MXPA00010739A - Indole derivatives and their use in the treatment of malignant and other diseases caused by pathological cell proliferation - Google Patents

Abstract

The invention relates to tyrosine kinase inhibitors of bis-indolyl compounds of formula (I), to the medicaments containing said inhibitors and to their use in treating malignant and other diseases caused by pathological cell proliferation.

Description

DERIVATIVES OF INDOL AND ITS USE FOR THE TREATMENT OF MALIGNANT DISEASES AND OTHERS, CAUSED BY PATHOLOGICAL CELLULAR PROLIFERATION Description of the invention The invention relates to inhibitors of tyrosine kinase of the type of bis-indole compounds, with drugs containing them, and with their use for the treatment of malignant and other diseases, caused by cell proliferation. The activation of tyrosine-specific protein kinase is a key event for the stimulation of the division of animal cells. In general, this stimulation is caused by exogenous factors, for example growth factors when the proliferation of a certain type of cell is required for the total function of a tissue or organ. In tumors, cell proliferation is also associated with the activity of tyrosine kinases. However, in tumor cells there is often an aberrant activity of the kinases, caused by overexpression, constitutionally active kinase mutants or ectopic activity of growth factors. The PDGF receptor is one of the growth factors with relevance for human tumors. PDGF is one of the main mitogens in serum and is found in high trophic concentrations. The most important function in the adult organism is the healing of wounds. An undesired activity of the PGDF receptor participates in the proliferation of various tumors, for example gliomas, glioblastomas, sarcomas, mammary carcinomas, ovarian carcinomas and colon carcinomas. An aberrant activation of the PDGF / PDGF receptor system also has a key position for pathological hyperproliferations of mesenchymal cells in context with arteriosclerosis, restenosis after balloon angioplasty, arthritis and fibrotic diseases. Tyrosinokinase receptors of the growth factor whose tyrosine kinase domains have high sequence homology with the tyrosine kinase domain of the PDGF receptors are also significant for tumor events and pathological hyperproliferations. Among them are the receptors for the vascular growth factor of endothelial cells (VEGF) KDR / Fl -1 and Flt-1, with great significance for tumor vascularization, the Kit / SCF receptor for which constitutively active versions were observed in carcinomas, and Flk-2 / Flt-3, a receptor involved in the proliferation of leukemia cells of various types of diseases. It can be assumed that other members of this family of kinases with relevance to pathological proliferation will be identified. Among the effects of the ligands of these receptors, in addition to the mitogenic stimulus, the stimulus to cell migration, anx.i-apoptotic effects and effects on membrane systems for ions, water and chemical compounds are also frequently counted. The uncontrolled effects of this nature also participate to varying degrees in the pathological occurrence in tumors and other diseases. Among the various possibilities of interrupting the signal of receptor tyrosine kinases the most promising is the direct specific inhibition of kinase activity. Accordingly, the invention is directed to creating suitable compounds as inhibitors of tyrosine kinases, in particular of the tyrosinokinase of the PDGF receptor, as well as of other similar tyrosine kinases such as KDR / Flk-1, Kit / SCF receptor and FLK / Flt-3. This task is solved by means of the compounds according to the invention, of the general formula I (!) wherein Z is a group of the general formula (Ii; (ii) where A can be a nitrogen, oxygen or sulfur atom, and B, B 'a carbon, nitrogen, oxygen or sulfur atom, and the cyclic systems F and G can be independently of each other rings 5 and 6, both saturated as also unsaturated, X represents a group of the general formula III or IV, - (CH2) i- [CR14R15] ra- (CH) n (III) where A has the same meaning as in the above, 1 and n can be the numbers 0 to 6, m the numbers 1 and 2, as well as R14 and R15 or together they form an oxygen atom, or R14 means a group hydroxyl and R15 a hydrogen atom, or R14 and R15 mean hydrogen atoms and in which R16 means a hydrogen atom, an alkyl or aryl radical, alkyl or aryl radical substituted with halogen, amino or azido, an alkoxymethyl radical or alkoxymethyl radical substituted, R2 and R13 together form a ligate with the general formula V or VI (V) (SAW) being that the striped league means a double or single league, A and R16 have the same meaning as in the previous, I can adopt the numbers 1 and 2, R2 and R13 mean equal or different radicals of the general formula VII or atoms of hydrogen being that the striped link means a double or single link, A and R, 16 have the same meaning as in the above, and R, 17 means a halogen atom or a radical of the general formula VIII, (VIII) so that p can be = 0, 1 or 2 (if p = 0 is a primary acyclic amine and Y has an additional hydrogen atom, Y can be a carbon, oxygen or nitrogen atom, and if Y is a carbon atom or nitrogen, R18 is a nitrogen atom or an alkyl or aryl radical, an alkyl or substituted aryl radical, a saturated or unsaturated heterocycle, an alkoxycarbonyl radical, an aminocarbonylmethyl radical, a substituted aminocarbonylmethyl radical, R2 and R13 form together a league with the general formula IX or X (IX) (X) being that it represents either a carbon atom or a nitrogen atom, q can take a number between 0 and 6, and R19 and R20 can mean hydrogen atoms, alkyl radicals, or substituted alkyl radicals, wherein R1 and R7 are equal or different and meaning carbon atoms, alkyl and aminoalkyl radicals, phenylsulfonyl radicals, alkylsilylmethoxymethyl radicals, a sugar or substituted sugar, where R3, R4, R5, R6, R8, R9, R10 and R11 are the same or different and in each case represents a hydrogen atom, an alkyl, alkoxy, alkoxymethyl, substituted alkoxy, amino, halogen, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, a halogen atom or a 0-alkoxy group of the general formula -O- (C = 0) -R21, where R21 means an alkyl, alkoxy, substituted alkoxymethyl group of alkoxy, amino, halogen, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl. Preference is given to the compounds according to the invention of the general formula I above, in which Z represents a group with the general formula II and X is a group with the general formula III, R2 and R13 are hydrogen atoms, A is a hydrogen atom, nitrogen and B a nitrogen, oxygen or sulfur atom, as well as R3, R4, R5, R6, R7, R8, R9, R10, R11, R14 and R15 have the same meaning as in the above, being that these compounds correspond to The following formula XI: Especially preferred are compounds of formula XI in which R14 and R15 together form an oxygen atom. Further preferred are the compounds according to the invention with the general formulas I above in which Z represents a group with the general formula II and X a group with the general formula III, R1 and R2 mean hydrogen atoms, A and B mean Nitrogen atoms, as well as R 1, R 3, R 4, R 5, R 5, R 7, R 8, R 9, R 10, R 11 and R 16 have the same meaning as in the above, these compounds corresponding to the following formula XII: (XII) Further preferred are the compounds according to the invention with the following general formulas XIII and XIV: where n means the numbers 3, 4, 5, 8, 12, q the numbers 0, 1, 2, 3, 5, 6, R19, R20 denote hydrogen atoms or alkyl groups, and R1, R3, R4, R5 , R6, R7, R8, R9, R10, Ru and R16- are the same or different and have the same meaning as in the above. The compounds according to the invention are furthermore preferred with the following general formula XV wherein n means the numbers 1, 2, 3, R16 means a hydrogen atom or an alkyl group, and R1, R3, R4, R5, R °, R7, R8, R9, R10, Ru and R16 are the same or different and have the same meaning as in the previous. The compounds of formula XI can be prepared according to one of the following two schemes a) LDA / THF, b) HSiPh3 / THF, c) PDC / DMF, d) 10% NaOH / EtOH, e) K2C03 / Me0H, f) N2H4 / 2- (2-hydroxyethyloxy) -1-ethanol n = 2 or 3 For the preparation of the compounds according to the invention in which R2 and R13 mean a radical with the above general formula VII or together form a ligate with the general formula V, IX or X, it is first reacted with a dibro omaleinimide a 2,2'-bis-lH-indolilalcano or a derivative thereof with the general formula XI wherein X, R1, R3, R4, R5, R6, R7, R8, R9, R10 and R11 have the same meaning as in the foregoing. The compounds according to the invention in which R2 and R13 together form a ligand with the general formula VII are then reacted with a primary or secondary amine with the general formula XVI or XVII or with piperazine (XV!) Rxvti) where p, q, R, 11 and W have the same meaning as in the previous.

