RU2327696C2 - Indole derivatives, with stimulating apoptosis effect (alternatives), pharmaceutical compositions based on these derivatives - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of indole with general formula 1:

where R is unsubstituted or substituted quinolyl, pyridopyrazinyl, indazolyl or pyridyl and which is directly bonded to nitrogen of the amide group; R1 is unsubstituted or substituted alkly-aryl; R2 represents hydrogen; R3-R6 represent hydrogen, R7 represents (C₁-C₆)-alkylcarbonyl or (C₁-C₆)- alkoxycarbonyl, and X, Y represent oxygen or sulphur, under the condition that, when R is an unsubstituted or substituted 2-, 3-, 4-, 5- and 6-pyridyl group and R1-R6 have the above mentioned values, R7 is not an acetyl radical or tert-butyloxycarbonyl group. The invention also relates to physiologically tolerant salts of the indole derivatives, as well as to pharmaceutical compositions based on them and their use in obtaining medicinal preparations.

EFFECT: obtaining of medicinal preparations, used as medicines for curing tumorous diseases, especially in case of resistance to other drugs and metastasising carcinomas.

14 cl, 7 tbl, 6 dwg, 25 ex

Description

FIELD OF THE INVENTION

The present invention relates to the field of organic chemistry and pharmacology, specifically relates to new indole derivatives that have a more pronounced biological effect, are better tolerated, exhibit higher oral bioavailability and are used as an active drug base for the treatment of cancer, especially when resistance occurs to other active compounds and when the carcinoma metastasizes.

State of the art

Cancer treatment is of great importance in medicine. Around the world, there is a need for effective methods of cancer therapy in order to achieve a treatment suitable for the patient and with targeted exposure.

This can be seen in the large number of works that have appeared recently in the field of applied oncology, and in basic research related to the treatment of cancer.

The effects of cancer inhibitors are due to a wide variety of mechanisms, and only a few are known. And it is often found that known anti-cancer drugs have new mechanisms of action. This is also expected with respect to the compounds of this invention. Many anti-cancer agents act by mechanisms such as blocking the cell division mechanism in cells, preventing the supply of the tumor with nutrients and oxygen (antiangiogenesis), preventing metastasis, preventing the reception and transmission of growth signals to the cancer cell, or by introducing the cancer cell into the cell death program (apoptosis) .

Agents suitable for clinical use are often administered in combination to achieve a synergistic therapeutic effect for the reason that they have different mechanisms of action, including interaction with different intracellular targets.

Indole derivatives are used in many different ways as pharmacologically active compounds and as building blocks for synthesis in pharmacological chemistry.

Documents WO 99/51224 A1 and WO 01/22954 A1 describe indol-3-yl derivatives which have an antineoplastic effect and which can be substituted by a large number of groups, including 2-, 3-, 4- and 8-quinoline radicals or 2- , 3-, 4-, 5- and 6-pyridine radicals. The 2-methyl-8-quinoline group is mentioned in Example 60 as a substituent on the amide group. However, there is no mention of biological properties.

WO 99/55696 A1 describes substituted oxyindoles as phosphodiesterase 4 inhibitors. However, there are no reports that the compounds of this invention have antineoplastic activity, and there is no suggestion that they may have such activity.

WO 02/08225 A1 describes derivatives of 2- (1H-indol-3-yl) -2-oxoacetamide, which exhibit an antineoplastic effect against solid tumors. However, there is no mention of examples of special implementation, including radicals of quinoline, pyridopyrazine or indazolyl.

WO 00/67802 describes indole-3-glyoxylamides, which are replaced by relatively long chain fatty acids, as potential antineoplastic agents. However, there is no mention of examples of special implementation, including radicals of quinoline, pyridopyrazine and indazolyl. Nor do they provide any biological data regarding examples of such an implementation.

Publication W.-T. Li et al. (J. Med. Chem. 2003, 46, 1706 ff.) Describes N-heterocyclic indolylglyoxylamides as orally active compounds having antineoplastic activity. However, they do not provide any information regarding their mechanism of action.

