CA2496859A1 - Indole derivatives and their use for the treatment of malignant and other diseases based on 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

INDOLE DERIVATIVES AND THEIR USE FOR THE TREATMENT
OF MALIGNANT AND OTHER DISEASES BASED ON PATHOLOGICAL
CELL PROLIFERATION
This is a divisional application of Canadian Patent Application Serial No. 2,330,756 filed on April 22, 1999.
The invention relates to tyrosine kinase inhibitors of the bis-indolyl compound type, pharmaceuticals containing them l0 and their use for the treatment of malignant and other diseases based on pathological cell proliferation. It should be understood that the expression "the invention" and the like encompasses the subject matter of both the parent and the divisional applications.
The activation of tyrosine-specific protein kinases is a key event in stimulation of the division of animal cells.
Norma7.ly, this stimulation is effected by exogenous factors, e.g. growth factors, when the proliferation of a certain cell type is necessary for the overall function of a tissue or organ. In tumours, cell proliferation is also linked with the activity of tyrosine kinases. In tumour cells, however, an aberrant activity of kinases is often present, which is caused by overexpression, constitutively active kinase mutants or ectopic activity of growth factors. The PDGF

la receptor is one of the growth factors with relevance for human tumours. PDGF is one of the main mitogens in the serum and is present in high concentrations in blood platelets.
Its most important function in the adult body is wound healing. An undesired activity of the PDGF receptor is involved in the proliferation of various tumours, e.g.
gliomas, glioblastomas, sarcomas, mastocarcinomas, ovarian carcinomas and colonic: carcinomas. An aberrant activation of the PDGF/PDGF receptor- system also assumes a key position in l0 patho7_ogical hyperproliferation of mesenchymal cells in the context of arteriosclerosis, restenosis after balloon angioplasty, arthritis and fibrotic diseases.
A few growth factor receptor tyrosine kinases, whose tyrosine kinase domains have high sequence homology to the tyrosine kinase domain of the PDGF receptors, are also of importance for the tumour process and WO 99/5711? - 2 - PCT/DE99/01214 pathological hyperproliferation. These include the receptors for the vascular endothelial cell growth :factor (VEGF)KDR/Flk-1 and Flt-1 with great importance for tumour vascularization, 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 forms of disease. It can be expected that further members of i:his kinase family with relevance for pathological proliferation will be identified. In addition to mitogenic stimulation, the actions of the ligands of these receptors often also include the stimulation of cell migration, anti-apoptotic actions and effects on membrane transport. systems for ions, water and chemical compounds. To a varying extent, uncontrolled effects of this type are also involved in the pathological process in tumours and other diseases.
Uf the various possibilities for switching off the signal of receptor tyrosine kinases, the specific direct inhibition of the activity of the kinase is the most promising.
'I'he invention is therefore aimed at creating compounds which are suitable as inhibitors of tyrosine kinases, in particular of the PDGF receptor tyrosine kinases and further, related tyrosine kinases such as KDR/Flk-1, Kit/SCF receptor and FLK/Flt-3. This object is achieved by the compounds of the general formula I according to the invention:
Rs .A~ X ~Z
R' in which Z is a group having the general formula (II) R~s B. Rio F G( wB~~~Rs R' _'R8 (~~) where A can be a nitrogen, oxygen or sulphur atom [sic]
and B, B' can be a carbon, nitrogen, oxygen or sulphur atom and the ring systems F and G independently of one another can be either saturated or unsaturated 5- and 6-membered rings, X is a group having the general formula III or IV
~CH2)~C'R~4R~~m~CH~n A
R~s in which A has the same meaning as above, 1 and n can assume the numbers from 0 to 6, m the numbers 1 and 2, and R1° and R15 either together form an oxygen atom or R14 is a hydroxyl group and Rls is a hydrogen atom or Rl4 and R15 are hydrogen atoms and where R16 is a hydrogen atom, an alkyl or aryl radical, halogen-, amino-, or azido-substituted alkyl or aryl radical, an alkyloxymethyl radical or substituted alkyloxymethyl radical, Rz and R13 together form a linkage having the general formula V or VI

(V) Nt) where the dashed bond is a double or single bond, A and R16 have the same meaning as above and o can assume the numbers 1 and 2, RZ and R13 are identical or different radicals of the general formula VII or hydrogen atoms, Ntl) where the dashed bond is a double or single bond, A and R16 have the same meaning as above and R1' is a halogen atom or a radical. of the general formula VIII
Nt ~ JP
~R'°
(VIII) such that p can be = 0, 1 or 2 (if p = 0 then it is an ar_yclic primary amine and Y carries an additional hydrogen atom), Y can be a carbon, oxygen or nitrogen atom and if Y is a carbon or nitrogen atom, R1g is a WO 99!57117 - 5 - PCT/DE99/01214 hydrogen atom or an alkyl or aryl radical, substituted alkyl or aryl radical, saturated or unsaturated heterocycle, alkoxycarbonyl radical, aminocarbonyl methyl radical or substituted aminocarbonylmethyl radical, Rz and R13 together form a linkage having the general formula IX or X
Rss Rio I
O~N~O O~Nw (X) (IX) where W is either a carbon or a nitrogen atom, q can assume a number [ sic ] between 0 and 6 and R'9 and Rz°
can be hydrogen atoms, alkyl radicals or substituted alkyl radicals, in which R1 and R' are identical or different and are hydrogen atoms, alkyl or aminoalkyl radicals, phenylsulphonyl radicals, alkylsilylmethoxymethyl radicals, a sugar or substituted sugar, where R3, R4, R5, R~', Re, R9, R1° and R11 are identical or different and in each case is a hydrogen atom, an alkoxy-, amino-, halogen-, cycloalkyl-, cyclohetero-alkyl-, aryl- or heteroaryl-substituted alkyl, alkoxy or alkoxymethyl group, nitro group, a halogen atom or an O-alkoxy group of the general form -O-(C=O)-Rzi, where RZ1 is an alkoxy-, amino-, halogen-, cycloalkyl-, cycloheteroalkyl--, aryl- or heteroaryl-substituted alkyl, alkoxy or alkoxymethyl group.
Preferred compounds according to the invention are those having the above general formula I, in which Z is a group having the general formula II and X is a group having the general formula III, R2 and R13 are hydrogen atoms, A is a nitrogen~atom and B is a nitrogen, oxygen or sulphur atom and R3, R°, R5, R6, R?, R8, R9, R1°, Rll, R14 and R15 have the same meaning as above, where these compounds correspond to the following formula XI:
Ra Rn Rio w i Rs ~ ~ N ~ ~ B ~ ~ R9 R° R' R' R°
R~4 R~s (Xl) Particularly preferred compounds are those of the formula XI in wh_Lch Rl~ and R15 together form an oxygen atom.
Additionally preferred compounds according to the invention are those having the above general formula I
in which z is a group having the general formula II and X is a group having the general formula III, R1 and RZ
are hydrogen atoms, A and B are nitrogen atoms, and Ri, R3, Rq; R5, R6, R', R8, R9, R1°, R11 and R16 have the same meaning as above, where these compounds correspond to the following formula XII:

D
r~
R'~
(Xil) Additionally preferred compounds according to the invention are those having the general formulae XIII
and XIV below (XIII) (XIV) in which a is the numbers 3. 4, 5, 8 or 12, q is the numbers 0 , 1, 2 , :3 , 5 or 6 . R19 , Rz° are hydrogen a toms or alkyl groups and Rl, R3, R°, R5, R6, R', Re, R9, Rlo, Rll and R16 are identical or different and have the same meaning as above.
Additionally preferred compounds according to the invention are those having the following general formula XV
R'°
I
R3 O ~ R~s Rio \ N N ~ R9 R~

_ g _ in which b is the numbers 1, 2 or 3, R16 is a hydrogen atom or an alkyl group and Ri, R3, R4, R5, R6, R', R8, R9, Rlo~ Rii and R16 are identical or different and have the same meaning as above.
Exemplified carbon ranges for substituents are as follows:
Ci-iz alkyl; C6_1q aryl; C1_6 alkoxymethyl; C1_6 alkoxycarbonyl;
amino Ci_6 alkyl; C,3_~ cycloalkyl; Cz_6 heterocycloalkyl; C3_g heteroaryl; C1_6 alkoxy; and C1_6 alkylsilylmethoxymethyl.
The invention also provides a pharmaceutical composition comprising a compound as defined herein, together with a pharmaceutically acceptable carrier, for the inhibition of a PDGF receptor tyrosine kinase. The invention also provides such a pharmaceutical composition for the treatment of tumours, arteriosclerosis, restenosis after balloon angioplasty, arthritis or fibrotic diseases.