The following examples explain the invention without limiting it. Example 1 Bis (N-phenylsulfonylindol-2-yl) -1-methanol At -78 ° C lithium diisopropylamide is prepared from 30.40 ml (216.3 mmol) of diisopropylamine and 125.3 ml (200.5 mmol) of n-buLi (1.6 M in hexane) in absolute THF. The solution is stirred for 10 minutes at -78 ° C and then 30 minutes at 0 ° C, before adding dropwise at 0 ° C, within a period of 10 minutes, 49.13 g (190.9 mmol) of 1-phenylsulfonylindole. in 300 ml of absolute THF. The reaction solution is stirred for a further 30 minutes at 0 ° C. After cooling down to -78 ° C, 60.00 g (210.3 mmol) of phenylsulfonyl-2-carbaldehyde are added dropwise in 200 ml of absolute THF and allowed to warm to room temperature overnight. The mixture is poured into 1 percent HCl and the organic phase is separated with ether after addition. The aqueous phase is extracted with ether, the combined organic phases are washed successively with NaHCO 3 and saturated NaCl solution, and dried over Na 2 SO 4. The solvent is removed in vacuo and the crude product is purified by column chromatography (SiO2, CH2C12). Colorless crystals, yield: 86.5 g (84%). P.f. : 185 ° C (MeOH). The following were analogously produced: Example 2 Bis (5-methoxy-N-phenylsulphonylindol-2-yl) -1-methanol P.f. : 113-114 ° C (MeOH) Example 3 (5-methoxy-N-phenylsulfonylindol-2-yl) - (N-phenyl-sulfonylindol-2-yl) -1-methanol P..f .: 104-105 ° C (CH2Cl2 / hexane) Example 4 (5-methoxy-N-phenylsulfonylindol-2-yl) - (7-methoxy-N-phenylsulfonylindol-2-yl) -1-methanol Mp: 119-121 ° C (CH2Cl2 / hexane Example 5 (7-methoxy-N-phenylsulfonylindol-2-yl) - (N-phenylsulfonylindol-2-yl) -1-methanol Mw .: 99-101 ° C (CH 2 Cl 2 / hexane) Example 6 5-methoxy-2- phenylmethyloxy (1-phenylsulfonylindol-2-yl) methyl-1-phenylsulfonylindole Pf : 62-64 ° C Example 7 Di- (5-methyloxy-l-phenylsulfonylindol-2-yl) phenylmethyloxy-methane P.f. : 100-101 ° C Example 8 (3-dimethylaminomethyl-1-phenylsulfonylindol-2-yl) (1-phenylsulfonylindol-2-yl) methan-1-o1 P.f. : 116-117 ° C Example 9 (7-methoxy-N-phenylsulfonylindol-2-yl) - (N-phenylsulfonylindol-2-yl) -1-methanol m.p. : 149 - 151 ° C Example 10 Dibenzothiophen-2-i1-1-methanol P.f. : 130 - 131 ° C Example 11 6-methoxy-l-phenylsulfonyl-lH-2-indolyl (1-phenylsulfonyl-1H-2-indolyl) methanol P.f. : 180 ° C Example 12 7-methoxy-1-phenylsulfonyl-lH-2-indolyl (1-phenylsulfonyl-lH-2-indolyl) ethanol P.f. : 148-150 ° C Example 13 Benzo [b] thiof en-2-yl (5-methoxy-l-f-enylsulfonyl-lH-2-indolyl) -1-methanol P. f. : 71-73 ° C Example 14 Benzo [b] thiophen-2-yl (7-methoxy-l-f-enylsulfonyl-lH-2-indolyl) -1-methanol P.f. : 118-119 ° C Example 15 Benzo [b] furan-2-yl (5-methoxy-l-phenylsulfonyl-lH-2-indolyl) -1-methanol P.f. : 71 - 73 ° C Example 16 Bis (N-phenylsulfonylindol-2-yl) methan-1-one The solution of 20.00 g (36.0 mmol) of Bis (N-phenylsulfonylindol-2-yl) -1-methanol in 200 ml of absolute DMF is cooled to 0sC. After the addition of 90.4 g of pyridinium dichromate (PDC) it is stirred for 20 h at room temperature. For working up, 700 ml of H20 and 700 ml of CH2C12 are added. The aqueous phase is extracted 2 x with 200 ml of CH2C12. The combined organic extracts are washed with 500 ml of H20. After extraction of the solvent by vacuum and addition of CH2C12, the product is precipitated: colorless crystals, yield: 15.0 g (75%). Mp: 244 ° C (MeOH / ether) Analogously there were produced: Example 17 (5-methoxy-N-phenylsulfonylindol-2-yl) - (N-phenyl-sulfonylindol-2-yl) methan-1-one P. f. : 205 ° C (MeOH) Example 18 Bis (5-methoxy-N-phenylsulfonylindol-2-yl) -1-methanone P.f. : 190 - 191 ° C Example 19 Bisindol-2-ylmetan-l-one 10.0 g (18.5 mmol) of Bis (N-phenylsulfonylindol-2-yl) -1-methanone are dissolved in 380 ml of 99 percent EtOH. After the addition of 210 ml of 10% NaOH, the solution is heated at reflux for 20 h. For working up, the EtOH is extracted, 500 ml of a saturated solution of NaCl and 500 ml of CH2C12 are added, and the phases are separated. The aqueous phase is extracted with 2 x 200 ml of CH2C12, the combined organic extracts are dried over Na2SO4 and concentrate by vacuum. The bisindole is precipitated as crude product and can be recrystallized with CHC12, yellow crystals, yield: 4.5 g (93%). P.f. : 272-273 ° C (CH2C12) Analogously there were produced: Example 20 (5-methoxyindol-2-yl) - (indol-2-yl) ethan-1-one P.f. : 233-235 ° C (MeOH) Example 21 Bis (5-methoxyindol-2-yl) -1-methanone P.f. : 202 - 204 ° C Example 22 Dibenzothiophen-2-yl-1-methanone P.f. : - 161 ° C Example 23 5-methoxy-1-phenylsulfonyl-3-indolyl (1-phenylisulfonyl-2-indolyl) -1-methanone P. : 114-116 ° C Example 24 (lH-indol-2-yl) - (l-H-indol-3-yl) -1-methanone P.f. : 260-261 ° C MeOH) Example 25 Benzo [b] iofen-2-yl (7-methoxy-1-phenylsulfonyl-1 H-2-indolyl) -1-methanone Pf: 190 ° C Example 26 Benzo [b] thiof en-2-yl (7-methoxy-lH-2-indolyl) -1-methanone Mp: 155 ° C Example 27 Benzo [b] thiophen-2-yl (5-methoxy-1-phenylsulfonyl-1H-2-indolyl) - 1-methanone Pf : 82 - 83 ° C Example 28 Benzo [b] thiophen-2-yl (5-methoxy-lH-2-indolyl) -1-methanone P.f. : 200 ° C Example 29 7-methoxy-l-phenylsulfonyl-lH-2-indolyl (1-phenylsulfonyl-lH-2-indolyl) ethanone P.f. : 129-130 ° C Example 30 7-methoxy-lH-2-indolyl (lH-2-indolyl) methanone Pf: 151 ° C Example 31 6-methoxy-1-phenylsulfonyl-1H-2-indolyl (1-phenylsulfonyl- lH-2-indolyl) ethanone Pf : 184-186 ° C Example 32 6-methoxy-lH-2-indolyl (1H-2-indolyl) methanone P.f. : 184-186 ° C Example 33 l-Methyl-lH-2-indolyl (l-ethyl-5-methyloxy-lH-2-indolyl) -1-methanone P.f. : 148-149 ° C Example 34 lH-2-Indolyl (l-methyl-5-methyloxy-lH-2-indolyl) -1-methanone P.f .: 190 ° C Example 35 l-methyl-lH-2-indolyl (5-methyloxy-lH-2-indolyl) -1-methanone P.f. : 176-177 ° C Example 36 l-ethyl-lH-2-indolyl (l-ethyl-5-methyloxy-lH-2-indolyl) -1-methanone P.f. : 99-100 ° C Example 37 lH-2-indolyl-1-ethyl-5-methyloxy-lH-2-indolyl) -1-methanone P.f. : 142-143 ° C Example 38 l-ethyl-lH-2-indolyl (5-methyloxy-lH-2-indolyl) -1-methanone P.f. : 101-102 ° C Example 39 l-benzyl-lH-2-indolyl (l-benzyl-5-methoxy-lH-2-indolyl) -1-methanone Pf ..- 132 ° C Example 40 lH-2-indolyl (l-benzyl-5-methoxy-lH-2-indolyl) -1-methanone P.f. : 180-1B2 ° C Example 41 l-benzyl-lH-2-indolyl (5-methoxy-lH-2-indole) -1-methanone P.f .. - 167 - 168 ° C Example 42 5-Benzyloxy-lH-2-indolyl (lH-2-indolyl) methanone P.f. : 199 - 201 ° C. Example 43 5-hydroxy-1H-2-indolyl (lH-2-indolyl) ethanone P.f. : > 220 ° C. Example 44 5-Ethoxy-lH-2-indolyl (lH-2-indolyl) methanone P.f ..-. 168 - 169 ° C. Example 45 lH-2-indolyl [5- (2-morpholin-1-ylethyloxy) -lH-2-indolyl] -methanone P.f. : 98 - 101 ° C. Example 46 lH-2-indolyl [5- (3-dimethylaminopropyloxy) -lH-2-indolyl] -methanone P.f. : 163 - 166 ° C. Example 47 5- (4-iodobutyloxy) -lH-2-indolyl (lH-2-indolyl) methanone P.f. : 110 - 113 ° C. Example 48 lH-2-indolyl [5- (2-dimethylaminoethyloxy) -lH-2-indolyl] -methanone P.f. : 143 - 145 ° C. Example 49 5-Cyclohexylmethyloxy-lH-2-Indolyl (1H-2-indolyl) methanone P.f. : 185 ° C (Desc.). Example 50 5- (5-iodopentyloxy) -1H-2-indolyl (lH-2-indolyl) methanone P.f. : 127 - 130 ° C. Example 51 l-H-2-indolyl [5- (1-phenylethyloxy) -lH-2-indolyl] methanone P.f. : 151 - 153 ° C. Example 52 lH-2-indolyl [5- (2-piperidin-1-ylethyloxy) -lH-2-indolyl] -methanone-P.f. : 104 - 106 ° C. Example 53 [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] ethanoate P.f. : 223-224 ° C. Example 54 [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] 4-methoxybenzoate P.f. : > 230 ° C.

Example 55 [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] butanoate P.f. : 201 - 204 ° C. Example 56 [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] 2- (N, N) -dimethyl-aminoethanoate P.f. : 215 - 217 ° C. Example 57 [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] propanoate P. f. : > 230 ° C. Example 58 [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] 2-thiophenylethanoate P.f. : 224-226 ° C. Example 59 [2- (1H-2-indolylcarbonyl) -lH-5-indolyl)] 0-acetylsalicylate P.f. : 133 - 135 ° C. Example 60 [2- (lH-2-indolylcarbonyl) -lH-5-indolyl) -4-phenylbenzoate P.f. : > 220 ° C. Example 61 [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] 2-phenylpropanoate P.f .: 211 - 313 ° C. Example 62 [2- (lH-2-indolylcarbonyl) -lH-5-indolyl] a-acetyl nyl-ethanoate P.f. : 194 - 196 ° C. Example 63 [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] benzoate P.f. : > 230 ° C. Example 64 [2- (1H-2-indolylcarbonyl) -lH-5-indolyl)] 3-methoxyphenyl-ethanoate P.f. : 212 - 215 ° C. Example 65 [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] 2-chlorobenzoate P.f. : > 230 ° C. Example 66 [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] -nitrobenzoate P.f. : > 230 ° C. Example 67 [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] 3,4,5-trimethoxybenzoate P.f. : 216 - 219 ° C. Example 68 [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] cinnamate P.f. : 226-228 ° C. Example 69 [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] 2-furanyl-carboxylate P.f. : > 230 ° C.

EXAMPLE 70 Di (1-phenylsulfonyl-1H-2-indolyl) methane To a solution of 26.67 g (49.2 mmol) of Bis (N-phenylsulfonylindol-2-yl) -1-methanol and 15.00 g (57.8 mmol) of triphenylsilane in 400 ml of absolute CH2C12 are added after 30 minutes dropwise 22.4 ml of trifluoroacetic acid (TFA). After stirring for 1 h at room temperature, H2O is added. and the mixture is carefully neutralized with solid Na 2 CO 3. After separating the phases, drying the organic phase under Na 2 SO 4 and removing the solvent by distillation, the crude product is purified by column chromatography (SiO 2; CH2Cl2 / hexane 6: 4), colorless crystals, yield: 22.5 g (87%). P.f. : 144-145 ° C (ether) Analogously there were produced: Example 71 Bis (5-methoxy-N-phenylsulfonylindol-2-yl) ethane P.f .: 159-16 ° C (CH 2 Cl 2 / hexane). Example 72 (S-methoxy-N-phenylsulfonyl-indol-2-yl) - (N-phenyl-sulfonyl-indol-2-yl) methane P. f. : 98-100 ° C (CH2Cl2 / hexane). Example 73 (5-methoxy-N-phenylsulfonylindol-2-yl) - (7-methoxy-N-phenyl-sulfonyldindole-2-yl) methane P. f. : 168 - 170 ° C (CH2Cl2 / hexane) Example 74 Di (lH-2-indolyl) methane 15.0 g (28.5 mmol) of 57 are boiled for 14 days with 20 g of K2C03 in 800 ml of MeOH and 200 ml of H20.