WO 03/022280 A2 describes 3-glyoxylamididines and their use as drugs for the treatment of neoplastic diseases. Their general formula also includes derivatives of 6-quinolines. In addition, two examples are mentioned containing the 6-quinoline radical as examples of implementation and supported by biological results. However, there is no mention of examples of special implementation, including radicals of pyridopyrazine and indazolyl.

US 03/0181482 A1 describes novel indolyl glyoxylamides. In this case, the compounds of this invention are characterized as antineoplastic agents having cytotoxic activity and are inhibitors of angiogenesis. In addition, it was shown that the 6-quinoline derivative can be an example of implementation (compound 3; p. 10), as well as the facts of the presence of antiproliferative activity (see p. 19; Tables 1a and 1b) and antiangiogenic properties (see p. twenty). However, there is no mention of examples of special implementation, including radicals of pyridopyrazine and indazolyl.

WO 02/10152 A2 describes a second class of indole derivatives for the treatment of tumor diseases. In this document, the active compound N- (2-methyl-6-quinolyl) - [1- (4-chlorobenzyl) indol-3-yl] glyoxylamide, among other things, has been tested for antiproliferative effects on a number of cancer cell lines.

Clinically tested compounds that either bind to microtubules (paclitaxel and vincristine) or inhibit topoisomerase II (doxorubicin, etoposide and mitoxantrone) are now widely used in cancer therapy, including breast cancer, ovarian cancer, stomach cancer and cancer lung, as well as in the case of Kaposi’s sarcoma and with leukemia. However, their use is limited by the emergence of drug resistance, as well as serious neurological, gastrointestinal, cardiovascular and hepatic side effects.

Disclosure of invention

The aim of this invention is to provide affordable cytotoxic substances that have combined mechanisms of action and which are suitable for the treatment of a large number of tumor diseases, especially when drug resistance to other drugs occurs and when carcinomas metastasize.

This goal is achieved using indole derivatives of the general formula I

wherein

R: it is a saturated, unsaturated or aromatic, substituted or unsubstituted (C ₂ -C ₁₄ ) heterocycle that contains one or more heteroatoms selected from the group N, O and S, and which is directly bonded to the amide nitrogen, the heterocycle being advantageously

(i) unsubstituted or substituted with 5-, 6-, 7-quinolyl,

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

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

(iv) unsubstituted or substituted with 2-, 3-, 4-, 5- and 6-pyridyl,

(v) unsubstituted or substituted with 3-, 4- and 5-isoxazolyl,

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

R1: unsubstituted or substituted alkyl aryl,

R2: (i) hydrogen,

(ii) unsubstituted or substituted (C ₁ -C ₁₆ ) -alkyl,

R3-R6:

(i) hydrogen,

(ii) unsubstituted or substituted (C ₁ -C ₆ ) -alkyl,

(iii) unsubstituted or substituted (C ₃ -C ₆ ) -cycloalkyl,

(iv) amino, mono (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino,

(v) halogen,

(vi) (C ₁ -C ₄ ) -alkyl, which is substituted by one or more fluorine atoms, preferably a trifluoromethyl group,

(vii) straight or branched chain cyano, C ₁ -C ₆ alkyl,

(viii) (C ₁ -C ₆ ) -alkylcarbonyl,

(ix) carboxyl, (C ₁ -C ₄ ) -alkoxycarbonyl, carboxy- (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -alkoxycarbonyl- (C ₁ -C ₆ ) -alkyl,

(x) hydroxyl,

(xi) - (C ₁ -C ₆ ) -alkoxy,

(xii) aryl- (C ₁ -C ₆ ) alkoxy, preferably benzyl oxy,

(xiii) (C ₁ -C ₆ ) -alkoxycarbonylamino, (C ₁ -C ₆ ) -alkoxycarbonylamino (C ₁ -C ₆ ) -alkyl,

R7: (C ₁ -C ₆ ) -alkylcarbonyl, preferably acetyl or propionyl,

(C ₁ -C ₆ ) -alkoxycarbonyl, preferably methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl,

and

X, Y: oxygen or sulfur,

their tautomers and stereoisomers, including diastereomers and enantiomers, as well as their physiologically tolerant salts.

