WO2004108702A1

WO2004108702A1 - Indole derivatives with apoptosis-inducing effect

Info

Publication number: WO2004108702A1
Application number: PCT/EP2004/005593
Authority: WO
Inventors: Matthias Gerlach; Tilmann Schuster; Peter Emig; Peter Schmidt; Silke Bassner; Eckhard Günther
Original assignee: Zentaris Gmbh
Priority date: 2003-06-05
Filing date: 2004-05-25
Publication date: 2004-12-16
Also published as: CN1816543A; CN1816543B; JP4878285B2; CA2526663C; RS20050901A; JP2007523850A; KR20060034230A; NZ543853A; RU2327696C2; AU2004245198B2; CA2526663A1; RU2006100022A; MXPA05013121A; AU2004245198A1; KR101132599B1; EP1641777A1; BRPI0410998A

Abstract

The invention relates to indole derivatives used as medicaments for the treatment of tumoral diseases, particularly in case of resistance of medicaments against other active ingredients and metastasing carcinoma.

Description

Indole derivatives with apoptosis inducing effects

[0001] The present invention relates to new indole derivatives with improved biological activity, improved tolerance and improved oral bioavailability, which are used as medicaments for the treatment of tumor diseases, in particular in the case of drug resistance to other active substances and in metastatic carcinoma.

[0002] The treatment of cancer has a great deal in medicine

Importance. There is a worldwide need for effective cancer therapies for patient-oriented and goal-oriented treatment. This is reflected in the large number of scientific papers that have recently appeared in the field of applied oncology or basic research on cancer therapy.

The effect of tumor inhibitors is based on a wide variety of mechanisms and is only partially known. It is not uncommon for new mechanisms of action to be found for known tumor drugs. This is also to be expected for the compounds according to the invention. Many tumor drugs work through mechanisms such as blocking the cell's cell division mechanism, preventing the tumor from being supplied with nutrients and oxygen (anti-angiogenesis), preventing metastasis, preventing the reception and transmission of growth signals to the tumor cell or the Forcing the tumor cell into programmed cell death (apoptosis).

Due to different mechanisms of action, inter alia the interaction with different intracellular targets, the clinically relevant cytostatics are often given in combination in order to achieve a synergistic therapeutic effect. Indole derivatives find a wide variety of uses as pharmacodynamically active compounds and as synthesis components in pharmaceutical chemistry.

In documents W099 / 51224 A1 and WO01 / 22954 A1, indol-3-yl derivatives with antitumor activity, which are associated with numerous groups and others. can also be substituted with 2-, 3-, 4- and 8-quinoline or 2-, 3-, 4-, 5- and 6-pyridine residues. In Example 60, a 2-methyl-8-quinolinyl group is mentioned as a substituent on the amide group. However, no biological properties are mentioned.

In W099 / 55696 A1 substituted hydroxyindoles are considered

Phosphodiesterase 4 inhibitors described. An antitumor activity for the compounds according to the invention is neither described nor suggested.

[0008] WO 02/08225 A1 describes 2- (1 H-indol-3yl) -2-oxoacetamide derivatives with an anti-tumor effect against solid tumors. However, specific embodiments with quinoline, pyridopyrazine or indazolyl residues are not given.

Patent specification WO 00/67802 describes indoI-3-glyoxylamides which are substituted with higher-chain fatty acids as potential antitumor agents. However, specific embodiments with quinoline, pyridopyrazine or indazolyl radicals are not given. No biological data are also given for such exemplary embodiments.

[0010] In the publication by W.-T. Li et al. (J. Med. Chem. 2003, 46, 1706 ff.) N-heterocyclic indolylglyoxylamides are described as orally active compounds with antitumoral activity. However, details of the mechanism of action are not given.

In patent application WO03 / 022280 A2 3-

Glyoxylamidindole and their use as medicines for the anti Tumor treatment described. Their general formula includes 6-quinoline derivatives. In addition, two examples with 6-quinoline residue are named as exemplary embodiments and supported with biological results. However, specific embodiments with pyridopyrazine or indazolyl radicals are not given.

[0012] New indolylgloxamides are described in US application US03 / 0181482A1. The compounds according to the invention are described here as antitumor agents with cytotoxic activity and as angiogenesis inhibitors. In addition, a 6-quinoline derivative is shown as an exemplary embodiment (compound 3; p.10) and supported with antiproliferative data (see p. 19; Table 1 a, 1 b) and antiangiogenic properties (see p. 20). However, specific embodiments with pyridopyrazine or indazolyl radicals are not given.

[0013] WO 02/10152 A2 from the applicant already describes another

Class of indole derivatives for the treatment of tumors. Among other things, the active ingredient N- (2-methyl-6-quinolyl) - [1 - (4-chlorobenzyl) indol-3-yl] - glyoxylic acid amide was tested for its anti-proliferative effect on various tumor cell lines.

Clinically proven compounds that either bind to the microtubules (paclitaxel, vincristine) or inhibit topoisomerase II (doxorubicin, etoposide, mitoxantrone) are currently used in cancer therapy, among others. successfully used for breast, ovarian, stomach, lung cancer, Kaposi's sarcoma and leukemia. However, their use is limited by the occurrence of drug resistance as well as serious neurological, gastrointestinal, cardiovascular and hepatic side effects.

One object of the invention is to provide cytotoxic substances with combined mechanisms of action which can be used to treat a large number of tumors, in particular in the case of active substances. resistance to other drugs and metastatic carcinomas. suitable.

[0016] This object is achieved by indole derivatives of the general

Formula I.

Formula I.

wherein

R: for one or more heteroatoms selected from the group N,

O and S containing saturated, unsaturated or aromatic substituted or unsubstituted (C ₂ -Cι) heterocycle directly connected to the amide nitrogen, the heterocycle preferably

(i) unsubstituted or substituted 5-, 6-, 7-quinolyl, (ii) unsubstituted or substituted 2-, 3-, 6-, 7- and 8-

Pyridopyrazinyl, (iii) unsubstituted or substituted 3-, 4-, 5-, 6- and 7-indazolyl, (iv) unsubstituted or substituted 2-, 3-, 4-, 5- and 6-pyridyl, (v) unsubstituted or substituted 3-, 4- and 5-isoxazolyl means

(vi) denotes unsubstituted or substituted 3-, 4- and 5-isothiazolyl,

R1: unsubstituted or substituted alkyl aryl, R2: (i) hydrogen,

(ii) unsubstituted or substituted (CrC ₆ ) alkyl,

R3-R6: (i) hydrogen

(ii) unsubstituted or substituted (-CC ₆ ) alkyl,

(iii) unsubstituted or substituted (C ₃ -C ₇ ) cycloalkyl,

(iv) amino, mono- (CrC ₄ ) -alkylamino, di- (CrC) -alkylamino,

(v) halogen, (vi) (C 1 -C ₄ ) -alkyl, preferably trifluoromethyl group, substituted with one or more fluorine atoms,