For the elaboration Tage gekocht. Zur Aufarbeitung 500 ml of saturated NaCl solution are added and the phases are separated. After drying the organic phase, the solvent is removed by vacuum.

The crude product is purified by column chromatography, colorless crystals, yield: 5.4 g (76%). P.f. : 189-191 ° C Analogously, the following were produced: Example 75 (5-methoxyindol-2-yl) - (indol-2-yl) methane "mp: 112aC (MeOH) Example 76 (lH-indol-2-yl) ) - (lH-indol-3-yl) -1-methane MP: 161 - '163 ° C (aqueous EtOH) Example 77 1,3-di (lH-2-indolyl) propane 38.0 g (0.21 mol) are dissolved of trimethylsilyl-o-toluidide in 959 ml of absolute hexane and at room temperature 291.0 ml (0.47 mol) of n-buLi (1.6 M in hexane) are added dropwise, and the mixture is heated at reflux for 4 hours. Then, it is cooled to -78 ° C, and at this temperature 20.5 ml (0.11 mol) of glutaric acid diethyl ester in 380 ml of absolute THF are added dropwise, stirring is carried out for 1 hour at -78 ° C. Then, cool slowly overnight at room temperature, then heat for another 2 hours at boiling, after cooling, pour over 1 1 of water / ice and extract with 5 * 500 ml of ethyl acetate, the organic phases re NaHCO4 is dried over Na2SO4 and the solvent is removed in vacuo. White crystals, Yield: 6.55 g (23.9 mmol, 22%) M.p .: 143-145 ° C (ethanol) Analogously there was: Example 78 1, 3-di (lH-2-indolyl) ethane P.f. : 264-267 ° C Example 79 1, 2-di- (1-phenylsulfonyl-1H-2-indolyl) -1-ethene (17.9 mmol) of TiCl with a syringe and then 2.0 g (30.5 mmol) of powder are added of Zn. The initial preparation is heated for 30 minutes at reflux. * After that, at 0 ° C, 3 g (10.5 mmol) of 22 dissolved in 50 ml of THF are added dropwise. The solution is heated overnight at reflux. To the cooled solution, 300 ml of 20 percent K2K03 solution is poured, and stirring is allowed to continue overnight at room temperature. The mud residue is then filtered off and washed with THF, the organic phase is separated from the filtrate and the aqueous phase is extracted with CH2C12. The combined organic phases are washed with water, dried over Na 2 SO and freed from the solvent in vacuo. Purification is carried out by column chromatography (Si02; CH 2 Cl 2 / hexane 2: 1). Yield: 1.1 g (2.0 mmol, 39%) of yellow crystals. P.f. : 272 ° C Example 80 Bis (5-methoxy-N-phenylsulfonylindol-2-yl) phenoxymethane To a solution of 2 g (3.7 mmol) of bis (N-phenylsulfonylindol-2-yl) -1-methanol in 20 ml of THF is added at 0 ° C 188 mg NaH (60% paraffin). Then, 13.5 mg of tetrabutylammonium iodide and 0.45 ml of benzyl bromide are added and the mixture is stirred at 20 ° C. Then water and ether are carefully added, the ether is separated and the aqueous phase is washed twice with ether. The organic phase is dried over Na 2 SO 4 and then the solvent is removed. Yield: 0.86 mg (81%). P.f. : 192 ° C (Desc.) Example 81 1,2,3,8, 9,10-hexahydroindolo [3 ', 2': 5, 6] pyrolo [3 ', 4': 3,4] -cyclohepta [b ] indol-l, 3-dione To 236 mg (9.75 mmol) of Mg chips in 6 ml of absolute THF is added half of 0.73 ml (9.75 mmol) of anhydrous ethyl bromide. After the reaction is turned on, the rest of the ethyl bromide is added dropwise in such a manner that the solution is kept boiling. It is then boiled until the dissolution of the Mg chips (approximately 30 minutes). After cooling to room temperature, 1.00 g (4.06 mmol) of methylene-2,2'-bisindol in 25 ml of absolute toluene and 1 ml of absolute THF are added and the mixture is stirred at 45 [deg.] C. for 45 minutes. After cooling to room temperature again, 1.04 g (4.06 mmol) of dibromomaleinimide in 50 ml of absolute toluene and 2 ml of absolute THF are added dropwise over one hour, then heated to reflux overnight. For working up, 100 g of ice and 50 ml of 20% citric acid are added, followed by shaking off 2 x with 50 ml of ethyl acetate. The organic extracts are washed with H20, dried over Na2SO4 and concentrated. The crude product is purified by column chromatography (Si02; 1. CH2Cl2 / ethyl acetate 8: 2; 2. CH2Cl2 / ethyl acetate 7: 1): red crystals, yield: 290 mg (22%), melting point : > 350 ° C (ethyl acetate).

Analogously, there were produced: Example 82 1,2,3,8,9, 10-hexahydro-5-methoxyindolo [3 ', 2': 5,6] pyrolo- [3 ', 4': 3, 4] - cyclohepta [b] indol-l, 3-dione Pf. : > 350 ° C (EtOH) Example 83 1,2,3,8,9,10,11, 12-octahydroindolo [3 ', 2': 5,6] pyrolo- [3 ',': 3,4] -cyclone [b] indole-1,3-dione MP: 137 ° C (CH2C12) (Desc.) Example 84 1,2,3,8,9,10,1-heptahydro-2-methylindolo [3 ', 2': 5, 6] -pirol [3 ', 4': 3,4] cycloocta [b] indole-1,3-dione Pf. : > 350 ° C Example 85 2-benzyloxymethyl-1, 2,3,8,9, 10-hexahydroindolo [3 ', 2': 5, 6] -pyrolo [3 ', 4": 3, 4] -cyclohepta [ blindol-1, 3 -di ona Pf. : > 350 ° C (EtOH) Example 86 1,2,3,8,9, 10-hexahydro-2-methylindolo [3 ', 2': 5,6] pyrolo- [3 ', 4': 3, 4] - cyclohepta [b] indol-l, 3-dione Pf. : > 350 ° C (CH2C12) Example 87 3.8 / 9, 10-tetrahydro-8- [2- (N, N-dimethylamino) ethyl-lH-indolo- [3 ', 2': 5, 6] furo- [ 3 ', 4': 3,] cyclohepta [b] indole-1,3-dione Pf: > 350 ° C (MeOH) Example 88 2-Benzyloxymethyl-1, 2,3,8, 9, 10-hexahydro-8- [2- (N, N-dimethylamino) -ethyl] indolo [3 ', 2' : 5,6] pyrolo [3 ', 4': 3,4] cyclohepta- [b] indol-l, 3-dione Pf. : 164-165 ° C (MeOH) Example 89 1,2,3,8,9, 10-hexahydro-2-methyl-8- [2- (N, N-dimethylamino) -ethyl] indole [3 ', 2 ': 5, 6] -pirol [3', 4 ': 3, 4] ciciohepta [b] -indol-1, 3-dione Pf: 185 ° C (MeOH) Example 0 1,2,3,8, 9, 10-hexahydro-8- [2- (N, N-dimethylamino) ethyl] indole- [3 ', 2 5, 6] pyrolo- [3', 4 ': 3, 4] ciciohepta [b] indole- 1, 3-dione P.f. : 213-214 ° C (EtOH) EXAMPLE 91 3-Bromo-4- (2- (2- (lH-2-indolyl) ethyl) -lH-3-indolyl) -1-methyl-2, 5-dihydro- lH-pyrol-2, 5-dion Mp: 169 ° C Example 92 3-bromo-4- (2- (4- (lH-2-indolyl) util) -lH-3-indolyl) -1-methyl- 2 , 5-dihydro-lH-pyrol-2, 5-dione Pf : 165 ° C (Desc.) Example 93 3-bromo-4- (2- (5- (lH-2-indolyl) pentyl) -lH-3-indolyl) -1-methyl-2, 5-dihydro-1H -pyrol-2, 5-dione Pf : 125 ° C (Desc.) Example 94 Bis- (indol-3-yl) methanone Analogously to example 31, mit triphosgene instead of di-omeleimide. P.f. : 297-299 ° C Example 95 Diastereomeric mixture of 8- (3, 4, 6-tri-0-benzyl-β-D-glucopyranosyl) -2-benzyloxymethyl-l, 2,3,8,9, 10-hexahydro -indole [3 ', 2': 5, 6] pyrolo [3 ', 4': 3, 4] cyclohepta [b] indol-l, 3-dione and 8- (3, 4, 6-tri-O- benzyl- -D-mannopyranosyl) -2-benzyloxymethyl-1,2,3,8,9,10-hexahydroindolo [3 ', 2': 5,6] pyrolo [3 ', 4': 3,4] -cyclohepta [b] indol-l, 3-dione Diastereomeric mixture of the disubstituted O-glucosides 468.7 mg (1.02 mmol) of 2-benzyloxymethyl-1,2,3,8, 9,10-hexahydroindolo [3 ', 2': 5 , 6] pyrolo [3 ', 4': 3, 4] -cyclohepta [b] indol-l, 3-dione are added to a suspension of 91.8 mg (3.06 mmol) of NaH (80 percent in paraffin oil ) in 16 ml of absolute THF. After 30 minutes, the solution of 1,2-anhydro-3,6,6-tri-O-benzyl-D-glucopyranose in 16 ml of absolute THF is added dropwise. The preparation is stirred for 5 hours at 50 ° C and 1 hour at 60 ° C. For working up, the reaction mixture is poured into 10 ml of a saturated solution of NaHCO 3 and 3 x extracted with 10 ml of ethyl acetate. The combined organic extracts are washed with 15 ml of a saturated NaCl solution, dried over Na 2 SO 4 and concentrated in vacuo. The product is separated from the by-products and the final product which did not react by column chromatography (1. column: Si02, toluene / isopropylamine 8: 2, 2. column: SiO2, CH2Cl2 / MeOH 12: 1). The separation of the diastereomeric mixture is carried out by high performance liquid chromatography. Example 96 Diastereomeric mixture of 8- (β-D-glucopyranosyl) -1,2,3,8,9,10-hexahydroindolo [3 ', 2': 5,6] pyrolo [3 ', 4': 3,4 ] -cyclohepta [b] indol-l, 3-dione and 8- (aD-mannopyranosyl) -1,2, 3,8, 9,10-hexahydroindolo [3 ', 2': 5, 6] pyrolo [3 ' , 4 ': 3,4] -cyclohepta [b] indole-l, 3-dione 150 mg (0.17 mmol) of 8- (3, 4, 6-tri-O-benzyl-D-glucopyranosyl) -2-benzyloxymethyl -l, 2, 3, 8, 9, 10-hexahydro-indole [3 ', 2': 5, 6] pyrolo [3 ', 4': 3, 4] cyclohepta [b] indol-l, 3-dione , as a diastereomeric mixture, they are dissolved in 50 ml of absolute EtOH and, after the addition of 200 mg of Pd / C (5%) are stirred for 5 hours under a pressure of 7 bar of H2. After this, it is suctioned through Celite, washed with 50 ml of CH2C12 and the solution is concentrated in vacuo. The product is dissolved without purification in 15 ml of absolute THF, and the solution is cooled to 0 ° C. Then, it is swept for 10 minutes with NH3 and stirred for 1 hour at room temperature. After extracting the THF in vacuo the remaining oil is purified by column chromatography (Si02; CH2Cl2 / MeOH 8: 2): red oil, yield: 10 mg (12%). Example 97 1,2, 3, 3a, 8, 9, 10, 14c-octahydroindolo [3 ', 2': 5, 6] pyrolo- [3 ', 4': 3, 4] cyclohepta [b] indole-1 , 3-dione 1.20 g (18.4 mmol) of Zn granules are washed with 2 x 3 ml of 2 N HCl, then immediately added to 90 mg (0.33 mmol) of HgCl2 in 1.5 ml of H20 and 1.5 ml of HCl concentrate, and shake for 10 minutes at room temperature. The aqueous phase is decanted and the zinc amalgam is still washed with 2 x 3 ml of diluted HCl before adding it to a solution of 60.0 mg (0.18 mmol) of 1, 2, 3, 8, 9, 10-hexahydro-indole [3 ', 2': 5, 6] -pyrogol [3 ', 4 A 3, 4] cyclohepta [b] indol-l, 3-d-one in 1.5 ml of 5 N HCl, 1.5 ml of EtOH and 1.5 ml of toluene and heat to reflux. After 1 hour, as soon as the reaction mixture was cooled to room temperature, H20 is added and extracted with 2 x 10 ml of CH2Cl2. The organic extracts are dried over Na 2 SO 4, concentrated in vacuo and purified by column chromatography (SiO 2, CH 2 Cl 2 / ethyl acetate / MeOH 8: 2: 0.5). Colorless wax, yield 14 mg (23%).