8a The compounds of the formula XI can be prepared by one of the two following schemes:
R"
R,o a t I N~R~
IO= Ra Ph d _ R" ~ R"
R~ ,o t ~ R,o ~ ~I I ~ ~ i I
Rs ~ N~~ ~ R° Rs ~ N~N~R°
H 'Of H H H R°
a) LDA/THF, b) HSiPh3/THF, c) PDC/DMF, d) 10~
NaOH/EtbOH, e) KzCOs/MeOH, f) N2H9/2-(2-hydroxyethyloxy)-ethanol R"
R
\ CH3 O p H3C \ Rio Me Si RS / N~SiMe3 EtO~~~OEt 3 ~N ~ R9 R° H H R°

D
n = 2 or 3 For the preparation of the compounds according to the invention in which R2 and R13 are a radical having the above general formula VII or together form a linkage having the general formula V, IX or X, a 2,2'-bis-1H-i_ndolylalkane or a derivative thereof having the general formula XI
R
R
D
(XI) in which X, Ri, R3, R9, R5, R6, R', Ra, R9, Rl° and Rli have the same meaning as above, is initially reacted with dibromomaleimide.
Compounds according to the invention in which R2 and R13 together form a linkage having the general formula VII
are then reacted with a primary or secondary amine having the following general formula XVI or XVII or piperazine H
I
'N[:~,p ~Y\ H-N W-~-C-~W N-H
(~I) - (XVII}
in which p, q, Rl' and W have the same meaning as above.
_ ., The following examples illustrate the invention, without restricting it.
Example 1 Bis(N-phenylsulphonylindol-2-yl)-1-methanol Lithium diisopropylamide is prepared at -78°C 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 200 ml of absol. THF. The solution is stirred at -78°C for 10 min and then at 0°C for 30 min, before 49.13 g (190.9 mmol) of 1-phenylsulphonylindole in 300 ml of absol. THF are added dropwise at 0°C in the course of 10 min. The reaction solution is stirred at 0°C for a further 30 min. After cooling again to -78°C, 60.00 g (210.3 mmol) of phenylsulphonyl-2-carbaldehyde in 200 ml of absol. THF are added dropwise and the mixture is allowed to warm to room temp. overnight. The mixture is poured onto 1 per cent HC1 and the org. phase is separated off after addition of ether. The aq. phase is extracted with ether, and the combined org. phases are washed successively with NaHC03 and satd. NaCl solution and dried over Na2S0q. The solvent is stripped off in vacuo and the crude product is purified by column chromatography (SiOZ; CH2C12): colourless crystals, yield 86.5 g (84~).
M.p.: 185°C (MeOH).
The following were prepared analogously:
Example 2 Bis(5-methoxy-N-phenylsulphonylindol-2-yl)-1-methanol M.p.: 113 - 114°C (MeOH) Example 3 (5-Methoxy-N-phenylsulphonylindol-2-yl)-(N-phenyl-sulphonylindol-2-yl)-1-methanol M..p.: 104 - 105°C (CHzCl2/hexane) Example 4 (5-Methoxy-N-phenylsulphonylindol-2-yl)-(7-methoxy-N-phenylsulphonylindol-2-yl)-1-methanol M.p.: 119 - 121°C (CHZC12/hexane) Example 5 (5-Methoxy-N-phenylsulphonylindol-2-yl)-(N-phenyl-sulphonylindol-2-;yl)-1-methanol M.p.. 99 - 101°C (CHzClz/hexane) Example 6 (5-Methoxy-2-phenylmethyloxy(1-phenylsulphonylindol-2-yl)methyl-1-phenylsulphonylindol M.p.: 62 - 64°C
Example 7 Di-(5-Methyloxy-l-phenylsulphonylindol-2-yl)phenyl-methyloxymethane M.p.: 100 - 101°C
Example 8 (3-Dimethylaminomethyl-1-phenylsulphonylindol-2-yl)(1-phenylsulphonylindol-2-yl)methan-1-of M.p.. 116 - 117°C
Example 9 (7-Methoxy-N-phenylsulphonylindol-2-yl)(N-phenyl-sulphonylindol-2-yl)-1-methanol M.p.: 149 - 151°C
Example 10 Dibenzothiophen-2--yl-1-methanol M.p.: 130 - 131°C
Example 11 Ei-Methoxy-1-phenylsulphonyl-1H-2-indolyl(1-phenyl-sulphonyl-1H-2-indolyl.)methanol M.p.: 180°C

Example 12 7-Methoxy-1-phenylsulphonyl-1H-2-indolyl(1-phenyl-sulphonyl-1H-2-indolyl)methanol M.p.: 148 - 150°C
Example 13 Benzo[b]thiophen-2-yl(5-methoxy-1-phenylsulphonyl-1H-2-indolyl)-1-methanol M.p.: 71 - 73°C
Example 14 Benzo[b]thiophen-2-yl(7-methoxy-1-phenylsulphonyl-1H-2-indolyl)-1-methanol M.p.: 118 - 119°C
Example 15 Benzo(b]furan-2-y:l(5-methoxy-1-phenylsulphonyl-1H-2-indolyl)-1-methanol M.p.: 71 - 73°C
Example 16 :Bis(N-phenylsulphonylindol-2-yl)methan-1-one 'rhe solution of 20.00 g (36.9 mmol) of bis-(N-phenylsulphonylindol-2-yl)-1-methanol in 200 ml of absol. DMF is cooled to 0°C. After addition of 90.4 g of pyridinium dichromate (PDC), it is stirred at room temp. for 20 h. For work-up, 700 ml of H20 and 700 ml of CHZC12 are added. The aq. phase is extracted with 2 x 200 ml of CHZC12. The combined org. extracts are washed with 500 ml of HzO. After stripping of the solvent in vacuo and addition of CHZC12, the product precipitates:
colourless crystals; yield 15.0 g (75$).
M.p.: 244°C (MeOH/ether) The following were prepared analogously:

WO 9915?117 - 13 - PCT/DE99/O1Z14 Example 17 5-Methoxy-N-phenylsulphonylindol-2-yl)-(N-phenylsulphonylindol-2-yl)methan-1-one M.p.. 205°C (MeOH) Example 18 Bis(5-methoxy-N-phenylsulphonylindol-2-yl)-1-methanone Example 19 Bisindol-2-ylmethan-1-one 10.0 g (18.5 mmo:1) of bis(N-phenylsulphonylindol-2-yl)methan-1-one are dissolved in 380 ml of 99 per cent EtOH. After addition of 210 ml of 10 per cent NaOH, the solution is heated under reflex for 20 H. For work-up, the EtOH is stripped off, 500 ml of satd. NaCl solution and 500 ml of CHZC12 are added and the phases are separated. The aq. phase is extracted with 2 x 200 ml of CHZC12, and the combined org. extracts are dried over Na2S09 and concentrated in vacuo. The bisindole is deposited as a crude product and can be recrystallized from CH2C12, yellow crystals, yield 4.5 g (93$) M.p.: 272 - 273°C (CHZC12) The following were prepared analogously:
Example 20 (5-Methoxyindol-2-:yl)-(indol-2-yl)methan-1-one M.p.: 233 - 235°C (MeOH) Example 21 Bis(5-methoxyindol-2-yl)-1-methanone M.p.: 202 - 204°C
Example 22 D:ibenzothiophen-2-yl-1-methanone M.p.: 161°C

Example 23 5-Methyl-1-phenylsulphonyl-3-indolyl(1-phenylsulphonyl-2-indolyl)-1-methanone M.p.: 114 - 116°C
Example 24 (1H-Indol-2-yl)-(1H-indol-3-yl)-1-methanone M.p.: 260 - 261°C (MeOH) Example 25 :Benzo[b]thiophen-2-yl(7-methoxy-1-phenylsulphonyl-1H-2-indolyl)-1-methanone M.p.: 190°C
Example 26 Benzo[b]thiophen-2-yl(7-methoxy-1H-2-indolyl)-1-methanone M.p.: 155°C
Example 27 Benzo[b]thiophen-2-yl(5-methoxy-1-phenylsulphonyl-1H-:Z-indolyl)-1-methanone M.p.: 82 - 83°C
2 5 l:xamp 1 a 2 8 Benzo[b]thiophen-2-yl(5-methoxy-1H-2-indolyl)-1-methanone M.p.. 200°C
Example 29 7-Methoxy-1-phenylsulphonyl-1H-2-indolyl(1-phenyl-sulphonyl-1H-2-indolyl)methanone M.p.: 129 - 130°C
Example 30 7-Methoxy-1H-2-indolyl(1H-2-indolyl)methanone M.p.: 151°C

Example 31 6-Methoxy-1-phenylsulphonyl-1H-2-indolyl(1-phenyl-sulphonyl-1H-2-indolyl)methanone M.p.: 184 - 186°C
Example 32 6-Methoxy-1H-2-indolyl(1H-2-indolyl)methanone td.p.: 184 - 186°C
Example 33 1-Methyl-1H-2-indalyl(1-ethyl-5-methyloxy-1H-2-indolyl)-1-methanone M.p.: 148 - 149°C
Example 34 1H-2-Indolyl(1-met.hyl-5-methyloxy-1H-2-indolyl)-1-methanone M.p.: 190°C
Example 35 1-Methyl-1H-2-indolyl(5-methyloxy-1H-2-indolyl)-1-methanone M.p.: 176 - 177°C
Example 36 l.-Ethyl-1H-2-indolyl(1-ethyl-5-methyloxy-1H-2-indolyl)-l.-methanone M.p.: 99-100°C
Example 37 1H-2-Indolyl(1-ethyl-5-methyloxy-1H-2-indolyl)-1-methanone M.p.: 142 - 143°C
Example 38 1-Ethyl-1H-2-indolyl(5-methyloxy-1H-2-indolyl)-1-methanone M.p.: 101 - 102°C