(vii) cyano, straight-chain or branched cyano- (-C-Ce) -alkyl,

(viii) (CC ₆ ) alkylcarbonyl,

(ix) carboxyl, (-CC ₄ ) -alkoxycarbonyl, carboxy- (CrC ₆ ) -alkyl or (d- C ₆ ) -alkoxycarbonyl- (CrC ₆ ) -alkyl,

(x) hydroxy,

(xi) - (CC ₆ ) alkoxy,

(xii) aryl- (CrC ₄ ) alkoxy, preferably benzyloxy,

(xiii) (CrC ₆ ) alkoxycarbonylamino, (CrC ₆ ) alkoxycarbonylamino (Cr C ₆ ) alkyl,

R7:

(CrC ₆ ) -alkylcarbonyl, preferably acetyl, propionyl, (-C-C ₆ ) -alkoxycarbonyl, preferably methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,

and

X, Y: mean oxygen or sulfur,

their tautomers, stereoisomers, including the diastereomers and enantiomers, and the physiologically tolerable salts thereof. In the event that R represents an unsubstituted or substituted 2-, 3-, 4-, 5- or 6-pyridyl group and R1-R6 has the above-mentioned meaning, R7 must not be an acetyl radical or a te / f-butyloxycarbonyl group.

Another object of the invention are indole derivatives of

Formula I, wherein

Formula I.

R: directly related to the amide nitrogen

(i) substituted 6-quinolyl, unsubstituted or substituted 7-quinolyl, whereby 2-methyl-6-quinolyl is excluded, where if X is a sulfur atom, R can also be unsubstituted 6-quinolyl.

(ii) unsubstituted or substituted 2-, 3-, 6-, 7- and 8-pyridopyrazinyl,

(iii) unsubstituted or substituted 3-, 4-, 5-, 6- and 7-indazolyl,

R1: unsubstituted or substituted alkyl aryl,

R2 hydrogen

R3-R6:

(xiv) hydrogen

(xv) unsubstituted or substituted (CrC ₆ ) alkyl,

(xvi) unsubstituted or substituted (C ₃ -C) cycloalkyl, (xvii) amino, mono- (CrC ₄ ) -alkylamino, di- (-C-C ₄ ) -alkylamino,

(xviii) halogen,

(xix) (CrC ₄ ) -alkyl substituted with one or more fluorine atoms, preferably trifluoromethyl group, (xx) cyano, straight-chain or branched cyano- (CrC ₆ ) -alkyl,

(xxi) (-CC ₆ ) alkylcarbonyl, (xxii) carboxyl, (-C-C ₄ ) alkoxycarbonyl, carboxy- (CC ₆ ) alkyl or (C

C ₆ ) -alkoxycarbonyl- (-C-C ₆ ) -alkyl, (xxiii) - (CrC ₆ ) -alkoxy, (xxiv) aryl- (-C-C ₄ ) -alkoxy, preferably benzyloxy,

(xxv) (CrCβJ-alkoxycarbonylamino, (-C-C ₆ ) -alkoxycarbonylamino- (Cr

C ₆ ) alkyl

and

R7 hydrogen

X, Y: mean oxygen or sulfur,

their tautomers, stereoisomers, including the diastereomers and enantiomers, and the physiologically tolerable salts thereof.

The present invention is a further development of the invention described in WO 02/10152. It was found that when the 2-methyl-6-quinolyl group was replaced by unsubstituted or substituted 2-, 3-, 6-, 7- and 8-pyridopyrazinyl, unsubstituted or substituted 3-, 4-, 5-, 6- and 7-indazolyl, show an improved antiproliferative effect on various tumor cell lines.

It has also been found that the compounds according to the invention have a strong cytotoxic effect which can be based on a wide variety of mechanisms. A mechanism of the compounds according to the invention which is proven in the invention is based on the inhibition the tubulin polymerization and on the inhibition of topoisomerase II. This leads to a cell locking of tumorigenic cells in the G2M phase. In addition, the compounds according to the invention induce apoptosis.

It was also found that the compounds according to the invention have improved water solubility and thus also improved oral bioavailability.

[0021] Furthermore, an improved in vivo activity with better tolerance was demonstrated for the compounds according to the invention by introducing an acetyl residue as the R7 residue.

With the class of substances described in the invention, the possibility of a lower, longer-lasting and better tolerated medication with antitumor effect is to be opened than with the classic cytostatics. In particular, the disadvantageous development of resistance, as is known from many antitumor agents, is to be avoided. The increase in activity achieved with the indole derivatives according to the invention is intended to make drug consumption more effective. In addition, it should be possible to extend treatment to therapy-resistant cases.

[0023] In a preferred embodiment, in the case of the indole

Derivative of the formula I R1 4-chlorobenzyl, R2-R6 hydrogen, R heterocycle and R7 alkylcarbonyl or alkoxycarbonyl.

In a further preferred embodiment, the

Indole derivative of the formula I R unsubstituted 5-quinolyl, unsubstituted 6-quinolyl or unsubstituted 7-quinolyl and R7 acetyl or propionyl.

In a further preferred embodiment, the

Indole derivative of the formula IR unsubstituted 5-quinolyl, unsubstituted 6-quinolyl or unsubstituted 7-quinolyl and R7 methoxycarbonyl, ethoxycarbonyl or propionoxycarbonyl. [0026] Some terms are defined below which are used in the description and the claims.

In connection with "heterocycle" is understood by the

Term, unless explicitly mentioned above, pyrrole, furan, thiophene, pyrazole, thiazole, indole, oxazole, imidazole, isothiazole, isoxazole, 1, 2,3-triazole, 1, 2,4-triazole, 1, 2,4, oxadiazole , 1, 3,4-oxadiazole, 1, 2,5-thiadiazole, 1, 3,4-thiadiazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, benzofuran, indazole, carbazole, benzoxazole, benzimidazole, benzothiazole, benzotriazole, quinoline , Cinnoline, quinoxaline, quinazoline, phthalazine, pyridopyrazine, 1, 2,3-triazine, 1, 2,4-triazine, 1, 3,5-triazine, purine, pteridine, acridine and phenanthridine.

For the purposes of this invention, the term “alkyl” encompasses acyclic saturated or unsaturated hydrocarbons, which can be straight-chain or branched.

In connection with “alkyl”, the term “substituted” in the sense of this invention, insofar as not explicitly defined above, means the substitution of a hydrogen radical by F, Cl, Br, I, CN, NH ₂ , NH-alkyl, NH-cycloalkyl , OH, O-alkyl, where multiply substituted radicals are to be understood as meaning those which are substituted several times, for example twice or three times, on different or on the same atoms, for example three times on the same C atom as in the case of -CF ₃ , -CH ₂ CF ₃ or at different positions as in the case of -CH (OH) -CH ₂ - CH ₂ -CHCl 2. The multiple substitution can be carried out with the same or different substituents.