When R is an unsubstituted or substituted 2-, 3-, 4-, 5- and 6-pyridyl group, and R1-R6 are as defined above, R7 should not be an acetyl radical or a tert-butyloxycarbonyl group in this case.

The invention further relates to indole derivatives of the general formula I:

wherein

R: it is directly related to the amide nitrogen

(i) substituted 6-quinolyl, substituted or unsubstituted 7-quinolyl,

where 2-methyl-6-quinolyl is excluded and where, when X is a sulfur atom, R may 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 (C ₁ -C ₆ ) -alkyl,

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

(xvii) amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino,

(xviii) halogen,

(xix) (C ₁ -C ₄ ) -alkyl, which is substituted by one or more fluorine atoms, preferably a trifluoromethyl group,

(xx) cyano, straight- or branched-chain cyano- (C ₁ -C ₆ ) -alkyl,

(xxi) (C ₁ -C ₆ ) -alkylcarbonyl,

(xxii) carboxyl, (C ₁ -C ₄ ) -alkoxycarbonyl, carboxy (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -alkoxycarbonyl- (C ₁ -C ₆ ) -alkyl,

(xxiii) - (C ₁ -C ₆ ) -alkoxy,

(xxiv) aryl- (C ₁ -C ₆ ) -alkoxy, preferably benzyl-oxy,

(xxv) (C ₁ -C ₆ ) -alkoxycarbonylamino, (C ₁ -C ₆ ) -alkoxycarbonylamino (C ₁ -C ₆ ) -alkyl,

and

R7: hydrogen,

X, Y: oxygen or sulfur,

their tautomers and stereoisomers, including diastereomers and enantiomers, as well as their physiologically tolerant salts.

The present invention is a further development of the invention, which is described in WO 02/10152. Indole derivatives that were prepared by replacing a 2-methyl-6-quinolyl group with unsubstituted or substituted 2-, 3-, 6-, 7- and 8-pyridopyrazinyl or unsubstituted or substituted with 3-, 4-, 5- , 6- and 7-indazolyl, demonstrate a high antiproliferative effect on a number of tumor cell lines.

It was further noted that the compounds of this invention exhibit a potent cytotoxic effect, which may result from a wide range of different mechanisms. One mechanism of action of the compounds of this invention that has been demonstrated in this invention is based on the inhibition of tubulin polymerization and the inhibition of topoisomerase II. This leads to the suppression of oncogenic cells in the G2M phase. In addition to this, the compounds of this invention induce apoptosis.

It was further noted that the compounds of this invention have very high solubility in water and, therefore, also high bioavailability.

In addition, it was shown that the introduction of an acetyl radical as an R7 radical leads to the preparation of compounds of the invention having extremely high in vivo activity, which are at the same time more tolerant.

The class of substances that is described in this invention should open up the possibility of obtaining an antineoplastic drug, which at lower doses has a longer lasting effect and is better tolerated than can be achieved using conventional cytotoxic drugs. In particular, it should be possible to circumvent the unfavorable development of resistance, which, as you know, takes place in the case of the use of many antineoplastic agents. The enhancement effect that is achieved when using the indole derivatives of this invention should make the use of drugs more effective. In addition to this, it will be possible to extend treatment to cases that are characterized by resistance to therapy.

In a preferred embodiment, R1 is 4-chlorobenzyl, R2-R6 is hydrogen, R is a heterocycle and R7 is an alkylcarbonyl or alkoxycarbonyl derivative of an indole with the formula I.

In another preferred embodiment, R is unsubstituted 5-quinolyl, unsubstituted 6-quinolyl or unsubstituted 7-quinolyl, and R7 is acetyl or propionyl in an indole derivative of formula I.

In another preferred embodiment, R is unsubstituted 5-quinolyl, unsubstituted 6-quinolyl or unsubstituted 7-quinolyl, and R7 is methoxycarbonyl, ethoxycarbonyl or propionoxycarbonyl in an indole derivative of formula I.