Example 39 1-Benzyl-1H-2-indolyl(1-benzyl-5-methoxy-1H-2-indolyl)-1-methanone M.p.: 132°C
:Example 40 1H-2-indolyl(1-benzyl-5-methoxy-1H-2-indolyl)-1-methanone M.p.. 180 - 182°C ' Example 41 :l-Benzyl-1H-2-indolyl(5-methoxy-1H-2-indolyl)-1-methanone M.p.: 167 - 168°C
Example 42 5-Benzyloxy-1H-2-indolyl(1H-2-indolyl)methanone M.p.: 199 - 201°C
Example 43 '.~-Hydroxy-1H-2-indolyl(1H-2-indolyl)methanone M.p.: > 220°C
Example 44 5-Ethoxy-1H-2-indolyl(1H-2-indolyl)methanone M.p.. 168 - 169°C
Example 45 1H-2-Indolyl[5-(2-morpholin-1-ylethyloxy)-1H-2-indolyl]methanone M.p.: 98 - 101°C
Example 46 LH-2-Indolyl[5-(3-dimethylaminopropyloxy)-1H-2-i.ndolyl]methanone M.p.: 163 - 166°C
Example 47 5-(4-Iodobutyloxy)-1H-2-indolyl(1H-2-indolyl)methanone M.p.: 110 - 113°C
Example 48 1H-2-Indolyl[5-(2-dimethylaminoethyloxy)-1H-2-indolyl]methanone M.p.: 143 - 145°C
Example 49 5-Cyclohexylmethy:foxy-1H-2-indolyl(1H-2-indolyl)-methanone M.p.: 185°C (dec.) Example 50 5-(5-Iodopentyloxy)-1H-2-indolyl(1H-2-indolyl)methanone M.p.: 127 - 130°C
Example 51 1H-2-Indolyl[5-(1-phenylethyloxy)-1H-2-indolyl]-methanone M.p.: 151 - 153°C
Example 52 1H-2-Indolyl[5-(2--piperidin-1-ylethyloxy)-1H-2-indolyl]methanome M.p.: 104 - 106°C
Example 53 [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl))[sic] ethanoate M.p.: 223 - 224°C
Example 54 [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic] 4-meth-axybenzoate M.p.: > 230°C
Example 55 [2-(1H-2-Indolylcarbonyl)-1N-5-indolyl)][sic] butanoate M.p.: 201 - 204°C

Example 56 [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic] 2-(N,N)-dimethylaminoethanoate M.p.. 215 - 217°C
Example 57 [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic]
propanoate M.p.. > 230°C
Example 58 [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic]
2-thiophenylethanoate M.p.: 224 - 226°C
Example 59 [2-(1H-2-Indol_ylcarbonyl)-1H-5-indolyl)][sic] O-acetyl-salycylate [sic]
M.p.: 133 - 135°C
Example 60 [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic] 4-phenyl-benzoate M.p.: > 220°C
Example 61 [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic] 2-phenyl-propanoate M.p.. 211 - 313°C [sic]
Example 62 [2-(1H-2-Indolylcarbonyl)-1N-5-indolyl)][sic] a-acetyl-phenylethanoate M.p.: 194 - 196°C
Example 63 [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic] benzoate M.p.: > 230°C

Example 64 [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic]

3-methoxyphenylethanoate M.p_: 212 - 215°C
Example 65 [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)][sic] 2-chloro-benzoate M.p.. > 230°C
Example 66 [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl))[sic]