The term "alkyl aryl" means (CC ₆ ) alkyl (C ₆ -C ₄ ) aryl and preferably (C 1 -C ₆ ) alkyl-C ₆ aryl.

With regard to "alkyl-aryl" and "cycloalkyl" in the sense of this invention - insofar as not explicitly mentioned above, "one or more times substituted" means the one or more times, for example two, three or four times substitution of one or more Hydrogen atoms of the ring system by F, Cl, Br, I, CN, NH ₂ , NH-alkyl, OH, O-alkyl, CF ₃ , alkyl, (C ₆ -Cι ₀ ) aryl, (C ₆ -Cιo) aryl - (CRC6) alkyl and / or heterocyclyl, on one or possibly different atoms (where a substituent may in turn be substituted). The multiple substitution takes place with the same or with different substituents.

With regard to "heterocycle" in the sense of this invention - insofar as not explicitly mentioned above, "one or more times substituted" means the one or more, for example, two, three or four times substitution of one or more hydrogen atoms of the ring system F, Cl, Br, I, nitro, amino, -CC ₆ alkyl, preferably methyl, mono- (CrC ₆ ) alkylamino, di (-C ₆ ) alkylamino, hydroxy, -C ₆ alkoxy , Benzyloxy, carboxy, (-C-C ₆ ) alkoxycarbonyl, (CrC ₆ ) - alkoxycarbonylamino or mono- or polysubstituted with fluorine (CC ₆ ) - alkyl, preferably trifluoromethyl, (C ₆ -Cι ₀ ) aryl and / or (C ₆ -Cιo) -aryl- (-C-C ₆ ) - alkyl on one or possibly different atoms (where a substituent may be substituted in turn). The multiple substitution takes place with the same or with different substituents.

If the compounds of the general

Formula I have at least one center of asymmetry, they can be in the form of their racemates, in the form of the pure enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or diastereomers. The mixtures can be present in any mixing ratio of the stereoisomers. If possible, the compounds of the invention may be in the form of the tautomers.

For example, the compounds of the general formula I according to the invention which have one or more centers of chirality and which occur as racemates can be separated into their optical isomers, ie enantiomers or diastereomers, by methods known per se. The separation can be carried out by column separation on chiral phases or by recrystallization from an optically active solvent or using an optically active acid or base or by derivatization with an optically active reagent, such as, for example, an optically active alcohol, and subsequent elimination of the rest. The compounds of general formula I according to the invention, if they contain a sufficiently acidic group, such as the carboxy group, can be converted into their physiologically tolerable salts with inorganic and / or organic bases. Examples of suitable inorganic bases are sodium hydroxide, potassium hydroxide, calcium hydroxide, and organic bases are ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylene diamine and lysine. The stoichiometry of the salts formed of the compounds according to the invention can be integer or non-integer multiples of one.

The compounds of general formula I according to the invention, if they have a sufficiently basic group, such as a secondary or tertiary amine, can be converted into salts with inorganic and organic acids. The pharmaceutically acceptable salts of the compounds according to the invention are preferably of the general structure I with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid , Grape acid, malic acid, embonic acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid. The salts formed include hydrochlorides, hydrobromides, sulfates, phosphates, methanesulfonates, sulfoacetic acid, tosylates, carbonates, bicarbonates, formates, acetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates, mandelates, fumarates, lactates, citrates and glutates. The stoichiometry of the salts formed of the compounds according to the invention can be integer or non-integer multiples of one.

Also preferred are solvates and in particular hydrates of the compounds I according to the invention, the z. B. can be obtained by crystallization from a solvent or from aqueous solution. One, two, three or any number of solvate or water molecules can combine with the compounds according to the invention to form solvates and hydrates. It is known that chemical substances form solids which are in various order states, which are referred to as polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds of general formula I according to the invention can exist in various polymorphic forms, certain modifications being metastable.

Both the compounds of formula I and their salts are biologically active. The compounds of formula I can be administered in free form or as salts with physiologically acceptable acids or bases.

The compounds of the general formula can be administered orally, rectally, buccally (e.g. sublingually), parenterally (e.g. subcutaneously, intramuscularly, intradermally or intravenously), topically or transdermally.

The invention further relates to medicaments containing at least one of the compounds of the formula I or their salts with physiologically tolerable inorganic or organic acids and, if appropriate, pharmaceutically usable excipients and / or diluents or auxiliaries.

These drugs are used for the treatment of tumor diseases, in particular for the treatment of tumor diseases with drug resistance to other active substances and / or for tumor diseases with metastatic carcinoma.

Suitable forms of application are, for example, tablets, tablets, capsules, solutions for infusion or ampoules, suppositories, plasters, inhalable powder preparations, suspensions, creams and ointments. The compounds of the invention can also in a microparticulate z. B. be dispersed nanoparticulate composition.

The therapeutically valuable properties found relate in detail to the following advantages:

• The compounds according to the invention are distinguished by strong antiproliferative properties;

• The compounds according to the invention inhibit tubulin polymerization;

• The compounds according to the invention inhibit topoisomerase II;

• The compounds according to the invention lock dividing cells in the G2 / M phase;

• the compounds according to the invention induce apoptosis; • The compounds according to the invention are notable for strong antitumor in vivo activities with, in addition, improved tolerances;

• The compounds of the formula I according to the invention are active in vitro on mdr-resistant Zeil lines, in contrast to paclitaxel, vincristine, doxorubicin or etoposide;

Most preferred are compounds according to the general

Formula I, which are made in the following selection:

2- [1- (4-chloro-benzyl) -1 H-indol-3-yl] -2-oxo-N-pyrido [2,3-b] pyrazin-7-yl-acetamide (1)

2- [1 - (4-chloro-benzyl) -1 H-indol-3-yl] -N- (1 H-indazol-5-yl) -2-oxo-acetamide (4) N- {2- [ 1 - (4-chloro-benzyl) -1 H-indol-3-yl] -2-oxo-acetyl} -N-quinolin-6-yl-acetamide (2)

{2- [1- (4-chlorobenzyl) -1 H -indol-3-yl] -2-oxo-acetyl} -quinolin-6-yl-carbamic acid methyl ester (3)

{2- [1 - (4-chloro-benzyl) -1 H-indol-3-yl] -2-oxo-acetyl} -quinolin-6-yl-carbamic acid ethyl ester (5) {2- [1- (4-Chlorobenzyl) -1 H -indol-3-yl] -2-oxo-acetyl} -quinolin-6-yl-carbamic acid propyl ester (6)

A / - {2- [1- (4-chloro-benzyl) -1 / - / - indol-3-yl] -2-oxo-acetyl} -Λ / -quinolin-6-yl-propionamide (7)

Ethyl {2- [1- (4-chloro-benzyl) -1 H-indol-3-yl] -2-oxo-acetyl} pyridin-4-yl-carbamic acid (8)

2- [1 - (4-chloro-benzyl) -1 H -indol-3-yl] -N-quinolin-6-yl-2-thioxo-acetamide (11)

The compounds (1), (4) and (11) are compounds, the radical R7 being hydrogen. The compounds (2), (3), (5) and (6) to (8) contain as group R7 an alkylcarbonyl or alkoxycarbonyl group.