Example 98 2.5-Dihydro-3,4-bis (N-trimethylsilylethoxymethylindol-2-yl) -lH-pyrolo-2, 5-dione To a solution of 22.65 mg (0.02 mmol) of tetrakistriphenylphosphinpalladium and 450.0 mg (1.77 mmol) of 3, -dibromo-2, 5-dihydro-lH-pyrolo-2, 5-dione in 10 ml of absolute DMF is added dropwise 1.05 g (1.96 mmol) of 2-tributylstannyl-N-trimethylsilylethoxymethylindole in 5 ml of Absolute DMF, and then heated 1 hour at 110 ° C. After cooling, it is poured onto 50 ml of H20 and extracted with 2 x 50 ml of ether. The ether phases are washed with 100 ml of H20, dried over Na2SO and concentrated.

The products can be separated by column chromatography (1. column: SiO2, CH2Cl2 / MeOH / hexane 20: 1: 2, 2. column: SiO2, CH2Cl2 / ethyl acetate 20: 1). Yellow wax, yield: 200 mg (19%) Analogously, Example 99 2, 5-dihydro-3,4-bisindol-2-yl-lH-pyrolo-2, 5-dione P was produced. f. : 197 ° C (Dec.) (CH2Cl2 / hexane) Example 100 2, 5-dihydro-3,4-bis (N-phenylsulfonylindol-2-yl) -lH-pyrolo-2, 5-dione Pf: 196 - 197 ° C (Dec.) (Acetone) Example 101 2, 5-dihydro-l-methyl-3,4-bis (N-phenylsulfonylindol-2-yl) -1 H -pyrolo-2, 5-dione Mp: 147 ° C (Ether) Example 102 2,5-Dihydro-3,4-bisindol-2-yl-l-methyl-lH-pyrolo-2, 5-dione Mw: 247 ° C (CH 2 Cl 2 / hexane) (Desc.) Example 103 2, 5-dihydro-3-indol-2-yl-l- [2- (N, -dimethylamino) ethyl] -4- (N-phenylsulfonylindol-2-yl) -lH-pyrolo-2, 5-dione 2,5-dihydro-l- [2- (N, N-dimethylamino) ethyl] -3,4-bis (N-phenyl-sulfonylindol-2-yl) -lH-pyrolo-2, 5-dione 4.12 mmol of 2,5-dihydro-3,4-bis (N-phenylsulfonyl-indol-2-yl) -lH-pyrolo-2, 5-dione is dissolved in 30 ml of absolute DMF and 200 mg (5.00 g. mmol) of KH. After stirring for 1 hour at room temperature, the haiogenide is added and stirred for 24 hours at room temperature. For working up the preparation is poured over water / ice. The DMF and the H20 are removed by vacuum distillation, the residue is dissolved in CH2C12 and washed with H20. After drying over Na2SO4, the solvent is removed in vacuo and the residue is purified by column chromatography.

(Si02; ethyl acetate). Yield: 448 mg. It was not possible to separate 121 and 122 by column chromatography.