4-nitrobenzoate M.p.. > 230°C
Example 67 [2-(1N-2-Indolylcarbonyl)-1H-5-indolyl)][sic]
3,4,5-trimethoxybenzoate M.p.: 216 - 219°C
Example 68 [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl))[sic) cinnamate M.p.: 226 - 228°C
Example 69 [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl))[sic]
2-furanylcarboxylate [sic]
M.p.: > 230°C
Example 70 Di(1-phenylsulphonyl-1H-2-indolyl)methane 22.4 ml of trifluoroacetic acid (TFA) are added dropwise after 30 min to a solution of 26.67 g (49.2 mmol) of bis(N-phenylsulphonylindol-2-yl)-1-methanol and 15.00 g (57.8 mmol) of triphenylsilane in 400 ml of absol. CH2C12. After stirring at room temp.
for 1 h, H20 is added and the mixture is cautiously neutralized with solid Na2C03 with ice-cooling. After separating the phases, drying the org. phase over Na2S04 and distilling off the solvent, the crude product is purified by column chromatography (Si02; CH2C12/hexane 6:4), colourless crystals, yield 22.5 g (87$).
M.p.: 144 - 145°C (ether) The following were prepared analogously:
Example 71 Bis(5-methoxy-N-phenylsulphonylindol-2-yl)methane M.p.: 159-160°C (CHZC12/hexane) Example 72 (5-Methoxy-N-phenylsulphonylindol-2-yl)-(N-phenyl-sulphonylindol-2-yl)methane M.p.. 98 - 100°C (CH2C12/hexane) Example 73 (5-Methoxy-N-phenylsulphonylindol-2-yl)-(7-methoxy-N-phenylsulphonylindol-2-yl)methane M.p.: 168 - 170°C (CH2C12/hexane) Example 74 Di(1H-2-indolyl)methane 15.0 g (28.5 mmol) of 57 are boiled with 20 g of KZC03 in 800 ml of MeOH and 200 ml of Hz0 for 14 days. For work-up, 500 ml of satd. NaCl solution are added and the phases are separated. After drying the org. phase, the solvent is stripped off in vacuo. The crude product is purified by column chromatography, colourless crystals, yield 5.4 g (76$).
M.p.: 189 - 191°C
The following were prepared analogously:
Example 75 (5-Methoxyindol-2-yl)-(indol-2-yl)methanone M.p.. 112°C (MeOH) Example 76 (1H-Indol-2-yl)-(1-H-indol-3-yl)-1-methane M.p.: 161 - 163°C (aq. EtOH) Example 77 1,3-Di(1H-2-indolyl)propane 38.0 g (0.21 mol) of trimethylsilyl-o-toluidide are dissolved in 950 ml of abs. hexane and 291.0 ml (0.47 mol) of n--BuLi (1.6 M in hexane) are added dropwise at room temp. and the mixture is heated to r_eflux for 4 h. It is then cooled to -78°C and 20.5 ml (0.11 mol) of diethyl glutarate in 380 ml of abs. THF
are added dropwise= at this temp. The mixture is stirred at -78°C for 1 h, and is then slowly allowed to come to x-oom temp. overnight and subsequently heated to bailing for a further 2 h.. After cooling, it is poured onto 1 1 c>f ice water and extracted with 5 x 500 ml of ethyl acetate, the combined org. phases are dried over Na2S09 and the solvent is stripped off in vacuo. White crystals, yield 6.55 g (23.9 mmol, 22~).
M.p.: 143 - 145°C (ethanol) The following was prepared analogously:
Example 78 1,3-Di(1H-2-indolyl)ethane M.p.: 264 - 267°C
Example 79 1,2-Di-(1-phenylsulphonyl-1H-2-indolyl)-1-ethene [lacuna] (17.9 mmol) of TiCl9 with a syringe and 2.0 g (30.5 mmol) of Zn powder are subsequently added. The mixture is heated under reflux for 30 min. After this, 3 g (10.5 mmol) of 22, dissolved in 50 ml of THF, are added dropwise again at 0°C. The solution is heated under reflux overnight. 300 ml of 20 per cent K2C03 soln. are poured into the cooled solution and it is stirred further overnight at room temp. The sludgy residue is then filtered off and washed with THF, the WO 99/57117 - 22 - PCT/DE99l01214 org. phase is separated off from the filtrate and the aqueous phase is extracted with CHZC12.
The combined org. phases are washed with water, dried over NazS04 and freed from the solvent in vacuo.
Purification is carried out by column chromatography (Si02; CHzClz/hexane 2:1) . Yield: 1.1 g (2.0 mmol, 390) of yellow crystals.
M.p.: 272°C
Example 80 Bis(5-methoxy-N-phenylsulphonylindol-2-yl)phenoxy-methane 188 mg of NaH (60o in paraffin) are added at 0°C to a solution of 2 g (3.7 mmol) of bis(-N-phenylsulphonyl indol-2-yl)-1-methanol in 20 ml of THF. 13.5 mg of tetrabutylammoniwn iodide and 0.45 ml of benzyl bromide are subsequently added and the mixture is stirred at 20°C. Water and ether are then cautiously added, the ether phase is separated off and the aqueous phase is washed twice with ether. The org. phase is dried over Na2S04 and the solvent is then stripped off. Yield:
0.86 mg (81g) M.p.: 192°C (dec.) Example 81 1,2,3,8,9,10-Hexahydroindolo[3',2':5,6]pyrrolo-[3',4':3,4)-cyclohepta[b)indole-1,3-dione Half of 0.73 ml (9.75 mmol) of anhydrous ethyl bromide i.s added to 236 mg (9.75 mmol) of Mg turnings in 6 ml of absol. THF. After the reaction has started, the remainder of the ethyl bromide is added dropwise such that the solution continues to boil. It is then boiled until the Mg turnings have dissolved (about 30 min).
After cooling to room temp., 1.00 g (4.06 mmol) of methylene-2,2'-bisindole in 25 ml of absol. toluene and 1 ml of absol. THF is added dropwise and the mixture is stirred at 45°C for 45 min. After cooling to room temp.
again, 1.04 g (4.06 mmol) of dibromomaleimide in 50 ml of absol. toluene and 2 ml of absol. THF are added dropwise over the course of 1 h, then the mixture is heated under reflux overnight. For work-up, 100 g of :ice and 50 ml of 20 per cent citric acid are added, then the mixture is extracted by shaking with 2 x 50 ml of ethyl acetate. The org. extracts are washed with H20, dried over Na2S04 and concentrated. The crude product is purified by column chromatography (Si02, 1.
CHZC12/ethyl acetate 8:2; 2. CHZC12/ethyl acetate 7:1):
red crystals, yield 290 mg (22~) m.p.. > 350°C (ethyl acetate).
The following were prepared analogously:
Example 82 1,2,3,8,9,10-Hexahydro-5-methoxyindolo[3',2':5,6]-pyrrola[3',4':3,4)-cyclohepta[b]indole-1,3-dione NI.p.. >350°C (EtOH) Example 83 1,2,3,8,9,10,11,12-Octahydroindolo[3',2':5,6]pyrrolo-[3',4'3,4]cyclonona[b]indole-1,3-dione M_p. . 137°C (CHZC12) (dec_ ) Example 84 1,2,3,8,9,10,11-Heptahydro-2-methylindolo[3',2':5,6]-pyrrolo[3',4':3,4]-cycloocta[blindole-1,3-dione M.p.: > 350°C
Example 85 2-Benzyloxymethyl-1,2,3,8,9,10-hexahydroindolo-[3',2':5,6]-pyrrolo[3',4':3,4]-cyclohepta[b]indole-1,3-d:ione M.p.: > 350°C (EtOH) Example 86 1,2,3,8,9,10,-Hexahydro-2-methylindolo[3',2':5,6]-pyrrolo[3',4':3,4)-cyclohepta[b]indole-1,3,dione M.p.. > 350°C (CHZC:12) Example 87 3,8,9,10-Tetrahydro-8-[2-(N,N-dimethylamino)ethyl]-1H-indolo[3',2':5,6]furo[3',4':3,4]cyclohepta[b]indole-1,3-dione M.p.. > 350°C (MeOH) Example 88 2-Benzyloxymethyl-1,2,3,8,9,10-hexahydro-8-[2-(N,N-di-methylamino)ethyl]indolo[3',2':5,6]pyrrolo[3',4':3,4]-cyclohepta[b]indole-1,3-dione 2d. p.: 164 - 165°C (MeOH) Example 89 1,2,3,8,9,10-Hexahydro-3-methyl-8-[2-(N,N-dimethyl-amino)ethyl]indolo[3',2':5,6]pyrrolo[3',4':3,4]-cyclohepta[b]indole-1,3-dione M.p.: 185°C (MeOH) Example 90 1.,2,3,8,9,10-Hexahydro-8-[2-(N,N-dimethylamino)ethyl]-indolo[3',2':5,6]pyrrolo[3',4':3,4]cyclohepta[b]indole-1,3-dione M.p.: 213 - 214°C (EtOH) Example 91 3-Bromo-4-(2-(2-(1Ii-2-indolyl)ethyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 169°C
Example 92 3-Bromo-4-(2-(4-(1H-2-indolyl)butyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione .
M.p.: 165°C (dec.) Example 93 3-Bromo-4-(2-(5-(1H-2-indolyl)pentyl)-1H-3-indolyl)-1-methyl-2,5-dihydro--1H-.pyrrole-2,5-dione M_p.: 125°C (dec.) Example 94 Bis(indol-3-yl)methanone Analogously to Example 31 using triphosgene instead of dibromomaleimide.
M.p.. 297 - 299°C
Example 95 Diastereomer mixture of 8-(3,4,6-tri-O-benzyl-(3-D-glucopyransoyl)-2-benzyloxymethyl-1,2,3,8,9,10-hexa-hydroindolo[3',2':5,6]pyrrolo[3',4':3,4]cyclohepta[b]-indole-1,3-dione and 8-(3,4,6-tri-O-benzyl-a-D-mannopyranosyl)-2-benzyloxymethyl-1,2,3,8,9,10-hexahydroindolo-[3',2':5,6]pyrrolo[3',4':3,4]cyclohepta[b]indole-1,3-dione Diastereomer mixture of the disubstituted O-glycosides 468.7 mg (1.02 mmol) of 2-benzyloxymethyl-1,2,3,8,9,10-hexahydroindolo[3',2':5,6]pyrrolo[3',4':3,4]cyclohepta-[b]indole-1,3-dione are added to a suspension of 91_8 mg (3.06 mmol) of NaH (80~ ~in paraffin oil) in 7.6 ml of absol. THF. After 30 min, the solution of 1,2-anhydro-3,4,6-tri-O-benzyl-D-glucopyranose in 16 ml of absol. THF is added dropwise. The mixture is stirred at 50°C for 5 h and at 60°C for 1 h. For work-up, the reaction solution is poured onto 10 ml of satd. NaHC03 solution and extracted with 3 x 10 ml of ethyl acetate.
The compbined org. extracts are washed with 15 ml of satd. NaCl solution, dried over NazS04 and concentrated in vacuo. The product is separated by column chromatography (1. column: SiOz; toluene/isopropylamine 8:2; 2. column: SiOz: CHZClz/MeOH 12:1) from by-products and unreacted starting material. The diastereomer mixture is separated by HPLC.
Example 96 Diastereomer mixture of 8-((3-D-glucopyranosyl)-1,2,3,8,9,10-hexahydroindolo[3',2':5,6]pyrrolo-[3',4':3,4]cyclohepta[b]indole-1,3-dione and 8-(a-D-mannopyranosyl)-1.,2,3,8,9,10-hexahydroindolo-[3',2':5,6]pyrrolo[3',4':3,4]cyclohepta[b]indole-1,3-dione 150 mg (0.17 mmol) 8-(3,4,6-tri-O-benzyl-2-benzylo-xymethyl-D-glucopyranosyl)-1,2,3,8,9,10-hexahydro-indolo[3',2':5,6]pyrrolo[3',4':3,4]cyclohepta[b]indole-1,3-dione, as a diastereomer mixture, are dissolved in 50 ml of absol. FtOH and, after the addition of 200 mg of Pd/C (5$), the solution is stirred under an Hz pressure of 7 bar for 5 h. It is then filtered off with suction through Celite, rinsed with 50 ml of CH2C12 and the solution is concentrated in vacuo. Without purification, the product is dissolved in 15 ml of absol. THF and the solution is cooled to 0°C. NH3 is then passed in for 10 min and the mixture is stirred at room temp. for 1 h. After stripping off the THF in vacuo, the residual oil is purified by column chromatography (S:i02: CHzCl2/MeOH 8:2) : red oil, yield 1.0 mg (12~) .
Example 97 1,2,3,3a,8,9,10,14c-Octahydroindolo[3',2':5,6]pyrrolo-[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 HC1., then immediately added to 90 mg 0 . 33 mmol ) of HgClZ in 1. 5 ml of H20 and 1. 5 ml of cons. HCl and the mixture is shaken at room temp. for 10 min. The aq. phase is decanted and the zinc amalgam is additionally washed with 2 x 3 ml of dil. HC1 before it is added to a solution of 60.0 mg (0.18 mmol) of 1,2,3,8,9,10-hexahydroindalo[3',2':5,6]pyrrolo-[3',4':3,4)cyclohepta(b]indole-1,3-dione in 1.5 ml of 5 N HC1, 1.5 ml of EtOH and 1.5 ml of toluene and heated under reflux. After 1 h, as soon as the reaction solution has cooled to room temp. Hz0 is added and the mixture is extracted with 2 x 10 ml of CHZCIz. The org.
extracts are dried over Na2S04, concentrated in vacuo and purified by column chromatography (Si02;
CHzClz/ethyl acetate/MeOH 8:2:0.5): colourless wax, yield 14 mg (23~).
Example 98 2,5-Dihydro-3,4-bis(N-trimethylsilylethoxymethylindol-2-yl)-1H-pyrrolo[sic]-2,5-dione 1.05 g (1.96 mmo.l) of 2-tributylstannyl-N-trimethyl-silylethoxymethylindole in 5 ml of absol. DMF are added dropwise to a solution of 22.65 mg (0.02 mmol) of tetrakistriphenylphosphine palladium and 450.0 mg (1.77 mmol) of 3,4-dibromo-2,5-dihydro-1H-pyrrolo[sic]-2,5-dione in 10 ml of absol. DMF and the mixture is subsequently heated at 110°C for 1 h. After cooling, it is poured onto 50 ml of Hz0 and extracted with 2 x 50 ml of ether. The ether phases are washed with 100 ml of H20, dried over Na2S09 and concentrated. The products can be separated by column chromatography (1. column:
Si02; CHzCl2/MeOH/hexane 20:1:2, 2. column: SiO2;
CHzCl2/ethyl acetate 20:1) .
Yellow wax, yield 200 mg (19~).
The following were prepared analogously:
Example 99 2,5-Dihydro-3,4-bisindol-2-yl-1H-pyrrolo[sic]-2,5-dione M.p.: 197°C (dec.) (CHZC12/hexane) Example 100 2,5-Dihydro-3,4-(N-phenylsulphonylindol-2-yl)-IH-pyrrolo[sic]-2,5-dione M.p.: 196 - 197°C (dec.) (acetone) Example 101 2,5-Dihydro-1-methyl-3,4-bis(N-phenylsulphonylindol-2-yl)-1H-pyrrolo[sic)-2,.5-dione M.p.: 147°C (ether) Example 102 2,5-Dihydro-3,4-b:isindol-2-yl-1-methyl-1H-pyrrolo[sic]-2,5-dione M.p.. 247°C (CH2C12/hexane) (dec.) Example 103 2,5-Dihydro-3-indol-2-yl-1-[2-(N,N-dimethylamino)-ethyl]-4-(N-phenylsulphonylindol-2-yl)-1H-pyrrolo[sic]-2,5-dione 2,5-Dihydro-1-[2-(N,N-dimethylamino)ethyl]-3,4-bis(N-phenylsulphonylindol-2-yl)-1H-pyrrolo[sic]-2,5-dione 4.12 mmol of 2,5-dihydro-3,4-bis(N-phenylsulphonyl-indol-2-yl)-1H-pyrrolo[sic]-2,5-dione are dissolved in 30 ml of absol. DMF, and 200 mg (5.00 mmol) of KH are cautiously added with stirring. After stirring for 1 h at room temp., the halide is added and the mixture is ~;tirred at toom temp. for 24 h. For work-up, the mixture is poured onto ice water. DMF and HZO are distilled off in vacuo, the residue is dissolved in CH2C12 and the solution is washed with H20. After drying over Na2S09, the solvent is stripped off in vacuo and the residue is purified by column chromatography (Si02;
ethyl acetate). Yield 448 mg. 121 and 122 could be separated by column chromatography.
The following were obtained analogously:
Example 104 2,5-Dihydro-3,4-bis(indol-2-yl)-1[2-(N,N-dimethyl-amino)ethyl]-1H-pyrrolo[sic]-2,5-dione orange wax Example 105 1--(2-Bromoethyl)-2,5-dihydro-3,4-bis(N-phenylsulphonyl-indol-2-yl)-1H-pyrrolo[sic]-2,5-dione yellow-brown wax Example 106 1-(2-Bromoethyl)-2,5-dihydro-3-indol-2-yl-4-(N-phenyl-sulphonylindol-2-yl)-1H-pyrrolo[sicl-2,5-dione M.p.: 160°C (dec.) Example 107 1-(2-Bromoethyl)-2,5-dihydro-3,4~-bis(indol-2-yl)-1H-pyrrolo[sicl-2,5-dione M.p.: 104 - 109°C
Example 108 1-(2-Azidoethyl)-2,5-dihydro-3,4-bis(N-phenylsulphonyl-indol-2-yl)-1H-pyrrolo[sicl-2,5-dione M.p.: 165°C (dec.) Example 109 1-(2-Azidoethyl)-2,5-dihydro-3-indol-2-yl-4-(N-phenyl-sulphonylindol-2-yl)-1H-pyrrolo[sicl-2,5-dione M.p.: 190°C (dec.) Example 110 1-(2-Aminoethyl)-2,5-dihydro-3-indol-2-yl-4-(N-phenylsulphonylindol-2-yl)-1H-pyrrolo[sicl-2,5-dione M.p.: 180°C (dec.) Example 111 3-Bromo-4-(2-(3-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)propyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione 200 mg (0.7 mmol) of 1,3-di(1H-2-indolyl)propane are dissolved in 4 ml of absol. THF and cooled to 0°C.
1.09 ml (1.7 mmol) of n-BuLi (1.6 M in hexane) are then added dropwise in the course of 30 min and the mixture is stirred at room temp. for 2 h. 0.46 g (1.71 mmol) of N--methyldibromomaleimide in 4 ml of absol. THF is then slowly added dropwise. The mixture is stirred overnight at: room temp. -and then poured onto 10 ml of 2 N HC1_ The mixture is then extracted with ether (2 x 10 ml) and ethyl acetate (3 x 10 ml), the org. phase is dried over Na2S04 and the solvent is stripped off in vacuo.
The residue is purified by column chromatography (Si02, CAZClz). Red powder, yield: 0.20 g (44$).
M.p.: 160°C (dec.) The following were prepared analogously:
Example 112 3-Bromo-4-(2-(5-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 137°C (dec.) Example 113 3-Bromo-4-(2-(3-(3-(4-bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-i.ndolyl)propyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrolea-2,5-dione 2d.p.: > 350°C
Example 114 3-Bromo-4-(2-(5-(3-(4-bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione ri.p. : > 350°C (dec. ) Example 115 3-Bromo-4-(2-(8-(3-(4-bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)octyl)-1H-3-indolyl)-2,5-d.ihydro-1H-pyrrole-2,5-dione M.p.: 180°C (dec.) Example 116 3-Bromo-4-(2-(2-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)ethyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 179°C