The following compounds (9), (10), (12), (13), (14) and (15) are compounds which have been investigated for comparison purposes. The connections (9), (10), (14) and (15) are known from the prior art. Compound (9) is described in the applicant's WO02 / 10152, compound (10) in WO03 / 022280, compound (13) falls under the claims of WO02 / 08225 A1, compounds (12), (14) and (15) fall under the claims of W099 / 51224A1 and WO01 / 22954.

2- [1- (4-chloro-benzyl) -1 H -indol-3-yl] -N- (2-methyl-quinolin-6-yl) -2-oxoacetamide (9)

2- [1- (4-chloro-benzyl) -1 H -indol-3-yl] -2-oxo-N-quinolin-6-yl-acetamide (10) 2- [1- (4-chloro-benzyl ) -1 H-indol-3-yl] -2-oxo-N-quinolin-8-yl-acetamide (12) 2- [1- (4-chloro-benzyl) -1 H-indol-3-yl] -N-isoquinolin-5-yl-2-oxo-acetamide (13)

2- [1 - (4-chloro-benzyl) -1 H -indol-3-yl] -2-oxo-N-pyridin-4-yl-acetamide (14) 2- [1- (4-fluoro-benzyl ) -1 H-indol-3-yl] -N- (2-methyl-quinolin-8-yl) -2-oxo-acetamide (15) The compounds of the general formulas Ia and Ib of the scheme can be obtained according to the following scheme 1:

Scheme 1

1st stage

2nd stage

1. (COCI) ₂ 2. H ₂ N-Het

Ib la

The compounds of general formula Ic with X = S can according to

Scheme 2 are made:

Scheme 2

3rd stage (b)

la ic

Compounds of the general formula Ic with Y = S can be obtained by methods known from the literature (W.-D. Malmberg et al. Liebigs Ann. Chem. 10, 1983; 1649-1711).

The starting compounds II, III and IV are either commercially available or can be prepared by methods known per se. The starting materials II, III and IV are valuable intermediates for the preparation of the indole derivatives of the formula I according to the invention.

For the preparation of the starting and target compounds, reference is made, for example, to the following standard works of organic synthesis, the content of which is hereby intended to become part of the disclosure of the present application:

• Houben-Weyl, Volume E 7a (TeiH) pp. 290-492, pp.571-740

• Houben-Weyl, volume E 7a (part 2) pp. 119-156, pp.205-686, pp. 157-204

Monograph "Heterocyclic Compounds" (Elderfield),

Volume 1, pp.119-207, pp. 397-616

Volume 3, pp. 1 -274

Volume 6, pp. 101-135, pp. 234-323 • Monograph "Comprehensive Organic Chemistry" (SD Barton, WD Ollis)

Volume 4, p.155-204, p.205-232, p.493-564

The solvents and auxiliaries to be used and the reaction parameters to be used, such as reaction temperature and duration, are known to the person skilled in the art on the basis of his specialist knowledge.

According to this general rule for stages 1, 2 and 3, which are based on the synthesis schemes 1 and 2, the following compounds were synthesized, which can be seen from the following overview by specifying the respective chemical name. The compounds according to the invention were characterized analytically by their melting points or by 1 H-NMR spectroscopy and / or mass spectroscopy.

The chemicals and solvents used were purchased commercially from conventional suppliers (Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI etc.) or synthesized.

The invention is to be explained in more detail with reference to the following examples, without being restricted thereto.

Examples

Example 1 (implementation according to scheme 1. 1st stage):

Preparation of 1- (4-chlorobenzyl) indole

A solution of 5.86 g (0.05 mol) of indole in 25 ml of DMSO is added to a mixture of 1.32 g of sodium hydride (0.055 mol, mineral oil suspension) in 50 ml of dimethyl sulfoxide. The mixture is heated at 60 ° C. for 1.3 hours, then allowed to cool and 17.7 g (0.11 mol) of 4-chloro-benzyl chloride are added dropwise. The solution is heated to 60 ° C., left to stand overnight and then poured into 200 ml of water with stirring. It is extracted several times with a total of 75 ml of CH ₂ Cl ₂ , the organic phase is dried with anhydrous sodium sulfate, filtered and the filtrate is concentrated in vacuo. Yield: 11.5 g (95% of theory)

Example 2 (implementation according to stage 2 of scheme 1):

2- [1 - (4-chloro-benzyl) -1 H-indol-3-yl] -2-oxo-N-pyrido [2,3-b] pyrazin-7-yl-acetamide (1)

A solution of 10.2 g (10.7 mmol) of 1- (4-chlorobenzyl) indole in 200 ml of ether is added dropwise to a solution of 1, 12 ml of oxalyl chloride in 50 ml of ether at 0 ° C. and under nitrogen. The mixture is heated to reflux for 2 hours and then the solvent is evaporated off. 30 ml of DMF were then added to the residue, 1.93 g (13.9 mmol) of potassium carbonate were added, the suspension was cooled to 0 ° C. and added dropwise with a solution of 1.57 g (10.7 mmol) of amine component in 10 ml of DMF added. The mixture is stirred overnight at room temperature. The reaction mixture is finally stirred into ice water and the precipitate formed is suction filtered. The crude product obtained is chromatographed on 100 g of silica gel with n-heptane / ethyl acetate = 4: 1.

Yield: 3.23 g (68.0%) Mp .: 250 ° C

1 H NMR (DMSO-D6) δ = 11.56 (s, 1H), 9.53 (d, 1H), 9.12 (s, 1H), 9.09 (d, 1H) , 9.04 (s, 1H), 8.32 (d, 1H), 7.6 (d, 1H), 7.40 (d, 2H), 7.35 (m, 3H), 7.32 (m , 2H) s 5.64 (s, 2H) ppm

Example 3 (reaction according to 3rd stage (a) of scheme 1):

o Λ / - {2- [1 - (4-chloro-benzyl) -1 H -indol-3-yl] -2-oxo-acetyl} -Λ / -quinolin-6-yl-acetamide (2)

To a stirred solution of 6.0 g (13.6 mmol) of 2- [1 - (4-chlorobenzyl) -1 H-indol-3-yl] -2-oxo-N-quinolin-6-yl-acetamide in 60 ml DMF are added under nitrogen 0.833 g (6.82 mmol) DMAP, 1.38 g (13.6 mmol) triethylamine and 13.9 g (136 mmol) 5 acetic anhydride. The reaction mixture is stirred at room temperature for 10 minutes and then poured into 200 ml of ethyl acetate. After adding 300 ml of water, the mixture is shaken in a separating funnel, after which the two phases separate. Precipitation begins after 20 minutes. The light yellow crystals are filtered off and dried in vacuo at 60 ° C. 0

Yield: 4.04 g (61.5%)

Mp: 122.9 ° C

¹ H NMR (600 MHz, DMSO-d6) δ = 9.02 (d, 1 H), 8.54 (s, 1 H), 8.44 (d, 1 H), 8.21 (d, 1 H), 8.17 (d, 1 H), 8.10 (m, 1 H), 7.88 (m, 1 H), 7.65 (m, 1 H), 7.58 (m, 1 H), 7.44 (d, 2 H), 7.33 (d, 2 H) , 7.28 (m, 2H), 5.60 (s, 2H), 2.15 (s, 3H).