Analogously there were obtained: Example 104 2,5-dihydro-3,4-bis (indol-2-yl) -1 [2- (N, N-dimethylamino) -ethyl] -lH-pyrolo-2, 5- dione Orange wax Example 105 1- (2-Bromethyl) -2,5-dihydro-3,4-bis (N-phenylsulfonylindol-2-yl) -lH-pyrolo-2, 5-dione Yellowish brown wax Example 106 1- (2-Bromethyl) -2,5-dihydro-3-indol-2-yl-4- (N-phenylsulfonyl-indol-2-yl) -lH-pyrolo-2, 5-dione Pf: 160 ° C (Desc. .) Example 107 1- (2-Brometii) -2,5-dihydro-3,4-bis (indol-2-yl) -lH-pyrolo-2, 5-dione Pf : 104-109 ° C Example 108 1- (2-Azidoethyl) -2,5-dihydro-3,4-bis (N-f-enylsulfonylindol-2-yl) -lH-pyrolo-2, 5-dione, P.f. : 165 ° C (Desc.) Example 109 1- (2-Azidoethyl) -2,5-dihydro-3-indol-2-yl-4- (N-phenyl-sulfonylindol-2-yl) -lH-pyrolo- 2, 5-dione Pf: 190 ° C (Desc.) Example 110 1- (2-aminoethyl) -2,5-dihydro-3-indol-2-yl-4- (N-phenyl-sulfonylindol-2-yl) ) -lH-pirolo-2, 5-dion Pf : 180 ° C (Desc.) Example 111 3-Bromo-4- (2- (3- (3- (4-bromo-l-methyl-2, 5-dioxo-2, 5-dihydro-lH-3- pyrolyl) -lH-2-indolyl) propyl) -lH-3-indolyl) -1-methyl-2-, 5-dihydro-lH-pyrol-2, 5-dione 200 mg (0.7 mmol) of 1,3-di (lH-2-indolyl) propane are dissolved in 4 ml of absolute THF and cooled to 0 ° C. Then 1.09 ml (1.7 mmol) of n-buLi (1.6 M in hexane) are added dropwise over 30 minutes, and the mixture is stirred for 2 hours at room temperature. Then 0.46 g (1.71 mmol) of N-methyl-dibromomaleimide in 4 ml of absolute THF are slowly added dropwise. The preparation is stirred overnight at room temperature and then poured into 10 ml of 2 N HCl. The mixture is then extracted with ether (2 x 10 ml) and ethyl acetate (3 x 10 ml), the organic phase Dry over Na2SO and remove the solvent in vacuo. The residue is purified by column chromatography (Si0; CH2C12). Red powder, yield: 0.20 g (44%). P.f. : 160 ° C (Desc.) Analogously produced: Example 112 3-Bromo-4-. { 2- (5- (3- (4-bromo-l-methyl-2, 5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -lH-2-indolyl) pentyl) -lH-3-indolyl ) -1-methyl-2, 5-dihydro-lH-pyrol-2, 5-dione Pf: 137 ° C (Desc.) Example 113 3-Bromo-4- (2- (3- (3- (4- bromine-2, 5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -lH-2-indolyl) propyl) -lH-3-indolyl) -2,5-dihydro-lH-pyrol-2, 5 -diona Pf. : > 350 ° C Example 114 3-Bromo-4- (2- (5- (3- (4-bromo-2,5-dioxo-2,5-dihydro-lH-3-pyrolyl) -lH-2-indolyl) pentyl) -lH-3-indolyl) -2,5-dihydro-lH-pyrol-2, 5-dione Pf. : > 350 ° C Example 115 3-Bromo-4- (2- (8- (3- (4-bromo-2, 5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -lH-2-indolyl) octyl) -lH-3-indolyl) -2,5-dihydro-lH-pyrol-2, 5-dione Pf: 180 ° C (Desc.) Example 116 3-Bromo-4- (2- (2- (3 - (4-bromo-l-methyl-2, 5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -lH-2-indolyl) ethyl) -lH-3-indolyl) -l-methyl-2 , 5-dihydro-lH-pyrol-2, 5-dione Pf : 179 ° C Example 117 3-Bromo-4- (2- (4- (3- (4-bromo-l-methyl-2, 5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -lH -2-indolyl) butyl) -lH-3-indolyl) -1-methyl-2, 5-dihydro-lH-pyrol-2, 5-dione Pf : 190 ° C (Desc.) Example 118 3-Bromo-4- (2- (8- (3- (4-bromo-l-methyl-2, 5-dioxo-2, 5-dihydro-lH-3- pyrolyl) -lH-2-indolyl) octyl) -lH-3-indolyl) -1-methyl-2, 5-dihydro-lH-pyrol-2, 5-dione Pf: 185 ° C (Desc.) Example 119 3 -Bromo-4- (2- (10- (3- (4-br_. ~? Ol-methyl-2, 5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -lH-2-indolyl) decyl) -lH-3-indolyl) -1-methyl-2, 5-dihydro-lH-pyrol-2, 5-dione Pf: 164 ° C (Desc.) Example 120 3-Bromo-4- (2- ( 10- (3- (4-bromo-2, 5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -lH-2-indolyl) decyl) -lH-3-indolyl) -2,5-dihydro -lH-pyrol-2, 5-dione P. f. : 164 ° C (Desc.) Example 121 3-Bromo-4- (2- (12- (3- (4-bromo-l-methyl-2, 5-dioxo-2, 5-dihydro-lH-3 -pyrolyl) -lH-2-indolyl) dodecyl) -lH-3-indolyl) -1 methyl-2, 5-dihydro-lH-pyrol-2, 5-dione Pf : 126-129 ° C By the reaction of the compound of Example 114 with dimethylamine, Example 122 3-N, N-dimethylamino-4- (2- (5- (3- (4-N, N-dimethyl- amino-2, 5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -lH-2-indolyl) entyl) -1H-3-indolyl) -2,5-dihydro-lH-pyrol-2, 5 -dione Example 123 l-methyl-3- (1-pyrolidinyl) -4- (2- (5- (3- (l-methyl-4- (1-pyrolidinyl) -2,5-dioxo-2, 5- dihydro-lH-3-pyrolyl) -1H-2-indolyl) -pentyl) -lH-3-indolyl) -2,5-dihydro-lH-pyrol-2, 5-dione 1.0 g (1.5 mmol) of 3-bromo-4- (2- (5- (3- (4-bromo-l-methyl-2, 5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -1H-2-indolyl) pentyl ) -lH-3-indolyl) -l-metii-2, 5-dihydro-1H-pyrol-2, 5-dione in 5 ml (60.6 mmol) of pyrolidine and left stirring overnight at room temperature. The excess pyrrolidine is then removed by distillation. The residue is completely freed of solvent residues under vacuum from the oil pump, and then purified by column chromatography (SiO2, CH2Cl2 / ethyl acetate 95: 5). Yield: 480 mg (49%). Mp: 298 ° C Analogously there were produced: Example 124 l-Methyl-3- (1-piperidinyl) -4- (2- (5- (3- (l-methyl-4- (1-piperidinyl) -2 , 5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -1H-2-indolyl) pentyl) -lH-3-indolyl) -2,5-dihydro-lH-pyrol-2, 5-dione Pf : 262 ° C Example 125 l-methyl-3- (1-morpholinyl) -4- (2- (5- (3- (l-methyl-4- (1-morpholinyl) -2,5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -1H-2-indolyl) pentyl) -lH-3-indolyl) -2,5-dihydro-lH-pyrol-2, 5-dione Pf: 168-170 ° C Example 126 l -methyl-3- (1-tetrahydroisoquinolinyl) -4- (2- (5- (3- (1-methyl-4- (1-tetrahydroisoquinolinyl) -2,5-dioxo-2, 5-dihydro-lH-3 -pyrolyl) -lH-2-indolyl) pentyl) lH-3-indolyl) -2,5-dihydro-lH-pyrol-2, 5-dione Pf : 141-142 ° C Example 127 l-Methyl-3- (1- (4- (3-trifluoromethylphenyl) piperazinyl)) -4- (2- (5- (3- (l-methyl-4- (1- (4- (3-trifluoromethylphenyl) piperazine)) -2,5-dioxo-2,5-dihydro-lH-3-pyrolyl) -lH-2-indolyl) pentyl) -lH-3-indolyl) -2, 5 -dihydro-lH-pyrol-2, 5-dione Pf : 140-141 ° C Example 128 l-Methyl-3- (1- (4-isopropylaminocarbonylmethylpiperazini)) -4- (2- (5- (3- (l-methyl-4- (1- (4-isopropylaminocarbonylmethyl- piperazini)) -2, 5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -1H-2-indolyl) pentyl) -lH-3-indolyl) -2,5-dihydro-lH-pyrol-2, 5-dione P.f. : 126-128 ° C Example 129 l-Methyl-3- (1- (4-isopropylaminocarbonylmethylpiperazine)) -4- (2- (5- (3- (4-bromo-lmethyl-2,5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -lH-2-indolyl) pentyl) -lH-3-indolyl) -2,5-dihydro-lH-pyrol-2, 5-dione Pf : 156 ° C Example 130 l-Methyl-3- (1- (4-pyrrolidinylcarbonylmethylpiperazine)) -4- (2- (5- (3- (l-methyl-4- (1- (4-pyrrolidinylcarbonylmethyl-piperazinyl) ) -2,5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -1H2-indolyl) pentyl) -lH-3-indolyl) -2,5-dihydro-lH-pyrol-2, 5-dione Pf : 158 ° C (Desc.) Example 131 l-Methyl-3- (1- (4-pyrrolidinylcarbonylmethylpiperazine)) -4- (2- (5- (3- (4-bromo-l-methyl-2, 5- dioxo-2, 5-dihydro-lH-3-pyrolyl) -lH-2-indolyl) pentii) -lH-3-indolyl) -2,5-dihydro-lH-pyrol-2, 5-dione Pf : 158 - 159 ° C Example 132 L-methyl-3- (1- (4-piperidinopiperidini1)) -4- (2- (5- (3- (l-methyl-4- (1- (4-piperidinopiperidinyl)) -2, 5-dioxo-2, 5-dihydro-1H-3-pyrolyl) -lH-2-indolyl) pentyl) -lH3-indolyl) -2,5-dihydro-lH-pyrol-2, 5-dione Pf : 230-232 ° C (Desc.) Example 133 l-Methyl-3- (1- (4-piperidinopiperidinyl)) -4- (2- (5- (3- (4-bromo-1-methyl-2, 5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -1H-2-indolyl) pentyl) -lH-3-indolyl) -2,5-dihydro-lH-pyrol-2, 5-dione Pf : 162-164 OC Example 134 L-Methyl-3- (1- (4-ethoxycarbonylpiperazin-1-yl)) -4- (2- (5- (3- (1-methyl- (4-ethoxycarbonylpiperazine-1) il) -2,5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -lH-2-indolyl) pentyl) -lH-3-indolyl) -2,5-dihydro-lH-pyrol-2, 5-dione Pf : 149-150 ° C Example 135 L-methyl-3- (1- (4- (N- (4-hydroxyphenyl) -ethylamino)) -4- (2- (5- (3- (1-methyl- ( 4-bromo-2, 5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -1H-2-indolyl) pentyl) -lH-3-indolyl) -2,5-dihydro-lH-pyrol-2 , 5-dione Mp: 120-122 ° C (Desc.) Example 136 L-methyl-3- (1- (4- (Nl, 2-diaminoethyl)) -4- (2- (4- (3- ( 1-Methyl- (4-bromo-2, 5-dioxo-2,5-dihydro-lH-3-pyrolyl) -lH-2-indolyl) -butyl) -lH-3-indolyl) -2,5-dihydro -lH-pyrol-2, 5-dione Pf: 180 ° C (Desc.) Example 137 l-methyl-3- (1- (4- (Nl, 2-diaminoethyl)) -4- (2- (4- (3- (1-methyl- (4- (Nl, 2-diaminoethyl) -2,5-dioxo-2, 5-dihydro-lH-3-pyrolyl) -lH-2-indolyl) butyl) -lH-3 -indolyl) -2,5-dihydro-lH-pyrol-2, 5-dione Pf .:: >; 240 ° C (Desc.) Example 138 4.39-dimethyl-l, 4,14,29,39,42-hexaazaoctacyclo [40.2.2.0 (2.6) .0 (7, 15) .0 (8, 13 ) .0 (28, 36). 0 (30.35) .0 (37.41)] hexatetraconta-2 (6), 7 (15), 8 (13), 9, 11, 28 (36), 30 (35), 31, 33, 37 (41) decane-3, 5, 38, 0-tetraone 0.75 mmol of 3-Bromo-4- (2- (12- (3- (4-bromo-l-methyl-2, 5-dioxo-2, 5 -dihydro-lH-3-pyrolyl) -lH-2-indolyl) -dodecyl) -lH-3-indolyl) -l-methyl-2,5-dihydro-lH-pyrol-2, 5-dione are dissolved in 200 ml of absolute DMF, they are mixed with 0.5 ml of absolute NEt3 and heated to 80 ° C. Then, the solution of 0.75 mmol of piperazine in 100 ml of absolute DMF and 0.5 ml of NEt is slowly added dropwise to the hot solution and then it is stirred for 48 hours at 80 ° C. The solvent is then removed as much as possible under vacuum, and the residue is mixed with 100 ml of 1 N HCl. This solution is then extracted with ethyl acetate (total about 600 ml), the combined extracts are dried over Na2SO4. and the solvent is extracted under vacuum. Purification is carried out by column chromatography (SiO2; CH2Cl2 / ethyl acetate 9.5: 0.5). Orange crystals, yield: 0.267 g (52%). P.f. : 194 - 195 ° C Analogously there were produced: Example 139 8,43-dimethyl-5, 8, 18, 33, 43,46-hexaazanonacyclo [44.2.2.2 (2.5) .0 (6, 10). 