Brief Description of the Drawings

Figure 1 shows a photograph of the determination of cDNA.

Figure 2 shows the inhibition of the "unwinding" of cDNA.

Figure 3 shows a photograph of the determination of the output pRYG.

Figure 4 shows the inhibition of pRYG yield.

Figures 5 and 6 show CDD ^plus nucleosome ELISA tests with substance 1 and substance 2.

The implementation of the invention

Some of the terms used in the description and in the claims are defined below.

As for the term "heterocycle", it is understood as a term meaning, as still not mentioned in detail, 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, quinoline, cinnoline, quinoxaline, quinazoline, phthalazine, pyridopyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, purine, pteridine, acridine and phenatridine.

As used herein, the term “alkyl” embraces acyclic saturated or unsaturated hydrocarbons, which may be straight or branched chain. With respect to the term “alkyl,” the term “substituted” is understood within the scope of the present invention, but has not yet given a detailed definition of how to replace a hydrogen radical with F, Cl, Br, I, CN, NH ₂ , NH-alkyl, NH- cycloalkyl, OH or O-alkyl, where polysubstituted radicals are to be understood as meaning those which are substituted more than once, for example two or three times, either at different atoms or at the same atoms, for example three times at the same C atom as in the case of —CF ₃ and —CH ₂ CF ₃ , or at different sites, as in the case of —CH (OH) —CH ₂ —CH ₂ —CHCl ₂ . Polysubstitution can be carried out using the same or different substituents.

The expression "alkyl-aryl" means (C ₁ -C ₆ ) -alkyl- (C ₆ -C ₁₄ ) -aryl and preferably (C ₁ -C ₆ ) -alkyl-C ₆ -aryl.

In relation to the terms “alkyl-aryl” and “cycloalkyl”, “monosubstituted or substituted more than once” in the framework of the present invention is meant, but not yet specified above, in the meaning of one or multiple, for example, double, triple or quadruple, replacement of one or more hydrogen atoms in the ring system on F, Cl, Br, I, CN, NH ₂ , NH-alkyl, NH-cycloalkyl, OH or O-alkyl, -CF ₃ , alkyl, (C ₆ -C ₁₀ ) -aryl, (C ₆ -C ₁₀ ) -aryl- (C ₁ -C ₆ ) -alkyl and / or heterocyclyl at one or, where necessary, at different atoms (by what may be a substituent, its part, which is substituted where they should be). In this regard, multiple substitution is carried out using the same or different substituents.

In relation to the terms "heterocycle", "monosubstituted or substituted more than once" in the framework of this invention is meant, but not yet specified above, in the meaning of one or multiple, for example double, triple or quadruple, replacement of one or more hydrogen atoms in the ring system on F, Cl, Br, I, nitro, amino, (C ₁ -C ₆ ) -alkyl, preferably methyl, mono (C ₁ -C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) -alkylamino , hydroxyl, (C ₁ -C ₆ ) -alkoxy, benzyloxy, carboxyl, (C ₁ -C ₆ ) -alkoxycarbonyl, (C ₁ -C ₆ ) -alkoxycarbonylamino or (C ₁ -C ₆ ) -alkyl, which is substituted one or more times fluorine, preferably trifluoromethyl, (C ₆ -C ₁₀ ) -aryl, and / or (C ₆ -C ₁₀ ) -aryl- (C ₁ -C ₆ ) -alkyl, with one or, where necessary, with different atoms (by the fact that it can be a substituent, its part, which is replaced, where appropriate). In this regard, multiple substitution is carried out using the same or different substituents.

Provided that the compounds of the invention with formula 1 have at least one center of asymmetry, they can be presented in the form of their racemates, as pure enantiomers and / or diastereomers, or as a mixture of these enantiomers and / or diastereomers. Stereoisomers may be present in the mixture in any arbitrary proportions. If possible, the compounds of this invention may be present in the form of tautomers.