MS (ESI) m / z 482.1 (MH ⁺ ), (theor. 481.94) Example 4 (reaction according to 3rd stage (a) of scheme 1):

{2- [1 - (4-chloro-benzyl) -1 H-indol-3-yl] -2-oxo-acetyl} -quinolin-6-yl-carbamic acid methyl ester (3)

To a cooled, stirred solution of 10.0 g (22.7 mmol) of 2- [1 - (4-chlorobenzyl) -1 H-indol-3-yl] -2-oxo-N-quinolin-6-yl- Acetamide in 500 ml of dry THF are given 930.2 mg (27.3 mmol) of NaH (as a 60% dispersion in mineral oil) under nitrogen. The solution is stirred at 0 ° C. until a yellow precipitate precipitates and then stirred for a further 15 minutes. Then 2.58 g (27.3 mmol) of methyl chloroformate are added dropwise at a temperature below + 5 ° C. The reaction is followed by thin layer chromatography (eluent: n-heptane / ethyl acetate 1/1 RF = 0.11). The reaction mixture is poured into water, extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution and dried over anhydrous MgSO 4. Evaporation of the solvent gives a crude product which is purified to 3 by column chromatography (n-heptane / acetone 2/1). 3 still shows minor impurities in thin layer chromatography, which can be removed by stirring the crude 3 with acetone for 1 h. Filtration gives 3 as light yellow crystals.

Yield: 3.0 g (26.5%)

Mp: 178.5 ° C

¹ H NMR (600 MHz, DMSO-d6) δ = 9.02 (d, 1 H), 8.58 (s, 1 H), 8.47 (d, 1 H), 8.17 (m, 3 H), 7.84 (m, 1 H), 7.63 (m, 2 H), 7.44 (d, 2 H), 7.34 (m, 4 H), 5.60 (s, 2 H), 3.65 (s, 3 H).

MS (ESI) m / z 498.2 (MH ⁺ ), (theor. 497.94) Example 5 (reaction according to 3rd stage (b) of scheme 2):

Preparation of 2- [1 - (4-chlorobenzyl) -1 H-indol-3-yl] -N-quinolin-6-yl-2-thioxo-acetamide (11)

A suspension of 4.00 g (9.1 mmol) of 2- [1 - (4-chlorobenzyl) -1 H -indol-3-yl] -2-oxo-N-quinolin-6-yl-acetamide in 200 ml 3.68 g (9.1 mmol) of 2,4-bis (4-methoxyphenyl) -1, 3-dithia-2,4-diphosphetane-2,4-disulfide are added to toluene under nitrogen and then for 3 h heated to 75 ° C. The reaction solution is filtered hot from the residue formed and this is washed with 100 ml of methylene chloride. The filtrate is i. Vak. concentrated and the residue chromatographed on flash silica gel (eluent: methylene chloride / methanol 99: 1). The product fractions are i. Vak. filtered on flash silica gel (eluent: n-heptane / ethyl acetate 1: 1).

Yield: 0.46 g (11% of theory)

ESI-MS: m / e = 456.1 (MH +), (theor. 455.97)

1 H NMR (DMSO-D6) δ = 10.89 (s, 1 H), 8.8 (s, 1 H), 8.75 (s, 1 H), 8.55 (s, 1 H) , 8.12 (d, 1 H), 8.35 (d, 1 H), 8.0 (d, 1 H), 7.93 (d, 1 H), 7.63 (d, 1 H), 7.50 (m , 1H), 7.4 (m, 3H), 7.3 (m, 3H), 5.6 (s, 2H) ppm.

The following compounds of the formula I were synthesized analogously to the synthetic route in scheme 1 and according to examples 2 and 3. Example 6:

2- [1 - (4-chloro-benzyl) -1 H-indol-3-yl] -N- (1 H-indazol-5-yl) -2-oxo-acetamide (4)

s mp: 203 ° C

¹ H NMR (DMSO-D ₆ ) δ = 13.02 (s, 1 H), 10.7 (s, 1 H), 9.04 (s, 1 H), 8.48 (s, 1 H) ), 8.42 (d, 1 H), 8.06 (s, 1 H), 7.73 (d, 1 H), 7.6 (d, 1 H), 7.55 (d, 1 H), 7.40 (d, 2H), 7.28-7.35 (m, 4H), 5.63 (s, 2H) ppm 0

Example 7:

5 ethyl ethyl {2- [1 - (4-chloro-benzyl) -1 H-indol-3-yl] -2-oxo-acetyl} -quinolin-6-yl-carbamic acid (5)

Mp: 199 ° C 0

¹ H NMR (600 MHz, DMS0-d6) δ = 9.02 (m, 1 H), 8.60 (s, 1 H), 8.48 (d, 1 H), 8.15 (m, 3 H), 7.83 (m, 1 H), 7.63 (m, s H), 7.43 (d, 2 H), 7.32 (m, 4 H), 5.60 (s, 2 H), 4.15 (q, 2 H), 0.95 (t, 3 H) ,

5 MS (ESI) m / z 514.2, 512.1 (MH ⁺ ), (theor. 511.97)

Example 8: Propyl {2- [1 - (4-chloro-benzyl) -1 H -indol-3-yl] -2-oxo-acetyl} -quinolin-6-yl-carbamic acid (6)

Mp: 164 ° C 5 ¹ H NMR (600 MHz, DMSO-d6) δ = 9.02 (m, 1 H), 8.60 (s, 1 H), 8.48 (d, 1 H), 8.17 (m, 3 H), 7.84 (m, 1 H), 7.63 (m, 2 H), 7.43 (d, 2 H), 7.33 (m, 4 H), 5.61 (s, 2 H), 4.03 (t, 2 H), 1.32 (m, 2 H) , 0.56 (t, 3H).