Example 117 3-Bromo-4-(2-(4-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)butyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 190°C (dec.) Example 118 3-Bromo-4-(2-(8-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)octyl)-1H-3-indolyl)-1-methyl--2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 185°C (dec.) Example 119 3-Bromo-4-(2-(10-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)decyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 164°C (dec.) Example 120 3-Bromo-4-(2-(10-(3-(4-bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)decyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 164°C (dec.) Example 121 3-Bromo-4-(2-(12-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)doceyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 126 - 129°C
The following was obtained by reaction of the compound of Example 114 with dimethylamine:
Example 122 3-N,N-dimethylamino-4-(2-(5-(3-(4-N,N-dimethylamino-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)-pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione Example 123 1-Methyl-3-(1-pyrrolidinyl)-4-(2-(5-(3-(1-methyl-4-(1-pyrrolidinyl)-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione 1.0 g (1.5 mmo1) of 3-bromo-4-(2-(5-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione is dissolved in 5 ml (60.6 mmol) of pyrrolidine and stirred overnight at room temp. Excess pyrrolidine is then distilled off. The residue is completely freed from solvent residues in an oil-pump vacuum and then purified by column chromatography (Si02, CHZCIz/ethyl acetate 95:5). Yield: 480 mg (49~).
M.p.: 289°C
The following were prepared analogously:
Example 124 1-Methyl-3-(1-piperidinyl)-4-(2-(5-(3-(1-methyl-4-(1-piperidinyl)-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)--1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione M.p.. 262°C
Example 125 7.-Methyl-3-(1-morpholinyl)-4-(2-(5-(3-(1-methyl-4-(1-morpholinyl)-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1.H-2-indolyl)pentyl)-1X-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 168 - 170°C
Example 126 1-Methyl-3-(1-tetrahydroisoquinolinyl)-4-(2-(5-(3-(1-methyl-4-(1-tetrahydroisoquinolinyl)-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 141 - 142°C

Example 127 1-Methyl-3-(1-(4-(3-trifluoromethylphenyl)piperazinyl)-4-(2-(5-(3-(1-methyl-4-(1-(4-(3-trifluoromethyl-phenyl)piperazinyl))-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 140 - 141°C
Example 128 1-Methyl-3-(1-(4-isopropylaminocarbonylmethyl-piperazinyl))-4-(2-(5-(3-(1-methyl-4-(1-(4-isopropylaminocarbonylmethylpiperazinyl))-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione M.p.. 126 - 128°C
Example 129 1-Methyl-3-(1-(4-isopropylaminocarbonylmethyl-piperazinyl)-4-(2--(5-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 156°C
Example 130 l.-Methyl-3-(1-(4-pyrrolidinylcarbonylmethyl-piperazinyl))-4-(2-(5-(3-(1-methyl-4-(1-(4-pyrrolidinylcarbonylmethylpiperazinyl))-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 158°C (dec.) Example 131 1~-Methyl-3-(1-(4-pyrrolidinylcarbonylmethyl-piperazinyl))-4-(2--(5-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2;5-dione M.p.: 158 - 159°C