0 (11, 19) .0 (12,17) .0 (32,40) .0 (34,39) .0 (41,45)] dopentaconta-6 (10), 11 (19), 12 (17 ), 13.15, 32 (40), 34 (39), 35.37, 41 (45) -decaen-7, 9, 42, 4-tetraone Pf. : > 250 ° C Example 140 9, 44 -Dimethyl-6, 9,19,34,44,47-hexaazanonacyclo [45.2.2.2 (3,6) .0 (7, 11) .0 (12, 20) .0 ( 15, 18) .0 (33, 412) .0 (35, 40) .0 (42, 46)] tripentaconta-7 (11), 12 (20), 13 (18), 14, 16, 33 (41 ), 35 (40), 36, 38, 2 (46) -decaen-8, 10, 3, 45-tetraone Pf : 286 < C (Desc.) Example 141 10.45-Dimethyl-7,10,20,35, 45,48-hexaazanonacyclo [46.2.2.2 (4.7) .0 (8, 12) .0 (13.21). 0 (14, 19) .0 (34,42) .0 (36, 41) .0 (43, 47)] tetrapentaconta-Yes 12), 13 (21), 14 (19), 15,17, 34 ( 42), 36 (41), 37.39, 3 (47) -decaen-9, 11.44, 46-tetraone Pf. : > 250 ° C Example 142 11, 46-dimethyl-8,11,21,36,46,49-hexaazanonacyclo- [47.2.2.2 (5, 8) .0 (9, 13) .0 (14, 22) .0 (15, 20) .0 (35, 43) .0 (37, 42). 0 (44.48)] pentapentaconta-9 (13), 14 (22), 15 (20), 16, 18, 35 (43), 37 (42), 38, 40, 44 (48) -decaen-10 , 12, 45, 47-tetraone Pf : 276 ° C (Desc.) Example 143 13,48-dimethyl-10, 13,23,38,48,51-hexaazanonacyclo [49.2.2.2 (7, 10) .0 (11, 15) .0 (16, 24). 0 (1 7, 22) .0 (37, 45) .0 (39, 44) .0 (46, 50)] heptapentaconta 11 (15), 16 (24), 17 (22), 18, 20, 37 (45), 39 (44), 40, 42, 46 (50) -decaen-12, 14, 47, 49-tetraone Pf : 245 ° C (Desc.) Example 144 14, 49-dimethyl-1,1,14,24,39,49,52-hexaazanonacyclo [50.2.2.2 (8, 11) .0 (12,16) .0 ( 17,25) .0 (18, 23). 0 (38.46) .0 (40.45) .0 (47.51)] octapentaconta-12 (16), 17 (25), 18 (23), 19, 21, 38 (46), 40 (45), 41, 43, 47 (51) -decaen-13, 15, 48, 50-tetraone Pf: 325 ° C (Desc.) Example 145 4, 30-dimethyl-l, 4, 14, 20, 30, 33-hexaazaoctacyclo [31.2.2.0 (2.6) .0 (7, 15) .0 (8, 13) .0 (19, 27). 0 (2 1.26) .0 (28.32)] heptatriaconta-2 (6), 7 (15), 8 (13), 9,11,19 (27), 21 (26), 22,24,28 (32 ) -decaen-3, 5, 29, 31-tetraona Pf : 314 - 318 ° C Example 146 8.34-dimethyl-5,8,18,24,34,37-hexaazanonacyclo [35.2.2.2 (2.5) .0 (6, 10) .0 (11.19) .0 (12.17). 0 (23, 31) .0 (25, 30) .0 (32, 36)] tritetraconta-6 (10), 11 (19), 12 (17), 13, 15, 23 (31), 25 (30), 26, 28, 32 (36) -decaen- 7, 9, 33, 35-tetraone P.f. : 197 - 200 ° C Example 147 9,35-dimethyl-6,9,19,25,35,38-hexaazanonacyclo [36.2.2.2 (3,6) .0 (7, 11) .0 (12,20) .0 (13, 18) .0 24.32) .0 (26.31) .0 (33.37)] tetratetraconta-7 (11), 12 (20), 13 (18), 14, 16, 24 (32), 26 (31), 27, 29, 33 (37) -decaen-8, 10.34, 36-tetraone P.f. : 337 ° C (Desc.) Example 148 10.36-dimethyl-7,10,20,26,36,39-hexaazanonacyclo [37.2.2.2 (4, 7) .0 (8, 12) .0 (13, twenty-one) . 0 (14,19) .0 (25, 33) .0 (27, 32) .0 (34, 38)] pentatetraconta-8 (12), 13 (21), 14 (19), 15, 17, 25 (33), 27 (32), 28, 30, 34 (38) -decaen- 9, 11, 35, 37-tetraona Pf : 245 ° C (Desc.) Example 149 ll, 37-dimethyl-8, 11, 21,27,37,40-hexaazanonacyclo [38.2.2.2 (5.8) .0 (9,13) .0 (14, 22) .0 (15, 20) .0 (26, 34) .0 (28, 33) .0 (35, 39)] hexatetraconta- 9 (13), 14 (22), 15 (20), 16, 18, 26 (34), 28 (33), 29, 31, 35 (39) -decaen-10, 12, 36, 38-tetraone Pf: 325 ° C (Desc.) Example 150 13, 39-dimethyl-10 , 13,23,29, 39,42-hexaazanonacyclo [40.2.2.2 (7, 10) .0 (11, 15) .0 (16, 24). 0 (17.22) .0 (28.36) .0 (30.35) .0 (37, 41)] octatetraconta-ll (15), 16 (24), 17 (22), 18.20.28 (36), 30 (35), 31.33.37 (41) -decane-12, 14, 38, 40-tetraone P.f. : 245 ° C (Desc.) Example 151 14,40-dimethyl-ll, 14, 24, 30, 40,43-hexaazanonacyclo [41.2.2.2 (8, 11) .0 (12, 16). O (17, 25). 0 (18, 23) .0 (29, 37) .0 (31, 36) .0 (38, 42)] nonatetraconta-12 (16), 17 (25), 18 (23), 19, 21, 29 (37), 31 (36), 32, 34, 38 (42) -decaen-13, 15, 39, 41-tetraone Pf: 325 ° C (Desc.) Example 152 1.4.14.22.32, 35-hexaazaoctacyclo [33.2.2.0 (2.6) .0 (7, 15) .0 (8, 13) .0 (21.29) .0 (2 3.28) .0 (30.34)] nonatriaconta-2 (6), 7 (15), 8 (13), 9, 11, 21 (29), 23 (28), 24, 26, 30 (34) -decaen-3, 5, 31, 33-tetraone P.f. : 314 - 318 ° C Example 153 5,8,18,26,36,39-hexaazanonacyclo [37.2.2.2 (2.5) .0 (6.10) .0 (11.19) .0 (12.17 ). 0 (25, 33) .0 (27,32) .0 (34, 38)] pentatetraconta- 6 (10), 11 (19), 12 (17), 13, 15, 25 (33), 27 (32 ), 28, 30, 34 (38) -decaen-7, 9,35,37-tetraone Pf : 197 - 200 ° C Example 154 9,37-dimethyl-6,9,19,27,37,40-hexaazanonacyclo [38.2.2.2 (3, 6) .0 (7, 11) .0 (12,20) .0 (13, 18). 0 (26.34) .0 (28.33) .0 (35.39)] hexatetraconta-7 (11), 12 (20), 13 (18), 14, 16, 26 (34), 28 (33), 29, 31, 35 (39) -decaen-8, 10, 36, 38-tetraone P.f. : > 350 ° C Example 155 7,10,20,28,38,41 hexaazanonacyclo [39.2.2.2 (4, 7) .0 (8, 12) .0 (13, 21) .0 (14, 19). 0 (27, 35) .0 (29, 34) .0 (36, 40)] heptatetraconta- 8 (12), 13 (21), 14 (19), 15, 17, 27 (35), 29 (34 ), 30, 32, 36 (40) -decaen-9, 11, 37, 39-tetraone Pf : 290-292 ° C Example 156 11,39-dimethyl-8,11,21,29,39,42-hexaazanonacyclo [40.2.2.2 (5,8) .0 (9,13) .0 (14.22) .0 (15.20) .0 (28.36) .0 (30.35; 0 (37.41)] octatetraconta-9 (13), 14 (22), 15 (20), 16, 18, 28 (36), 30 (35), 31, 33, 37 (41) -decaen-10, 12, 38, 40-tetraone Mp: 310 ° C (Desc.) Example 157 13,41-dimethyl-10, 13,23, 31, 41,44-hexaazanonacyclo [42.2.2.2 (7, 10) .0 (11, 15) .0 (16, 24). 0 (17.22) .0 (30.38) .0 (32.37) .0 (39, 43) j entaconta 11 (15), 16 (24), 17 (22), 18,20,30 ( 38), 32 (37), 33, 35, 39 (43) -decane-12, 14, 40, 42-tetraone Pf: 310 ° C (Desc.) Example 158 14.42-dimethyl-ll, 14.24 , 32,42,45-hexaazanonacyclo [43.2.2.2 (8,11) .0 (12,16) .0 (17, 25). 0 (18, 23) .0 (31, 39) .0 (33, 38) .0 (40, 44)] unpentaconta- 12 (16), 17 (25), 18 (23), 19,21,31 (39), 33 (38), 34, 36, 40 (44) -decaen-13, 15, 41, 43-tetraone Pf : 321-324 ° C Example 159 6.13-dimethyl-5,6,7,8, 9,10,11,12,13,14,19,20,21,22,23,24-hexadecahydrodipirolo [3 ' , 4 ': 15.16: 3', 4 ': 5, 6] indolo [2', 3A13,14] [1,4] diazacyclohexadecino (8, 7: b) indole- 5,7, 12, 14 - tetraone Pf. : >; 240 ° C Example 160 1,4,14,29,39,42-hexaazaoctaciclo [40.2.2.0 (2,6) .0 (7,15) -0 (8,13) .0 (28, 36) 0 ( 30.35) .0 (37.41)] hexatetraconta-2 (6), 7 (15), 8 (13), 9, 11, 28 (36), 30 (35), 31, 33, 37 (41 ) -decaen-3, 5, 38, 40-tetraona P.f. : 194-195 ° C Example 161 5.8, 18, 33.43,46-hexaazanonacyclo [44.2.2.2 (2.5) .0 (6, 10). 0 (11, 19) .0 (12, 17) .0 (32, 40) .0 (34, 39) .0 (41, 45)] dopentaconta- 6 (10), 11 (19), 12 (17 ), 13,15,32 (40), 34 (39), 35,37,41 (45) decane-7, 9, 42, 44-tetraone Pf : 236-238 ° C Example 162 6, 9,19, 34, 44, 47-hexaazanonacyclo [45.2.2.2 (3.6) .0 (7, 11). 0 (12.20) .0 (15.18) .0 (33.412) .0 (35.40) .0 (42.46)] tripentaconta- (ll), 12 (20), 13 (18), 14 , 16.33 (41), 35 (40), 36.38.42 (46) -decaen-8, 10, 43, 45-tetraone P.f. : 231-233 ° C Example 163 7, 10, 20.35, 45, 48-hexaazanonacyclo [46.2.2.2 (4.7) .0 (8, 12). 0 (13, 21) .0 (14, 19) .0 (34, 42) .0 (36, 41) .0 (43, 47)] tetrapentaconta-8 (12), 13 (21), 14 (19 ), 15,17,34 (42), 36 (41), 37, 39, 43 (47) -decaen-9, 11, 44, 46-tetraone Pf : 209-211 ° C Example 164 8, 11, 21.36,46,49-hexaazanonacyclo [47.2.2.2 (5, 8) .0 (9, 13). 0 (14, 22) .0 (15, 20) .0 (35, 43) .0 (37, 42) .0 (44, 48)] pentapentaconta-9 (13), 14 (22), 15 (20 ), 16,18,35 (43), 37 (42), 38,40,44 (48) -decaen-10, 12, 45, 47-tetraone Pf : 282-284 ° C, Example 165 10, 13,23,38,48,51-hexaazanonacyclo [49.2.2.2 (7, 10) .0 (11, 15) 0 (16.24) .0 (17.22 ) .0 (37,45) .0 (39,44) .0 (46,50)] heptapentaconta-11 (15), 16 (24), 17 (22), 18,20,37 (45), 39 (44), 40, 42, 46 (50) -decaen-12, 14, 47, 49-tetraone Pf : 176-179 ° C Example 166 11, 14.24, 39.49.52-hexaazanonacyclo [50.2.2.2 (8.11) .0 (12, 16) 0 (17.25) .0 (18.23) .0 (38.46) .0 (40.45) .0 (47.51)] octapentaconta-12 (16), 17 (25), 18 (23 ), 19.21.38 (46), 40 (45), 41.43.47 (51) -decane-13, 15, 48, 50-tetraone, P.f. : 147-150 ° C Example 167 1, 4, 14,20, 30,33-hexaazaoctacyclo [31.2.2.0 (2.6) .0 (7, 15). 0 (8, 13) .0 (19,27) .0 (21,26) .0 (28,32)] heptatriaconta- 2 (6), 7 (15), 8 (13), 9,11,19 (27), 21 (26), 22,24,28 (32) -decaen- 3,5,29,31 -tetraone Pf: 350 ° C (Desc.) Example 168 5.8, 18, 24, 34, 37-hexaazanonacyclo [35.2.2.2 (2.5) .0 (6, 10). 0 (11, 19) .0 (12, 17) .0 (23, 31) .0 (25, 30) .0 (32, 36)] tritetraconta- 6 (10), 11 (19), 12 (17 ), 13, 15, 23 (31), 25 (30), 26, 28, 32 (36) -decaen-7, 9, 33, 35-tetraona Pf : 285 ° C (Desc.) Example 169 6, 9, 19, 25, 35, 38-hexaazanonacyclo [36.2.2.2 (3.6) .0 (7.11). 0 (12,20) .0 (13,18) .0 (24, 32) .0 (26, 31) .0 (33, 37)] tetratetraconta-7 (11), 12 (20), 13 (18 ), 14, 16, 24 (32), 26 (31), 27, 29, 33 (37) -decaen-8, 10, 34, 36-tetraone Pf: 215 ° C Example 170 7,10,20,26, 36,39-hexaazanonacyclo [37.2.2.2 (4.7). 0 (8, 12). 0 (13, 21) .0 (14, 19) .0 (25, 33) .0 (27, 32) .0 (34, 38)] pentatetraconta-8 (12), 13 (21), 14 (19 ), 15, 17, 25 (33), 27 (32), 28, 30, 34 (38) -decaen-9, 11, 35, 37-tetraone P.f. : 330 ° C (Desc.) Example 171 8, 11, 21, 27, 37, 40-hexaazanonacyclo [38.2.2.2 (5.8) .0 (9, 13). 0 (14.22) .O (15, 20) .0 (26.34) .0 (28.33) .0 (35.39)] hexatetraconta-9 (13), 14 (22), 15 (20 ), 16, 18, 26 (34), 28 (33), 29, 31, 35 (39) -decaen-10, 12, 36, 38-tetraone P.f. : 335.5 ° C (Desc.) Example 172 10,13,23,29,39, 42-hexaazanonacyclo [40.2.2.2 (7, 10) .0 (11,15) 0 (16, 24) .0 (17, 22) .0 (28, 36), 0 (30, 35) .0 (37, 41)] octatetraconta-ll (15), 16 (24), 17 (22 ), 18, 20, 28 (36), 30 (35), 31, 33, 37 (41) -decaen-12, 14, 38, 40-tetraone Pf : 243 - 245 ° C Example 173 ll, 14,24,30,40,43-hexaazanonacyclo [1.2.2.2 (8, ll) .0 (12,16) 0 (17, 25) .0 (18, 23) .0 (29, 37) .0 (31, 36) .0 (38, 42)] nonatetraconta-12 (16), 17 (25), 18 (23 ), 19,21,29 (37), 31 (36), 32, 34, 38 (42) -decaen-13, 15, 39, 41-tetraone Pf : 258 - 260 ° C Example 174 4,32-dimethyl-l, 4,14,22,32,35-hexaazaoctacyclo [33.2.2.0 (2,6) .0 (7, 15) .0 (8, 13) .0 (21, 29). 0 (23, 28) .0 (30, 34)] nonatriaconta-2 (6), 7 (15), 8 (13), 9, 11, 21 (29), 23 (28), 24, 26, 30 (34) -decaen-3, 5, 31, 33-tetraona P.f. : > 350 ° C Example 175 8,36-dimethyl-5,8, 18, 26, 36, 39-hexaazanonacyclo [37.2.2.2 (2,5) .0 (6, 10) .0 (11,19) .0 (12,17). 