Example 9:

Λ / - {2- [1 - (4-chloro-benzyl) -1 H -indol-3-yl] -2-oxo-acetyl} -Λ / -quinolin-6-yl-propionamide (7)

¹ H NMR (600 MHz, DMSO-d6) δ = 9.03 (m, 1 H), 8.52 (s, 1 H), 8.45 (d, 1 H), 8.23 (d, 2 H), 8.18 (d, 1 H), 8.13 (m, 1 H), 7.88 (m, 1 H), 7.65 (m, 1 H), 7.58 (m, 1 H), 7.45, (d, 2 H), 7.30 (m, 4 H) ), 5.59 (s, 2 H), 2.61 (q, 3 H), 0.88 (t, 3 H).

Example 10:

{2- [1 - (4-Chlorobenzyl) -1 H -indol-3-yl] -2-oxo-acetyl} pyridin-4-yl-carbamic acid ethyl ester (8)

Mp: 62 ° C

¹ H NMR (500 MHz, DMS0-d6) δ = 8.74 (m, 2 H), 8.52 (s, 1 H), 8.12 (m, 1 H), 7.60 (m, 1 H), 7.55 (m, 2 H), 7.40 (m, 2 H), 7.30 (m, 4 H), 5.57 (s, 2 H), 4.10 (q, 2 H), 0.95 (t, 3 H).

Example 11 (reference substance):

Preparation of 2- [1 - (4-chloro-benzyl) -1 H-indol-3-yl] -N- (2-methyl-quinolin-6-yl) -2-oxo-acetamide (9)

Yield: 14.8 g (77.3% of theory) mp: 182-185 ° C ¹ H NMR (CDCI ₃ ) δ = 9.58 (s, 1H), 9.12 (s, 1H), 8.5 (s, 1H), 8.41 (s, 1H), 8.05 ( t, 2H), 7.78 (d, 1H), 7.4 (dd, 1H), 7.32 (m, 4H), 7.26 (s, 1H), 7.15 (d, 1H), 5.38 (s, 2H), 2 , 73 (s, 3H) ppm

Example 12 (reference substance):

2- [1- (4-Chloro-benzyl) -1H-indol-3-yl] -2-oxo-N-quinolin-6-yl-acetamide (10)

Mp .: 200 ° C

¹ H NMR (DMSO-De) δ = 11.5 (s, 1H), 9.05 (s, 1H), 8.85 (s, 1H), 8.66 (s, 1H), 8.32 (d, 2H), 8.12 (d, 1H), 8.03 (d, 1H), 7.63 (d, 1H), 7.53 (dd, 1H), 7.42 (d, 2H), 7.30-7.38 (m, 4H), 5.63 (s, 2H) ppm

Example 13 (reference substance):

2- [1 - (4-chloro-benzyl) -1 H -indol-3-yl] -2-oxo-Λ / -quinolin-8-yl-acetamide (12)

Mp: 178 ° C

Example 14 (reference substance):

2- [1 - (4-chloro-benzyl) -1 H-indol-3-yl] - / V-isoquinolin-5-yl-2-oxo-acetamide (13)

Mp: 239-241 ° C

Example 15 (reference substance):

2- [1- (4-Chloro-benzyl) -1H-indol-3-yl] -2-oxo-/ V-pyridin-4-yl-acetamide (14)

Mp: 264 ° C Example 16 (reference substance):

2 [1 - (4-fluoro-benzyl) -1 H-indol-3-yl] -Λ / - (2-methyl-quinolin-8-yl) -2-oxo-acetamide (15)

Mp .: 200-202 ° C

Biological effects of the compounds according to the invention

In vitro and in vivo testing on selected tumor models revealed the following pharmacological activities.

Example 17: Antiproliferative effect on various tumor cell lines

The substances 1, 2, 4, 9, 11, 12, 13 and 15 were examined for their anti-proliferative activity in a proliferation test on established tumor cell lines (D.A. Scuderio et al. Cancer Res. 1988, 48, 4827-4833). The test used determines the cellular dehydrogenase activity and enables a determination of the cell vitality and indirectly the cell number. The cell lines used are the human cervical carcinoma cell line KB / HeLa (ATCC CCL17), the ovarian adenocarcinoma cell line SKOV-3 (ATCC HTB77), the human glioblastoma cell line SF-268 (NCI 503138) and the lung carcinoma cell line NCI- H460 (NCI 503473).

XTT proliferation assay EC50 in μg / ml

Example KB / Hela SKOV3 SF-268 NCI-H460

1 0.045 0.029 0.042 0.046

2 0.202 0.123 0.166 0.168

4 0.335 0.144> 3.16 0.233

11 0.036 0.029 0.036 0.057

9 (V) 0.183 0.174 0.261 0.344

12 (V)> 3.16> 3.16> 3.16> 3.16

13 (V)> 3.16> 3.16> 3.16> 3.16

15 (V)> 3.16 n.a. > 3.16 n.a.

V = comparative substance; n.a .: not determined

Table 1: Inhibition of proliferation of the substances according to the invention in the XTT cytotoxicity test on human tumor cells

The results show a very potent inhibition of the proliferation of selected tumor cell lines by working examples 1, 2, 4 and 11. Example 18: Antiproliferative effect on MDR tumor cell lines

For further characterization, substances 1, 2, 4 and 11 against multi-drug-resistant cell lines were examined in comparison to the non-resistant wild-type cell lines.

The cell lines examined are the murine L1210, the acute myeloid leukemia cell line LT12 and the resistant lines L1210 / mdr and LT12 / mdr. In addition, the murine P388 cell line (methyl-cholanthrene-induced lymphoid neoplasm) and the doxorubicin-resistant P388 were used as test systems.

The results are summarized in Table 2 below:

XTT proliferation assay, EC50 in μg / ml

Table 2: Inhibitory effects of the substances in the XTT proliferation test on human tumor cell lines.

The substances 1, 2, 4 and 11 show a very potent inhibitory effect on all cell lines tested, while in the case of the classic tubulin-inhibitory substances such as paclitaxel or vincristine also in the topoisomerase II Inhibitors (doxorubicin, mitoxantrone, etoposide) show an at least greatly reduced effect on the MDR1-resistant cell lines.

Example 19: Inhibition of tubulin polymerization

Substances 1, 4, 9, 11, 12, 13 and 15 were tested in an in vitro test for inhibition of the polymerization of bovine tubulin (DM Bollag et al. Cancer Res. 1995, 55, 2325-2333). In this test, tubulin purified by cycles of polymerization and depolymerization is used, which is brought to polymerization by adding GTP and heating. In Table 3, the EC are given ₅ o values of polymerization inhibition of tubulin with 30% associated proteins (MAPs).

Example inhibition of tubulin polymerization, EC50 in μg / ml

1 0.71

4 1.26

11 0.97

9 (V) 1.16

12 (V)> 10 sts

13 (V)> 10μM

15 (V)> 10μM

Vincristine 0.35 V = comparative example

Table 3: Inhibition of tubulin polymerization. Average of two independent tests.