Example 132 1-Methyl-3-(1-(4--piperidinopiperidinyl))-4-(2-(5-(3-(1-methyl-4-(1-(4-piperidinopiperidinyl))-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione M.p. . 230 - 232°C: (dec. ) Example 133 1-Methyl-3-(1-(4-piperidinopiperidinyl))-4-(2-(5-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 162 - 164°C
Example 134 1-Methyl-3-(1-(4-ethoxycarbonylpiperazin-1-yl))-4-(2-(5-(3-(1-methyl-(4-ethoxycarbonylpiperazin-1-yl)-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 149 - 150°C
Example 135 1-Methyl-3-(1-(4-(N-(4-hydroxyphenyl)ethylamine))-4-(2-(5-(3-(1-methyl-(4-bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 120 - 122°C (dec.) Example 136 1-Methyl-3-(1-(4-(N-1,2-diaminoethyl)-4-(2-(4-(3-(1-methyl-(4-bromo-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: 180°C (dec.) Example 137 1-Methyl-3-(1-(4-(N-1,.2-diaminoethyl)-4-(2-(4-(3-(1-methyl-(4-(N-1,2-diaminoethyl)-2,5-dioxo-2,5-dihydro-' WO 99/57117 - 35 - PCT/DE99/01214 1H-3-pyrrolyl)-1H-2-indolyl)butyl)-1X-3-indolyl)-2,5-dihydro-1H-pyrrole-2,5-dione M.p.: > 240°C (dec.) Example 138 4,39-Dimethyl-1,4,14,29,39,42-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)-decaene-3,5,38,40-tetraone 0.75 mmol of 3-bromo-4-(2-(12-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)dodecyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione is dissolved in 200 ml of absol. DMF, treated with 0.5 ml of abs. NEt3 and heated to 80°C. The solution of 0.75 mmol of piperazine in 100 ml of absol. DMF and 0.5 ml of NEt3 is then slowly added dropwise to the warm solution and the mixture is then stirred at 80°C
for 48 h. The solvent is then removed in vacuo to the greatest possible extent and the residue is treated with 100 ml of 1N HCl. This solution is then extracted with ethyl acetate (in total about 600 ml), the combined extracts are dried over Na2S0q and the solvent is stripped off i:n vacuo. Purification is carried out by column chromatography (SiOz, CHZC12/EA9.5:0.5).
Grange crystals, yield: 0.267 g (52~).
M.p.: 194 - 195°C
The following were prepared analogously:
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(391,35,37,41(45)-decaene-7,9,42,44-tetraone M.p.: > 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-?(11),12(20),-13(18),14,16,33(41),35(40),36,38,44(46)-decaene-8,10,43,45-tetraone M.p.: 286°C (dec.) 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-8(12),13(21),-14(19),15,17,34(42),36(41),37,39,43(47)-decaene-9,11,44,46-tetraone M.p.. > 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)-decaene-10,12,45,47-tetraone M.p.: 276°C (dec.) 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(17,22).0(37,45).-0(39,44).0(46,50)]heptapentaconta-11(15),16(24),-1'7(22),18,20,37(45),39(44),40,42,46(50)-decaene-12,14,47,49-tetraone M.p.: 245°C (dec.) Example 144 19,49-Dimethyl-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)-decaene-13,15,48,50-tetraone M.p.: 325°C (dec.) Example 145 4,30-Dimethyl-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)-decaene-3,5,29,31-tetraone M.p.. 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)-decaene-7,9,33,35-tetraone M.p.. 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)ltetratetraconta-7(11),12(20),13(18),-14,16,24(32),26(31),27,29,33(37)-decaene-8,10,34,36-tetraone M.p.: 337°C (dec.) Example 148 10,36-Dimethyl-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),-7.5,17,25(33),27(32),28,30,34(38)-decaene-9,11,35,37-tetraone M.p.: 245°C (dec.) Example 149 11,37-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)-decaene-10,12,36,38-tetraone _ M.p.: 325°C (dec.) 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-11(15),16(24),17(22),-18,20,28(36),30(35),31,33,37(41)-decaene-12,14,38,40-tetraone M.p.: 245°C (dec.) Example 151 14,40-Dimethyl-11,14,24,30,40,43-hexaazanonacyclo-[41.2.2.2(8,11).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)-decaene-13,15,39,41-tetraone M.p.: 325°C (dec.) 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(23,28).-0(30,34))nonatriaconta-2(6),7(15),8(13),9,11,21(29),-23(28),24,26,30(34)-decaene-3,5,31,33-tetraone M.p.. 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)-decaene-7,9,35,37-tetraone M.p.: 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)lhexatetraconta-7(11),12(20),13(18),-14,16,26(34),28(33),29,31,35(39)-decaene-8,10,36,38-tetraone M.p.. > 350°C

Example 155 7,10,20,28,38,41-Hexaazanonacyclo[39.2.2.2(4,7).
0(8,12).0(13,21).G(14,19).0(27,35).0(29,34).0(36,40)]-heptatetraconta-8(12),13(21),14(19),15,17,27(35),-'1.9(34),30,32, 36(40)-decaene-9,11,37,39-tetraone M.p.. 290 - 292°C
Example 156 :L1,39-Dimethyl-9,11,21,29,39,42-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)-decaene-10,12,38,40-tetraone M.p.. 310°C (dec.) 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)]pentaconta-11(15),16(24),17(22),18,-20,30(38),32(37),33,35,39(43)-decaene-12,14,40,42-tetraone M.p.: 310°C (dec.) Example 158 :14,42-Dimethyl-11,14,24,32,42,45-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)-decaene-13,15,41,43-tetraone M.p.: 321 - 324°C
Example 159 6,13-Dimethyl-5,6,7,8,9,10,11,12,13,14,19,20,21,22,23,-:?4-hexadecahydrodipyrrolo[3',9':15,16:3',4':5,6]indolo-[2',3':13,14](1,4]diazacyclohexadecyno[8,7:b]indol-5,-'7,12,14-tetraone M.p.: > 240°C

Example 160 1,4,14,29,39,42-Hexaazaoctacyclo[40.2.2.0(2,6).-G(7,15).0(8,13).0(28,36).0(30,35).0(37,41)]hexatetra-conta-2(6),7(15),8(13),9,11,28(36),30(35),31,33,37(41)-decaene-3,5,38,40-tetraone M.p.: 194 - 195°C
Example 161 '_~,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)-decaene-7,9,42,44-tetraone M.p.. 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)[sic].0(35,40).0(42,46)]-t:ripentaconta-(11),12(20),13(18),14,16,33(41),-35(40),36,38,42 (46)-decaene-8,10,43,45-tetraone M.p.: 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)-decaene-9,11,44,46-tetraone M.p.: 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)-decaene-10,12,45,47-tetraone M.p.: 282 - 284°C
Example 165 10,13,23,38,48,51--Hexaazanonacyclo(49.2.2.2(7,I0).-O(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)--decaene-12,14,47,49-tetraone M.p.: 176 - 179°C
Example 166 :L1,14,24,39,49,52--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)-decaene-13,15,48,50-tetraone M.p.: 147 - 150°C
Example 167 :L,4,14,20,30,33-Hexaazaoctacyclo[31.2.2.2(2,6).-I)(7,15).0(8,13).0(19,27).0(21,26).0(28,32))-heptatriaconta-2(Ei),7(15),8(13),9,11,19(27),-:Z1(26),22,24,28(32)-decaene-3,5,29,31-tetraone M.p.: 350°C (dec.) Example 168 5,8,18,24,34,37-Hexaazanonacyclo[35.2.2.2(2,5).-I)(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(3Ei)-decaene-7,9,33,35-tetraone 2d. p.: 285°C (dec.) Example 169 Ei,9,19,25,35,38-Hexaazanonacyclo[36.2.2.2(3,6).-0(7,11).0(12,20).CI(13,18).0(24,32).0(26,31).0(33,37)]-tetratetraconta-7f11),12(20),13(18),14,16,24(32),-26(31),27,29,33 (37)-decaene-8,10,34,36-tetraone M.p.. 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)-decaene-9,11,35,37-tetraone iri.p. : 330°C (dec. ) Example 171 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)-decaene-10,12,36,38-tetraone M.p_: 335.5°C (dec.) Example 172 20,13,23,29,39,42--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-11(15),16(24),17(22),18,20,28(36), 30(35),31,33,37(41)-decaene-12,14,38,40-tetraone M.p.. 243 - 245°C
Example 173 11,14,24,30,40,43-Hexaazanonacyclo[41.2.2.2(8,11).-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)-decaene-13,15,39,41-tetraone M.p.: 258 - 260°C
Example 174 4,32-Dimethyl-1,4,14,22,32,35-hexaazaoctacyclo-[33.2.2.2(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)-decaene-3,5,31,33-tetraone M.p.: > 350°C
Example 175 8,36-Dimethyl-5,8,18,26,36,39-hexaazanonacyclo-[37.2.2.2(2,5).0(8,10).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)-decaene-7,9,35,37-tetraone M.p_: 310°C (dec.) 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)-decaene-9,11,37,39-tetraone M.p.. 280°C (dec.) Example 177 13,46-Dimethyl-1,7,10,13,23,36,46,49-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)]pentapentaconta-11(15),16(24),17(22),18,20,35(43),37(42),38,40,44(48)-<iecaene-12,14,45,47-tetraone M.p.:> 220°C
Example 178 4,31-Dimethyl-1,4,14,21,31,34-hexaazaoctacyclo-[32.2.2.2(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,-:?0(28),22(27),23,25,29(33)-decaene-3,5,309(sic],32-tetraone M.p.:> 240°C (dec.) Example 179 8,35-Dimethyl-5,8,18,25,35,38-hexaazanonacyclo-[36.2.2.2(2,5).0((i,10).0(11,19).0(12,17).-O(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)-decaene-7,9,34,36--tetraone, m.p.:> 240 (dec.) F;xample 180 (1-(2-Dimethylaminoethyl)-1H-3-indolyl)(1H-3-indolyl)-1-methanone 0.5 g of bis(indol-3-yl)methanone is dissolved in 30 ml of acetone. After addition of 0.92 g of KZC03 and 0.27 g of 2-dimethylamino-1-chloroethane hydrochloride, the mixture is heated to reflux for 70 h. The acetone is stripped off and the residue is treated with 30 ml of water and 30 ml of ethyl acetate. After stirring for 15 min, the org. phase is separated off and the aqueous phase is extracted by shaking a further two times with 15 ml of ethyl acetate each time. The combined org.
phases are dried over Na2S04 and the solvent is stripped off_ Purification is carried out by column chromatography (Si02, EA/MeOH 10:1). Yield: 0.14 g (200) M.p.: 180 - 182°C
The following were prepared analogously:
Example 181 I;1-(2-Morpholinoet.hyl)-1H-3-indolyl)(1H-3-indolyl)-1-methanone rz.p.. 192 - 194°C
Example 182 E3is(1-(2-morpholinoethyl)-1H-3-indolyl)-1-methanone rz.p.: 91 - 93°C
Example 183 (1-(2-Piperidinoethyl)-1H-3-indolyl)(1H-3-indolyl)-1-methanone M.p.: 223 - 225°C
Example 184 Bis(1-(2-piperidinoethyl)-1H-3-indolyl)-1-methanone M.p.: 152 - 155°C
Example 185 (1-(3-Dimethylaminopropyl)-1H-3-indolyl)(1H-3-indolyl)-1-methanone M.p.: 144 - 146°C
Example 186 (1-(3-Pyrrolidinopropyl)-1H-3-indolyl)(1H-3-indolyl)-1-methanone M.p.: 148 - 152°C