0 (25.33) .0 (27.32) .0 (34.38)] pentatetraconta-6 (10), 11 (19), 12 (17), 13,15,25 (33), 27 (32), 28,30,34 (38) -decaen- 7, 9, 35, 37-tetraone P.f. : 310 ° C (Desc.) Example 176 10.38-Dimethyl-7,10,20,28, 38,41-hexaazanonacyclo [39.2.2.2 (4.7) .0 (8, 12) .0 (13, 21) .0 (14, 19) .0 27.35) .0 (29.34) .0 (36, 40)] heptatetraconta-8 (12), 13 (21), 14 (19), 15,17,27 (35), 29 (34), 30, 32, 36 (40) -decaen-9, 11, 37, 39-tetraone Pf: 280 ° C (Desc.) Example 177 13,46-dimethyl-l, 7,10,13,23,36,46,49-octaazanonacyclo [47.2.2.2 (7.10) .0 (11, 15) .0 (16, 24) .0 (17 , 22). 0 (35.43) .0 (37.42) .0 (44.48) lpentapentaconta-11 (1 5), 16 (24), 17 (22), 18, 20, 35 (43), 37 (42), 38, 40, 44 (48) -decaen-12, 14, 45, 47-tetraone P.f. : > 220 ° C Example 178 4, 31-dimethyl-1,4,4,21,31-34-hexaazaoctacyclo [32.2.2.0 (2.6) .0 (7,15) .0 (8,13) .0 ( 20, 28). 0 (22.27) .0 (29, 33)] octatriaconta-2 (6), 7 (15), 8 (13), 9, 11, 20 (28), 22 (27), 23, 25, 29 (33) -decaen-3, 5, 309, 32-tetraona P.f. : > 240 ° C (Desc.) Example 179 8, 35-dimethyl-5, 8, 18, 25, 35, 38-hexaazanonacyclo [36.2.2.2 (2.5) .0 (6, 10) .0 (11.19) ) .0 (12, 17). 0 (24, 32) .0 (26, 31) .0 (33, 37)] tetratetraconta- 6 (10), 11 (19), 12 (17), 13,15,24 (32), 26 (31 ), 27, 29, 33 (37) -decaen-7, 9, 34, 36-tetraona, Pf: > 240 (Desc.) Example 180 (1- (2-dimethylaminoethyl) -lH-3-indolyl) (lH-3-indolyl) -1-methanone 0.5 g of bis (indol-3-yl) methanone are dissolved in 30 ml of acetone. After the addition of 0.92 g K2C03 and 0.27 g of 2-dimethylamino-1-chloroethane hydrochloride, the mixture is heated under reflux for 70 hours. The acetone is extracted and the residue is mixed with 30 ml of water and 30 ml of ethyl acetate. After 15 minutes of stirring, the organic phase is separated and the aqueous phase is extracted by shaking a further two times with 15 ml of ethyl acetate respectively. The combined organic phases are dried over Na 2 SO 4 and the solvent is removed by suction. The purification is carried out by column chromatography (Si02, ethyl acetate / MeOH 10: 1). Yield: 0.14 g (20%) P.f. : 180 - 182 ° C Analogously, they were produced. Example 181 (1- (2-morpholinoethyl) -lH-3-indolyl) (lH-3-indolyl) -1-methanone P.f. : 192 - 194 ° C Example 182 Bis (1- (2-morpholinoethyl) -lH-3-indolyl) -1-methanone P.f. : 91-93 ° C Example 183 (1- (2-piperidinoethyl) -lH-3-indolyl) (lH-3-indolyl) -1-methanone P.f. : 223-225 ° C Example 184 Bis (1- (2-piperidinoethyl) -lH-3-indolyl) -1-methanone P.f. : 152 - 155 ° C Example 185 (1- (3-dimethylaminoprapyl) -lH-3-indolyl) (lH-3-indolyl) -1-methanone P.f. : 144-146 ° C Example 186 (1- (3-pyrrolidinopropyl) -lH-3-indolyl) (lH-3-indolyl) -1-methanone P.f. : 148-152 ° C Example 187 (1- (2-dimethylaminoethyl) -lH-2-indolyl) (lH-2-indolyl) -1-methanone P.f. : 147-150 ° C Example 188 (1- (2-morpholinoethyl) -lH-2-indolyl) (lH-2-indolyl) -1-methanone Wax Example 189 (1- (2-? Iperidinoethyl) -lH-2 -indolyl) (lH-2-indolyl) -1-methanone Wax Example 190 (1- (2-pyrrolidinoethyl) -lH-2-indolyl) (lH-2-indolyl) -1-methanone Wax Example 191 11, 46- dimethyl-21, 36-bis (2- (1-piperindinyl) -ethyl) -8,11,21,36,46,49-hexaazanone-cyclo [47.2.2.2 (5,8) .0 (9,13). 0 (14.22) .0 (15.20) .0 (35.43) .0 (37.42). 0 (44.48)] pentapentaconta-9 (13), 14 (22), 15 (20), 16, 18, 35 (43), 37 (42), 38.40.44 (48) -decaen-10, 12, 45, 47-tetraone P.f. : 125-130 ° C Example 192 3, 3'-dimethoxydiglioxyl-1,8- (2,2'-bisindolyl) octane. Under the atmosphere of N 2, oxalyl dichloride is added dropwise to a solution of 1.15 g (4.0 mmol). of 1, 8- (2, 2'-bisindolyl) octane in 20 ml of absolute THF and stirred for 2 hours at room temperature. Then 20 ml of MeOH is added dropwise. The preparation is stirred overnight at room temperature. For working up, the preparation is mixed with 100 ml of 1 N HCl, neutralized with 2 N NaOH and the mixture extracted with ethyl acetate (3 x 25 ml). After drying over Na 2 SO 4 the solvent is removed. P.f. : > 250 ° C (dec.) Example 193 3- (2- (4- (lH-2-indolyl) butyl) -lH-3-indolyl) -L-methyl-2,5-pyrrolidinedione Under an atmosphere of H2, stir for 24 hours at room temperature a solution of 240 mg (0.50 mmol) of 3-bromo-4- (2- (4- (lH-2-indolyl) butyl) -lH-3-indolyl) -1-methyl-2 , 5-dihydro-lH-pyrrole-2, 5-dione and 140 mg (0.25 mmol) of Pd (OH) 2 / C (20%) in 30 ml of MeOH. For working up the preparation is filtered, the filtrate is concentrated and the residue is purified by column chromatography (Si02; CH2Cl / ethyl acetate 95: 5). Concentrating the purified fraction causes crystallization of the product by the addition of PE. Yield: 48.0 mg (24%) beige powder. P.f. : 180 - 182 ° C Example 194 Test for measuring the inhibition of PDGF-dependent tyrosine phosphorylation for the compounds according to the invention. Swiss 3T3 cells are cultured for one week under standard conditions (DMEM with glutamine, 4 g glucose / 1, 10% FKS antibiotics, 5-7.5% C02, and at the end of the culture period they are confluent and no longer proliferating The medium is replaced by serum-free DMEM and the cells are incubated for 2 hours at 37 ° C with the compounds according to the invention or with DMSO (final concentration 0.1-1%.) In control tests. cells are stimulated by the addition of PDGF-BB to a final concentration of 100 ng / ml for 5 minutes at room temperature, the addition of the respective solvent is carried out in the controls, followed by washing the cells twice. with ice cold PBS and lysis of the cells in a lysis buffer containing Triton-X-100 (the composition and method as described in "Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation", M. Kovalenko , A. Gazit, A. Bóhmer, C. Rorsman, L. Ronnstrand, C.H. Heldin, J. Waltenberger, F.D. Bóhmer, A. Levitzki (1994) Cancer Res. 54, 6106-6114). The lysates are centrifuged and the concentration of the albumin is determined. 10 μg of the lysate protein are directly deposited on nitrocellulose membranes (Dot-Blot apparatus or similar multi-well plates with nitrocellulose bottom). The tyrosine phosphorylation check is carried out with antiphosphotyrosine antibodies according to standard methods. Typically, a horseradish peroxidase-conjugated monoclonal anti-phosphotyrosine (POD) antibody is used and detection of POD activity by chemo-luminescence assay. The quantification is carried out either by analysis of gray values of the films used for the detection of the luminescence or directly with a luminometer. In general, the PDGF stimulation of the cells results in an increase of 3-10 times the signal. The compounds were first applied twice in a final concentration of 10 μg / ml. In the case of the active compounds, a titration was carried out in the stages 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM and 0.1 μM as a double check. The results are shown in table 1 Table 1 Qualitative testing of the effects on tyrosine phosphorylation of the PDGF receptor and cell substrates is carried out by analysis of those used in the cells by means of polyacrylamide gel electrophoresis and immunoblotting with antiphosphotyrosine antibodies according to standard methods. Additionally the compounds according to the invention were examined in vitro with plasma membranes isolated from Swiss 3T3 cells and with PDGF receptor purified from overexpression cells, examined in intact A431 cells (and partly also in Swiss 3T3 plasma membranes) with respect to a possible inhibition of the tyrosine kinase of the EGF receptor and with respect to the inhibition of the recombinant Src-kinase. The results are shown in Table 2. Tests of DNA synthesis in 3T3 Swiss cells that were stimulated with different growth factors are adequate to characterize the selective anti-spraying effects of tyrosine kinase inhibiting substances in receptors. The compounds were examined for their effect to the synthesis of DNA stimulated in these cells by PDGF-BB, bFGF, FCS and the combination of EGF and insulin these stimulants are approximately equipotent and increase of 5-20 times the synthesis of DNA in Swiss cells 3T3 previously blocked growth. The dependencies of the doses of the corresponding assays as well as the IC 50 values obtained are also represented in Table 2. The compounds were further examined with respect to a possible anti-transforming effect by the use of sys-transformed NIH3T3 cells. In these cells, an expression of PDGF-BB and permanent activation of endogenous PDGF receptors is maintained. Transformed phenotype characterized inter alia by irregular multilayer growth and colony formation on soft agar. The IC50 values obtained are also shown in Table 2. After this the effects on the PDGF receptor kinase by the compounds were found in the following tests: autophosphorylation of the PDGF receptor in intact 3T3 Swiss cells, autophosphorylation of the PDGF receptor in isolated membranes of 3T3 Swiss fibroblasts, and autophosphorylation of the PDGF receptor in purified receptor preparations. No effects were observed for epidermal growth factor in analogous assays with the receptor tyrosine kinase as well as with the cytosolic tyrosine kinase Src up to a concentration of 30 μM. Accordingly, the compounds show a specificity for the inhibition of the tyrosine kinase of the PDGF receptor with respect to other tyrosine kinases. Table 2 Continuation table 2 Cl 50 test (μM) Example 19 Example 20 Example 21 Synthesis of DNA-stimulated PDGF 3-10 n.d. n.d. (3T3 cells stimulated by Swiss) FGF 3-10 n.d. n.d. stimulated by EGF / insulin > 30 n.d. n.d. 10% FCS > 30 n.d. n.d. Formation of colonies 3-10 n.d. n.d. (sis-3T3 cells)