The results (see Table 3) show a very potent inhibitory effect of substances 1, 4, 9 and 11 on the polymerization of tubulin while the compounds 12, 13 and 15 have no effect. Example 20: Inhibition of topoisomerase II

Substance 1 was tested in two different in vitro tests for the inhibition of topoisomerase II.

kDNA assay for testing topoisomerase II activity

In this assay described by P. Arimondo (Anti-Cancer Drug Design 2000, 15 (6), 413-421), kDNA is treated with human DNA topoisomerase II in the absence or presence of the test compounds. Compound 1 according to the invention was tested at three different concentrations (100, 31.6 and 10 μM). For comparison, a positive control and the reference compounds m-amsacrine (m-Amsa), paclitaxel (taxol) and vincristine were used at a respective concentration of 100μM.

Carrying out assay:

2 vL 10x assay buffer, 1μL kDNA (200ng), 0.5μL human topoisomerase II (1 unit) and 15.5μL H ₂ 0 are pipetted and mixed into 1μL of test substance (20-fold concentrated in 100% DMSO).

The reaction batches are placed in the heating block preheated to 37 ° C. and incubated at 37 ° C. for 10 minutes. The incubation is stopped after the addition of 4μL 5x stop buffer and the substance is subsequently extracted with CIA. Then 20 vL of the supernatant are applied to a 1% agarose gel with 0.25 g / mL ethidium bromide and separated for 1 h at 100V. Finally, the gel is photographed under UV excitation (see Figure 1). The inhibition of the decatenation of kDNA is quantified using the GelPro ^® analyzer software (see FIG. 2). • pRYG relaxation assay for testing topoisomerase II activity:

With this relaxation assay, the inhibitory properties of the compounds according to the invention on topoisomerase II could also be demonstrated. Compound 1 according to the invention was tested at three different concentrations (100, 31.6 and 10 μM). For comparison, the reference compounds m-amsacrine, paclitaxel (Taxol) and vincristine were used at concentrations of 316 and 100μM.

This is carried out as follows:

2μL 10x assay buffer, 0.5μL pRYG DNA (125ng), 0.5μL human topoisomerase II (1 unit) and 16μL H ₂ 0 are pipetted into and mixed with 1μL of test substance (20-fold concentrated in 100% DMSO). The reaction batches are placed in the heating block preheated to 37 ° C. and incubated at 37 ° C. for 30 minutes. The incubation is stopped after adding 4μL 5x Stop Buffer. Then 10μL of the mixture are applied to a 1.2% agarose gel with 0.25μg / mL ethidium bromide and separated at 100V for 2.5 hours. Finally, the gel is photographed under UV excitation (see Figure 3). The inhibition of pRYG relaxation is quantified using the GelPro ^® analyzer software (see FIG. 4).

Overall, it can be stated that a significant inhibition of topoisomerase II could be demonstrated for compound 1 according to the invention in the two assays. The results for compound 1 are comparable to the inhibition values of the topoisomerase II inhibitor m-amsacrine. As expected, no inhibitory effects were observed for paclitaxel and vincristine in the two assays. Example 21: Cell cycle analysis

The cell cycle includes the development of the cell from one cell generation to the next.

During the resting phase (GO) and pre-synthetic phase (G1) the cell has a diploid chromosome set (2c). In the synthesis phase (S) the amount of DNA is increased by replication. The S phase ends when the pre-critical phase (G2M) is reached, in which the cell has a reduplicated chromosome population (4c) and doubled DNA content. In the subsequent, short-lasting mitosis phase (M), the reduplicated chromosomes are evenly divided into two daughter cells, which then each show a diploid DNA content and are in the G01 phase, so that the cell cycle can start again.

For the cell cycle analysis, KB / HeLa cells were treated with the test substances in different concentrations (0.1-1000 nM) for 24 hours at 37 ° C.

The percentage of cells locked in the G2 / M phase of the cell cycle after treatment with reference or selected test substances is shown in Table 4 below. The results were evaluated with special analysis software (ModFit ™).

Example EC50 in nM (50% cells in G2 / M)

1 25.2

2 125.3

4,252

11 41.8

14 (V)> 1000

Paclitaxel 9/26

Mitoxantron 25.3 Table 4: Inhibitory concentration for a 50% portion of the cells in the G2 / M phase.

5 The compounds 1, 2, 4 and 11 according to the invention have comparable activities to the reference compounds paclitaxel and mitoxantrone.

0

Example 22: Detection of apoptosis

CDD ^plus nucleosome ELISA test:

5 Core fragmentation is a late consequence of apoptotic processes. The changes to be observed can be attributed to DNA strands cleaved by endonucleases and the resulting fragmentation into nucleosome particles.

o The CDD ^plus nucleosome ELISA test described by Röche Molecular Biochemicals was used to detect the nucleosome particles. For this purpose, compounds 1 and 2 were examined on the U-937 cell line at different concentrations (1 nM-10μM; 24 h treatment), (see FIG. 5 and FIG. 6) 5

In the case of compounds 1 and 2, a concentration-dependent increase in nucleosomes in the cell lysate was observed. No significant increase was detectable in the cell culture supernatant, which is evidence of apoptotic cell death after treatment with 1 and 2. Example 23: Detection of the saturation solubility in water for the compounds according to the invention

The saturation solubility in water for compounds 1, 2, 10 and 14 was determined as described below. A maximum of 1% DMSO was added to dissolve the substances and to improve the wetting of the samples. An HPLC-UV method was used to check the content. The results are summarized in Table 5 below:

Table 5: Saturation solubilities of compounds 1, 2, 10 and 14

Compounds 1 and 2 according to the invention are distinguished in comparison to compounds 10 and 14 by improved water solubilities.

Example 24: in vivo activity

The in vivo activity and tolerance of compound 2 according to the invention was checked in comparison to substances 10 and 14 in a human xenograft model (melanoma, MEXF462). The results are summarized in Table 6 below:

in vivo activities of compounds 2, 10 and 14 (melanoma; MEXF462)

1) Number of animals died compared to the total number Table 6: in vivo activities of compound 2, 10 and 14 (melanoma; MEXF462)

For compound 2, complete remission of the tumors in the treated animals was also observed in this xenograft model with very good tolerability (no death). Comparable antitumor effects were found for the compounds 10 and 14, but with deteriorated tolerances. Example 25: in vivo activity

The in vivo activity and tolerance of compound 2 according to the invention was checked in comparison with substance 10 in a further human xenograft model (Mamma, MAXF857).

The results are shown in the next table:

Effect of 2 and 10 on the Mammary Cancer MAXF857

0

1) Number of animals died compared to the total number

Table 7: in vivo activities of compounds 2 and 10 (Mamma; MAXF857) 5

Comparable antitumor effects were observed for compounds 2 and 10, however the tolerance of substance 10 (2/6 mice died) is significantly poorer than that of 2.