Example 187 (1-(2-Dimethylaminoethyl)-1H-2-indolyl)(1H-2-indolyl)-7_-methanone M.p.: 147 - 150°C
Example 188 (1-(2-Morpholinoet.hyl)-1N-2-indolyl)(1H-2-indolyl)-1-methanone V~ax Example 189 (1-(2-Piperidinoethyl)-1H-2-indolyl)(1H-2-indolyl)-1-methanone V~la x Example 190 (1-(2-Pyrrolidinoe~thyl)-1H-2-indolyl)(1H-2-indolyl)-1-methanone VVax Example 191 11,46-Dimethyl-21,36-bis(2-(1-piperidinyl)ethyl-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)]pentapent.aconta-9(13),14(22),15(20),-7_6,18,35,(43),37(42),38,40,44(48)-decaene-10,12,45,47-tetraone M.p.: 125 - 130°C
Example 192 3,3'-Dimethoxydiglyoxyl-1,8-(2,2'-bisindolyl)octane Oxalyl dichloride is added dropwise under an NZ
atmosphere to a solution of 1.15 g (4.00 mmol) of 1, 8-(2,2'-bisindolyl)octane in 20 ml of absol. THE at 0°C
and the mixture is stirred at room temperature for 2 h.
20 ml of MeOH are then allowed to run in dropwise. The mixture is stirred overnight at room temperature. For work-up, the mixture is treated with 100 ml of 1 N HC1, neutralized with 2 N NaOH and the mixture is extracted with EA (3 x 25 ml). After drying over NaS04 [sic], the solvent is stripped off.
M.p.. > 250°C (dec.) Example 193 3-(2-(4-(1H-2-Indolyl)butyl)-1H-3-indolyl)-1-methyl-2,5-pyrrolidinedione A solution of 240 mg (0.50 mmol) of 3-bromo-4-(2-(4-(1H-2-indolyl)butyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione and 140 mg (0.25 mmol) of Pd(OH)2/C (20~) in 30 ml of MeOH is stirred under an HZ
atmosphere at room temperature for 24 h. For work-up, the mixture is faltered, the filtrate is concentrated ~snd the residue is purified by column chromatography (SiO2:CHzCl2/EA 95:5). On concentrating the pure fraction, the product is crystallized by addition of PE. Yield: 48.0 mg (24$), beige powder M.p.: 180 - 182°C
Example 194 'test for measurement of the inhibition of PDGF-dependent tyrosine phosphorylation for compounds according to the invention Swiss 3T3 cells are cultured for 1 week under standard conditions (DMEM with glutamine, 4 g of glucose/l, 10~
FCS Antibiotika, 5-7.5~ COZ) and are confluent and no :longer proliferating at the end of the culture period.
The medium is replaced by serum-free DMEM and the cells are incubated at: 37°C for 2 h with the compounds according to the invention or, in control experiments, with DMSO (final concentration 0.1-1~). The cells are then stimulated at room temperature for 5 min by addition of PDGF-BB to a final concentration of 100 ng/ml, in controls addition of the corresponding ~:olvent takes place. The cells are then washed twice with ice-cold. PBS and lysed in a Triton X-100-containing lysis buffer (composition and process as described in Selective platelet-derived growth factor receptor kinase Mockers reverse sis-transformation M. Kovalenko, A. Gazit, A. Bohmer, C. Rorsman, L. Ronnstrand, C.H. Heldin, J. Waltenberger, F.D. Bohmer, A. hevitzki (1994) Cancer Res. 54, 6106-6114). The lysates are centrifuged and the protein concentration is determined. 10 ~g of lysate protein are applied directly to nitrocellulose membranes (Dot-blot apparatus or corresponding multi-well plates with nitrocellulose bares).
'tyrosine phosphorylation is detected by standard processes using antiphosphotyrosine antibodies.
'typically, a monoclonal antiphosphotyrosine antibody, conjugated to horseradish peroxidase (POD), and detection of the POD activity by means of chemiluminescence detection is used. Quantification is carried out either by grey value analyses of films used Eor the luminescence detection or directly using a :luminometer. Customarily, the PDGF stimulation of the cells results in a 3- to 10-fold increase in the aignal.
The compounds were primarily employed in duplicate in the final concentration 10 ~tg/ml. In the case of active compounds, a titration was carried out in the stages :30 E,~M, 10 ECM, 3 EtM, 1 ~M, 0.3 ~M and 0.1 N.M as a duplicate determination. The results are shown in Table 1.

Table 1 Exampl Compound IC 5 0 ( a ).tM ) 19 Bisindol-2-ylmethan-1-one 1 20 (5-Methoxyindol-2-yl)-(indol-2- 0.1-0.3 yl)methan-1-one 21 Bis(5-methoxyindol-2-yl)-1- 10-30 methanone~

28 Benzo[b]t.hiophen-2-yl(5-methoxy-1 1H-2-indolyl)-1-methanone 43 5-Hydroxy-1H-2-indolyl(1H-2- 0.1-0.3 indolyl)methanone 45 1H-2-Indolyl[5-(2-morpholin-1- 1-3 ylethyloxy)-1H-2-indolyl]methanone 48 1H-2-Indolyl[5-(2-dimethylamino- 0.3-1 ethyloxy)-1H-2-indolyl]methanone 53 [2-(1H-2-Indolylcarbonyl)-1H-5- 0.1-0.3 indolyl)] ethanoate 55 [2-(1H-2-Indolylcarbonyl)-1H-5- 1-3 indolyl)) butanoate 56 [2-(1H-2-Indolylcarbonyl)-1H-5- 0.1 indolyl))2-(N,N)-dimethylaminoethanoate 57 [2-(1H-2-Indolylcarbonyl)-1H-5- 0.3-1 indolyl)] propanoate 58 [2-(1H-2-Indolylcarbonyl)-1H-5- 0.3-1 indolyl)) 2-thiophenylethanoate The qualitative detection of the effects on the tyrosine phosphorylation of the PDGF receptor and cellular substrates is carried out by analysis of the cell - lysates by means of polyacrylamide gel electrophoresis and immunoblotting using anti phosphotyrosine antibodies according to standard processes.
The compounds according to the invention were furthermore investigated in vitro using isolated plasma membranes of Swiss 3T3 cells and using PDGF receptor purified from overexpressing cells, tested in intact A431 cells (and in some cases also in Swiss 3T3 plasma membranes) for po:>sible inhibition of the EGF receptor tyrosine kinase and tested for inhibition of recombinant Src kinase. The results are chosen in Table 2.
DNA synthesis tests in Swiss 3T3 cells which are stimulated with different growth factors are suitable for characterizing selective antiproliferative actions of receptor tyro~;ine kinase inhibitors. The compounds were investigated with respect to their action on the DNA sythesis stimulated in these cells by PDGF-BB, bFGF, FCS and the combination of EGF and insulin. These :stimulants are approximately equipotent and increase the DNA synthesis in previously growth-arrested Swiss 3T3 cells to 5- to 20-fold. The dose dependencies of the corresponding experiments and the IC50 values obtained are likewise shown in Table 2.
Furthermore, the compounds were investigated for a possible antitransforming action using sis-transformed IJIH3T3 cells. In these cells, a transformed phenotype characterized, inter alia, by irregular multilayered growth and colony formation in soft agar is maintained by expression of PDGF-BB and permanent activation of i=he endogenous PDGF receptors. The IC50 values obtained are likewise shown in Table 2.
Accordingly, actions on the PDGF receptor kinase by the compounds were found in the following tests:
-- PDGF receptor autophosphorylation in intact Swiss 3T3 cells -- PDGF receptor autophosphorylation in isolated membranes of Swiss 3T3 fibroblasts and -- PDGF receptor autophosphorylation in purified receptor preparations.
No actions were observed in analogous tests with the receptor tyrosine kinase for the epidermal growth factor and with the cytosolic tyrosine kinase Src up to a concentration of 30 ~M. The compounds thus have specificity for the inhibition of the PDGF receptor tyrosine kinase in relation to other tyrosine kinases.
Table 2 Test IC 50 ((.tM) Example Example Example PDGFR phosphorylation 1 0.1-0.3 10-30 in vivo (Swiss 3T3 cells) PDGFR phosphorylation 0.3-1 < 0.03 n.d.
in ~ritro (Swiss 3T3 membranes) PDGFR phosphorylation 0.1-0.3 n.d, n.d.
in ~ritro (purified PDGF receptor) EGFR phosphorylation in vivo > 10 > 10 n.d.