Claims (1)

1. CLAIMS Compounds of the general formula I ÍD wherein Z is a group of the general formula (II) (you) where A can be a nitrogen, oxygen or sulfur atom, and B, B 'a carbon, nitrogen, oxygen or sulfur atom, and the cyclic systems F and G can be independently of each other rings 5 and 6, both saturated as also unsaturated, X represents a group of the general formula III or IV, - (CH2)? - [CR1 R1] m- (CH) n (III) where A has the same meaning as in the above, 1 and n can be the numbers 0 to 6, m the numbers 1 and 2, as well as R14 and R15 or together they form an oxygen atom, or R14 means a group hydroxyl and R15 a hydrogen atom, or R14 and R15 mean hydrogen atoms and in which R16 means a hydrogen atom, an alkyl or aryl radical, an alkyl or aryl radical substituted with halogen, amino or azido, an alkoxymethyl radical or radical substituted alkoxymethyl, R2 and R13 together form a ligand with the general formula V or VI rv) (VI) being that the striped league means a double or single league, A and R16 have the same meaning as in the previous, I can adopt the numbers 1 and 2, R2 and R13 mean equal or different radicals of the general formula VII or atoms of hydrogen being that the striped link means a double or single link, A and R, 16 have the same meaning as in the above, and R17 means a halogen atom or a radical of the general formula VIII, (VIII) so that p can be = 0, 1 or 2 (if p = 0 is a primary acyclic amine and Y has an additional hydrogen atom, Y can be a carbon, oxygen or nitrogen atom, and if Y is a carbon atom or nitrogen, R18 is a nitrogen atom or an alkyl or aryl radical, an alkyl or substituted aryl radical, a saturated or unsaturated heterocycle, an alkoxycarbonyl radical, an aminocarbonylmethyl radical, a substituted aminocarbonylmethyl radical, R2 and R13 form together a league with the general formula IX or X (IX) (X) where W represents either a carbon atom or a nitrogen atom, q can take a number between 0 and 6, and R19 and R20 can mean hydrogen atoms, alkyl radicals, or substituted alkyl radicals, wherein R1 and R7 are the same or different and mean carbon atoms, alkyl and aminoalkyl radicals, phenylsulfonyl radicals, alkylsilylmethoxymethyl radicals, a sugar or substituted sugar, wherein R3, R4, R5, R6, R8, R9, R10 and R11 is the same or different and in each case represents a hydrogen atom, an alkyl, alkoxy, alkoxymethyl, substituted alkoxy, amino, halogen, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, a halogen atom or an O-alkoxy group of the general formula -0- (C = 0) -R21, where R21 is an alkyl, alkoxy, substituted alkoxymethyl group of alkoxy, amino, halogen, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl. Compounds according to claim 1 of the general formula II wherein A means a nitrogen atom and B a nitrogen, oxygen or sulfur atom, and R3, R4, R5, R6, R7, R8, R9, R10, R11, R14 and R15 have the same meaning as in the above . Compounds according to claim 1 with the general formula I in which X represents a group of the general formula III or IV according to claim 1 and R1 and R2 mean hydrogen atoms, A and B mean nitrogen atoms, as well as R3, R4 , R5, R6, R7, R8, R9, R10, R11 and R16 have the same meaning as in the above. Compounds according to claim 1, with one of the general formulas XIII and XIV where n means the numbers 3, 4, 5, 8, 12, q the numbers 0, 1, 2, 3, 5, 6, R19, R20 denote hydrogen atoms or alkyl groups, and R1, R3, R4, R5 , R6, R7, R8, R9, R10, R11 and R16 are the same or different and have the same meaning as in the above. Compounds according to claim 1 with the general formula XV wherein n means the numbers 1, 2, 3, R16 means a hydrogen atom or an alkyl group, and R1, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R16 are the same or different and they have the same meaning as in the previous. 6. Bisindol-2-ylmetan-l-one according to claim 1. 7. (5-methoxyindol-2-yl) - (indol-2-yl) methan-l-one according to claim 1. 8. Bis (5-methoxyindol-2-yl) -1-methanone according to claim 1. 9. Benzo [b] thiophen-2-yl (5-methoxy-lH-2-indolyl) -1-methanone according to claim 1. 10. 5-hydroxy-lH-2-indolyl (lH-2-indolyl) methanone according to claim 1. 11. lH-2-indolyl [5- (2-morpholin-1-ylethyloxy) -lH-2-indolyl] -methanone according to claim 1. 12. lH-2-indolyl [5- (2-dimethylaminoethyloxy ) -lH-2-indolyl] -methanone according to claim 1. 13. [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] ethanoate according to claim 1. 14. [2- (lH-2 -indolylcarbonyl) -lH-5-indolyl)] butanoate according to claim 1. 15. [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] 2- (N, N) -dimethylaminoethanoate according to claim 1 . 16. [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] propanoate according to claim 1. [2- (lH-2-indolylcarbonyl) -lH-5-indolyl)] 2-thiophenylethanoate according to claim 1 A medicament comprising a compound according to one of claims 1 to 17. 19. Use of a compound according to one of claims 1 to 17 as an inhibitor of a tyrosine kinase. 20. Use of a compound according to one of claims 1 to 17 as an inhibitor of a tyrosine kinase of the PDGF receptor or a tyrosine kinase of a structurally analogous receptor. 21. Use of a compound according to one of claims 1 to 17 for the treatment of tumors. 22. Use of a compound according to one of claims 1 to 17 for the treatment of arteriosclerosis, restenosis after balloon angioplasty, arthritis and fibrotic diseases. A method for the preparation of compounds according to claim 1 wherein R2 and R13 are a radical with the general formula V according to claim 1 or together form a ligand with the general formula VII according to claim 1, characterized in that it is reacted with dibromomaleinimide a 2, 2'-bis-lH-mdolyl alkan or a derivative thereof with the general formula XI wherein X, R1, R3, R4, R5, R6, R7, R8, R9, R10 and Ru have the same meaning as in the foregoing. Method for the preparation of compounds according to claim 1 wherein R2 and R13 together form a ligand with the general formula IX or X according to claim 1, characterized in that a 2,2'-b? S- is first reacted with dibromomaleimide. lH- indolyl alkan or a derivative thereof with the general formula XI wherein X, R1, R3, R4, R5, R6, R7, R8, R9, R10 and R11 have the same meaning as in the foregoing, and then with a primary or secondary amine with the general structures XVI or XVII or piperazine (XVI) (XVtl) in which p, q, R, 17 and have the same meaning as in the previous.