Claims

claims

1. Indole derivatives of the general formula I

Formula I.

wherein

R: for one or more heteroatoms selected from the group

N, O and S containing saturated, unsaturated or aromatic substituted or unsubstituted (C ₂ -C ₄ ) heterocycle directly connected to the amide nitrogen,

R1: unsubstituted or substituted alkyl aryl,

R2: i) hydrogen, ii) unsubstituted or substituted (C ₁ -C ₆ ) alkyl, R3-R6: i) hydrogen ii) unsubstituted or substituted (C 1 -C ₆ ) alkyl, iii) unsubstituted or substituted (C ₃ -C ₇ ) -cycloalkyl, iv) amino, mono- (CrC) -alkylamino, di- (CrC) -alkylamino, v) halogen, vi) (C ₁ -C ₄ ) - substituted with one or more fluorine atoms

Alkyl, preferably trifluoromethyl group, vii) cyano, straight-chain or branched cyano- (CrC ₆ ) -alkyl, viii) (CrCβJ-alkylcarbonyl, ix) carboxyl, (CrC ₄ ) -alkoxycarbonyl, carboxy- (-C-C ₆ ) -alkyl or (Crc ₆ ) -alkoxycarbonyl- (-C-C ₆ ) -alkyl, x) hydroxy, xi) - (C _r C ₆ ) -alkoxy, xii) aryl- (C1-C4) -alkoxy, preferably benzyloxy, xiii) ( CrC _δ J-alkoxycarbonylamino, (C-ι-C6) -alkoxycarbonylamino-

(-CC ₆ ) -alkyl, R7:

(CrC ₆ ) alkylcarbonyl or (-C-C ₆ ) alkoxycarbonyl and

X, Υ: mean oxygen or sulfur,

with the proviso that when R represents an unsubstituted or substituted 2-, 3-, 4-, 5- or 6-pyridyl group and R1 -R6 has the meaning given above, R7 does not represent an acetyl radical or a te / t-butyloxycarbonyl; their tautomers, stereoisomers, including the diastereomers and enantiomers, and the physiologically tolerable salts thereof.

2. Indole derivatives according to claim 1, wherein R

i) unsubstituted or substituted 5-, 6-, 7-quinolyl, ii) unsubstituted or substituted 2-, 3-, 6-, 7- and

8-pyridopyrazinyl, iii) unsubstituted or substituted 3-, 4-, 5-, 6- and 7-indazolyl, iv) unsubstituted or substituted 2-, 3-, 4-, 5- and 6-pyridyl, v) unsubstituted or substituted 3-, 4- and 5-isoxazolyl, vi) denotes unsubstituted or substituted 3-, 4- and 5-isothiazolyl,

3. Indole derivatives according to claim 1 or 2, characterized in that R7 is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, acetyl or propionyl.

4. Indole derivatives according to one or more of claims 1 to 3, characterized in that the compound of general formula I is selected from the following group of compounds:

N- {2- [1 - (4-chloro-benzyl) -1 H-indol-3-yl] -2-oxo-acetyl} -N-quinolin-6-yl-acetamide (2)

{2- [1 - (4-chloro-benzyl) -1 H-indol-3-yl] -2-oxo-acetyl} -quinolin-6-yl-carbamic acid ethyl ester (5)

{2- [1 - (4-chlorobenzyl) -1 H -indol-3-yl] -2-oxo-acetyl} -quinolin-6-yl-carbamic acid propyl ester (6)

Λ / - {2- [1- (4-chloro-benzyl) -1 H-indol-3-yl] -2-oxo-acetyl} - / V-quinolin-6-yl-propionamide (7) {2- [1 - (4-chlorobenzyl) -1 H-indol-3-yl] -2-oxo-acetyl} pyridin-4-yl-carbamic acid ethyl ester (8)

5. Indole derivatives of the general formula I in which

R: directly related to the amide nitrogen

(ii) unsubstituted or substituted 2-, 3-, 6-, 7- and 8-

Pyridopyrazinyl, (iii) unsubstituted or substituted 3-, 4-, 5-, 6- and 7-indazolyl, R1: unsubstituted or substituted alkyl aryl,

R2 hydrogen

R3-R6:

(i) hydrogen

(ii) unsubstituted or substituted (-CC ₆ ) alkyl,

(iii) unsubstituted or substituted (C ₃ -C ₇ ) cycloalkyl,

(iv) amino, mono- (CrC ₄ ) alkylamino, di- (CrC ₄ ) alkylamino, (v) halogen,

(vi) (CrC ₄ ) -alkyl, preferably trifluoromethyl group, substituted with one or more fluorine atoms,

(vii) cyano, straight-chain or branched cyano- (CrC ₆ ) -alkyl,

(viii) (CrC ₆ ) alkylcarbonyl, (ix) carboxyl, (CrC ₄ ) alkoxycarbonyl, carboxy (CrC ₆ ) alkyl or (C

C ₆ ) -alkoxycarbonyl- (-C-C ₆ ) -alkyl,

(x) - (CC ₆ ) alkoxy,

(xi) aryl (CrC) alkoxy, preferably benzyloxy,

(xii) (CrC ₆ ) alkoxycarbonylamino, (-C-C ₆ ) alkoxycarbonylamino- (Cr C ₆ ) alkyl

and

R7 hydrogen

X, Y: mean oxygen or sulfur,

6. Indole derivatives according to claim 5, characterized in that the compound of general formula I is selected from the following group of compounds: 2- [1 - (4-chloro-benzyl) -1 H-indol-3-yl] -N-quinolin-6-yl-2-thioxo-acetamide (11), 2- [1- (4-chloro benzyl) -1H-indol-3-yl] -2-oxo-N-pyrido [2,3-b] pyrazin-7-yl-acetamide

(1), s 2- [1 - (4-chlorobenzyl) -1 H -indol-3-yl] -N- (1H-indazol-5-yl) -2-oxo-acetamide (4).

7. Indole derivatives according to one or more of claims 1 to 6, characterized in that R1 is 4-chlorobenzyl, R2-R6 is hydrogen and X, Y is oxygen or sulfur. 0

8. Medicament containing at least one of the indole derivatives according to claims 1 to 7.

9. Medicament according to claim 8 containing the indole derivative in a micro-5 particulate or nanoparticulate composition.

10. Medicament according to claim 8 or 9 containing the indole derivative and a pharmaceutically usable carrier and / or diluent and auxiliary in the form of tablets, dragees, capsules, solutions for infusion or ampoules, suppositories, plasters, inhalable powder preparations, suspensions , Creams and ointments.

11. Use of the indole derivatives according to claims 1 to 6 for the manufacture of a medicament for the treatment of tumor diseases. 5

12. Use according to claim 11 for the treatment of tumor diseases with drug resistance to other active substances.

13. Use according to claim 11 for the treatment of tumor diseases with 0 metastatic carcinoma.