (5.08 mmol) of [1- (2,2-dimethyl-propioni 1) -6-nitro-lH-indol-3-yl] -acetonitrile (18) from Step B above in 90 ml of 2-10 propanol at 0-5 ° C. The reaction mixture was stirred at room temperature for 21 hours. The solvent was evaporated in vacuo to yield 1.95 g (100%) as a yellow solid (19). This material was subsequently used without further purification. ~~ ~~ D .3L- [1- (2, 2-Dimethyl-propionyl) -6-nitro-lH-indol-3-yl] -4- (l-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione (20) Using the procedure of Example 1, Step E, l.lg (4.96 mmol) of oxoacetyl chloride (17) from Step A above was reacted with 1.95 g (5.08 mmol) of 1-methyl ester hydrochloride. of the [1- (2, 2-dimethyl-propioni-1) -6-nitro-lH-indol-3-y1] -3-ethanimidic acid (19) _ of the above Step C and 2.1 ml (17.94 mmol) of triethylamine in 120 ml of methylene chloride, the resulting product was treated with 1.1 g (5.78 mmol) of p-toluenesulphonic acid monohydrate in 80 ml of toluene, yielding 1.3 g (62.1%) of 3- [1- (2, 2-dimethyl-propionyl) -6-nitro-lH-indol-3-yl] -4- (1-methyl-lH-indol-3-yl) -pyrrole-2, 5-dione (20) as an orange solid , mp> 245 ° C, with Dec. MS: (M +), m / z 470.

E. (l-Methyl-lH-indol-3-yl) -4- (6-nitro-1H-indol-3-yl) -pyrrole-2, 5-dione (1-2) Using the procedure of Example 1, Stage F, the reaction of N-desprot ection of 1.3 g (2.76 mmol) of 3- [l- (2, 2-dime thi 1-propioni 1) -6-nitro-1H-indol-3- i 11-4- (1-methyl-1H-indole - 3-yl) -pyridyl-2,5-dione (20) from Step D above with 4.3 ml (6.88 mmol) of a 1.6 molar solution of NaOCH, in 65 ml of methanol yielded 300.6 mg (28.1%) of 3 - (1-methyl-1H-indol-3-yl) -4- (6-nitro-1H-indol-3-yl) -pyrrole-2, 5-dione (1-2) as a red solid after crystallization from ethyl acetate and hexane; p.f. > 260 ° C. MS: (M +), m / z 386.

EXAMPLE 4 FORMULATION IN C OMPR IM I DO Compound A represents a compound of the invention Manufacturing procedure 1. Mix items or points 1, 2 and 3 in a suitable mixer for 15 minutes. 2. Granulate the powder mixture from Step 1 with 20% Povidone K30 Solution 20% (point 4). 3. Dry the granulation from Step 2 to 50CC. 4. Pass the granulation of Stage 3 through a suitable grinding equipment. 5. Add point 5 to Stage 4 granulation by grinding and mix for 3 minutes. 6. Compress the granulation of Step 5 in a suitable press.

E JEMPLO 5 FORMULAC ION IN CÁP SULA * Compound A represents a compound of the invention 1 n Manufacturing procedure 1. Mix the items or points 1, 2 and 3 in a suitable mixer for 15 minutes. 2. Add points 4 and 5 and mix for 3 minutes. 3. Fill in appropriate capsules.

EXAMPLE 6 PREPARATION SOLUTION / EMULSION FOR INJECTION Compound A represents a compound of the invention Manufacturing procedure 1. Dissolve the item or point 1 in item 2. 2. Add items 3, 4 and 5 to the item or point E and mix until dispersed; then homogenize. 3. Add the solution from step 1 to the mixture from step 2 and homogenize until the dispersion is translucent.

Sterile filtration through a 0.2 μm filter and fill in vials.

EXAMPLE 7 PREPARATION SOLUTION / EMULSION FOR INJECTION rCompound A represents a compound of the invention Manufacturing procedure 1. Dissolve the item or point 1 in item 2. 2. Add item or points 3, 4 and 5 to item 6 and mix until dispersed; then homogenize 3. Add the solution from step 1 to the mixture from step 2 and homogenize until the dispersion is translucent. 4. Sterile filtration through a Q.2 μm filter and fill in vials.

Claims (7)

RE IVINDICACIONE S
1. A compound of formula characterized in that R1 is hydrogen and R2 is methyl or R1 is methyl and R2 is hydrogen or R1 is hydroxymethyl and R2 is methyl as well as pharmaceutically acceptable prodrugs or pharmaceutically acceptable salts thereof.
2. 2. A compound of claim 1 characterized in that it is of the formula, 1-1 as well as pharmaceutically acceptable prodrugs or pharmaceutically acceptable salts of said compound.
3. 3. A compound characterized by the formula - as well as pharmaceutically acceptable prodrugs or pharmaceutically acceptable salts of said compound.
4. A compound characterized because it is of the formula as well as pharmaceutically acceptable prodrugs or pharmaceutically acceptable salts of said compound.
5. 5. A pharmaceutical composition characterized in that it contains a compound of formula wherein RX is hydrogen and R2 is methyl or R1 is methyl and R2 is hydrogen or is hydroxymethyl and R2 is methyl or a pharmaceutically acceptable salt or prodrug of said compound and a pharmaceutically acceptable carrier.
6. 6. A compound according to any one of claims 1 to 4 for use as an antitumor drug.
7. 7. The use of a compound claimed in any of claims 1 to 4 for the treatment of solid tumors or the preparation of pharmaceutical compositions.