(A 431 cells) src kinase phosphorylation in vivo > 30 > 30 n.d.

(src NIH
cells) Reversion of the transformed +++ . n.d. n.d.
morphology of sis-3T3 cells DNA synthesisPDGF-(Swiss 3T3 stimulated 3-10 n.d n..d cells) - FGF-stimulated 3-10 n.d. n.d.

EGF/insulin-stimulated > 30 n.d. n.d.

10$ F'CS > 30 n.d. n.d.

Colony formation (sis-3T3 3-10 I n.d I n.d cells) I

Claims (23)

1. A compound of the general formula I:
wherein Z is a group having the general formula II:
wherein A is nitrogen, oxygen or sulphur;
B and B' are each selected from the group consisting of carbon, nitrogen, oxygen and sulphur atoms; and the ring systems F and G independently of one another are each either a saturated or unsaturated 5- and 6-membered ring;
X is a group having the general formula III or IV:
-(CH2)1-[CR14R15]m-(CH2)n (III) in which A has the same meaning as above;
1 and n are each from 0 to 6;
m is 1 or 2; and R14 and R15 either together form an oxygen atom or R14 is a hydroxyl group and R15 is a hydrogen atom or R14 and R15 are hydrogen atoms; and wherein R16 is a hydrogen atom, a C1-12 alkyl or C6-14 aryl radical, a halogen-, amino-, or azido-substituted C1-12 alkyl or C6-14 aryl radial, a C1-6 alkyloxymethyl radical or substituted C1-6 alkyloxymethyl radical;
R2 and R13 are identical or different radicals selected from the group consisting of hydrogen atoms and groups of the general formula VII:
wherein the dashed bond is a double or single bond;
A and R16 have the same meaning as above; and R17 is a halogen atom or a radical of the general formula VIII:
wherein p = 0, 1 or 2 (if p = 0 then formula VIII is an acyclic secondary amine and Y carries an additional hydrogen atom);
Y is a carbon atom, an oxygen atom or a nitrogen atom, and if Y is a carbon atom or a nitrogen atom, R18 is selected from the group consisting of a hydrogen atom or a C1-12 alkyl or a C6-14 aryl radical, a substituted C1-12 alkyl or C6-14 aryl radical, a C3-9 heteroaryl radical, a C2-6 cycloalkyl, a C1-6 alkoxycarbonyl radical, an aminocarbonylmethyl radical or a substituted aminocarbonylmethyl radical;
wherein R1 and R7, R12 are identical or different and are selected from the group consisting of a hydrogen atom, a C1-12 alkyl radical, an amino C1-6 alkyl radical, a phenylsulphonyl radical, a C1-6 alkylsilylmethoxymethyl radical, a sugar and a substituted sugar;
wherein R3, R4, R5, R6, R8, R9, R10 and R11 are identical or different and in each case is selected from the group consisting of a hydrogen atom, C1-6 alkoxy-, amino-, halogen-, C3-7 cycloalkyl-, C2-6 heterocycloalkyl-, C6-14 aryl-, and heteroaryl-substituted C1-12 alkyl, C1-6 alkoxy and C1-12 alkoxymethyl groups, a nitro group, a halogen atom and an O-alkoxy group of the general formula -O-(CO)-R21 wherein R21 is a C1-6 alkoxy-, amino-, halogen-, C3-7 cycloalkyl-, C2-6 heterocycloalkyl-, C6-14 aryl- or C3-9 heteroaryl-substituted C1-12 alkyl, C1-6 alkoxy or C1-6 alkoxymethyl group.

2. The compound according to claim 1, wherein A is nitrogen.

3. 5-Hydroxy-1H-2-indolyl(1H-2-indolyl)methanone according to claim 1.

4. 1H-2-Indolyl [5-(2-dimethylaminoethyloxy)-1H-2-indolyl]methanone according to claim 1.

5. [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)ethanoate according to claim 1.

6. [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)butanoate according to claim 1.

7. [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)]2-(N,N)-dimethylaminoethanoate according to claim 1.

8. [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)]propanoate according to claim 1.

9. [2-(1H-2-Indolylcarbonyl)-1H-5-indolyl)]2-thio-phenylethanoate according to claim 1.

10. Compounds having the formula XI
wherein B is a nitrogen, oxygen or sulphur atom;
R1 and R7 are identical or different and are selected from the group consisting of a hydrogen atom, a C1-12 alkyl radical, an amino C1-6 alkyl radical, a phenylsulphonyl radical, a C1-6 alkylsilylmethoxymethyl radical, a sugar and substituted sugar;
R4 and R10 are identical or different and in each case is selected from the group consisting of a hydrogen atom, C1-6 alkoxy-, amino-, halogen-, C3-7 cycloalkyl-, C2-6 heterocycloalkyl-, C6-14 aryl-substituted C1-12 alkyl, C1-6 alkoxy and C1-6 alkoxymethyl groups, a nitro group, and an O-alkoxy group of the formula -O-(C=O)-R21, where R21 is a C1-6 alkoxy-, amino- , halogen- , C3-7 cycloalkyl-, C2-6 heterocycloalkyl-, C6-14 aryl- and C3-9 heteroaryl-substituted C1-12 alkyl, C1-6 alkoxy and C1-6 alkoxymethyl groups;

R14 and R15 either together form an oxygen atom, or R14 is a hydroxyl group and R15 is a hydrogen atom, or R14 and R15 are hydrogen atoms; and R3, R5, R6, R8, R9 and R11 are identical or different and in each case is selected from the group consisting of a hydrogen atom, C1-6 alkoxy-, amino-, halogen-, C3-7 cycloalkyl-, C2-6 heterocycloalkyl-, C6-14 aryl- and C3-9 heteroaryl-substituted C1-12 alkyl, C1-6 alkoxy and C1-6 alkoxymethyl groups, a nitro group, and an O-alkoxy group of the formula -O-(C=O)-R21, wherein R21 is a C1-6 alkoxy-, amino-, halogen-, C3-7 cycloalkyl-, C2-6 heterocycloalkyl-, C6-14 aryl- or C3-9 heteroaryl-substituted C1-12 alkyl, C1-6 alkoxy or C1-6 alkoxymethyl group.

11. Bisindol-2-ylmethan-1-one according to claim 10.

12. (5-Methoxyindol-2-yl)-(indol-2-yl)methan-1-one according to claim 10.

13. Bis(5-methoxyindol-2-yl)-1-methanone according to claim 10.

14. Benzo[b]thiophene-2-yl-(5-methoxy-1H-2-indolyl)-1-methanone according to claim 10.

15. 1H-2-Indolyl[5-(2-morpholin-1-ylethyloxy)-1H-2-indolyl]methanone according to claim 10.

16. A pharmaceutical composition for inhibiting tyrosine kinase, the pharmaceutical composition comprising the compound as defined in any one of claims 1 to 15, together with a pharmaceutically acceptable carrier.

17. A pharmaceutical composition for inhibiting a Platelet-Derived Growth Factor (PDGF) receptor tyrosine kinase or a structurally related tyrosine kinase, the pharmaceutical composition comprising the compound as defined in any one of claims 1 to 15, together with a pharmaceutically acceptable carrier.

18. A. pharmaceutical composition for treating a tumor selected from the group consisting of gliomas, glioblastomas, sarcomas, mastocarcinomas, ovarian carcinomas and colonic carcinomas, the pharmaceutical composition comprising the compound as defined in any one of claims 1 to 15, together with a pharmaceutically acceptable carrier.

19. A pharmaceutical composition for treating arteriosclerosis, restenosis after balloon angioplasty, arthritis, or a fibriotic disease, the pharmaceutical composition comprising the compound as defined in any one of claims 1 to 15, together with a pharmaceutically acceptable carrier.

20. Use of the compound as defined in any one of claims 1 to 15 in the manufacture of a medicament for inhibiting tyrosine kinase.

21. Use of the compound as defined in any one of claims 1 to 15 in the manufacture of a medicament for inhibiting a Platelet-Derived Growth Factor (PDGF) receptor tyrosine kinase or a structurally related tyrosine kinase.

22. Use of the compound as defined in any one of claims 1 to 15 in the manufacture of a medicament for treating a tumour selected from the group consisting of gliomas, glioblastomas, sarcomas, mastocarcinomas, ovarian carcinomas and colonic carcinomas.

23. Use of the compound as defined in any one of claims 1 to 15 in the manufacture of a medicament for treating arteriosclerosis, restenosis after balloon angioplasty, arthritis, or a fibriotic disease.