Thus, the methods that are still known can be used, for example, to separate the compounds of this invention with the general formula I, which have one or more chiral centers and exist as racemates, into their optical isomers, i.e. enantiomers or diastereomers . Separation can be carried out by column separation on chiral phases, or by recrystallization from an optically active solvent, or by using an optically active acid or base, or by derivatization with an optically active reagent such as an optically active alcohol, followed by cleavage of the residue.

If the compounds of this invention with the general formula 1 contain a sufficiently acidic group, such as a carboxyl group, they can be converted into their physiologically tolerant salts with inorganic and / or organic bases. Examples of suitable inorganic bases are sodium hydroxide, potassium hydroxide and calcium hydroxide, while examples of suitable organic bases are ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylenediamine and lysine. In this regard, the stoichiometry of the obtained salts of the compounds of the invention can be either an integer or a non-integer multiple of one.

If they have a sufficiently basic group, such as a secondary or tertiary amine, the compounds of this invention with the general formula I can be converted into salts using inorganic and organic acids. Pharmaceutically tolerated salts of the compounds of this invention with general structure I are preferably formed by the action of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, paratoluenesulfonic acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, malonic acid , maleic acid, succinic acid, tartaric acid, pyruvic acid, malic acid, embonic acid, mandelic acid, fumaric acid slots, lactic acid, citric acid, glutamic acid or aspartic acid. Salts that are formed, in particular, are hydrochlorides, hydrobromides, sulfates, phosphates, methanesulfonates, sulfoacetic acid salt, tosylates, carbonates, hydrocarbonates, formats, acetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates, mandelates, fumarates, lactates, citrates and glutamates. In this regard, the stoichiometry of the obtained salts of the compounds of the invention can be either an integer or a non-integer multiple of one.

Preference is also given to solvates, especially hydrates, of compounds of formula I according to the invention, which can be obtained, for example, by crystallization from a solvent or from an aqueous solution. In this regard, one, two, three or any arbitrary number of solvent or water molecules may be associated with the compounds of this invention with the formation of solvates or hydrates.

It is known that chemicals form solid particles that exist in a state of varying degrees of order and are called polymorphic forms or modifications. Different modifications of a polymorphic substance can vary greatly in their physical properties. The compounds of this invention with general formula I may be present in different polymorphic forms, with the possibility for special modifications, being metastable.

The compounds of formula I, as well as their salts, are biologically active. The compounds of formula I can be used in free form and in the form of salts of physiologically tolerant acids or bases.

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

The present invention further relates to pharmaceutical preparations having at least one of the compounds of formula I or their salts of physiologically tolerable inorganic or organic acids and, where appropriate, pharmaceutically acceptable carriers and / or diluents or additives.

These drugs are used to treat tumor diseases, especially for the treatment of such tumor diseases that are complicated by drug resistance to other active compounds and / or tumor diseases, including metastatic carcinoma.

Examples of convenient forms for use are tablets, sugar coated tablets, capsules, infusion solutions or ampoules, suppositories, patches, powdered preparations that can be used for inhalation, suspensions, creams and ointments.

The compounds of the invention can also be dispersed in a composition containing microparticles, for example nanoparticles.

In detail, the therapeutically beneficial properties that have been established are associated with the following advantages:

- the compounds of the invention are characterized by strong antiproliferative properties;

- the compounds of the invention inhibit tubulin polymerization;

- the compounds of the invention inhibit topoisomerase II;

- the compounds of the invention inhibit dividing cells in the G2M phase;

- the compounds of the invention induce apoptosis;

- the compounds of the invention are characterized by extremely high antineoplastic activity in vivo, while being more tolerant;

- the compounds of the invention with formula I are active in vitro on mdr-resistant cell lines, in contrast to paclitaxel, vincristine, doxorubicin or etoposide.

Most preferred are compounds of this invention with the general formula I, which are included in the following kit:

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

2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -N- (1H-indazol-5-yl) -2-oxoacetamide (4)

N- {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} -N-quinolin-6-yl-acetamide (2)

methyl {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} quinolin-6-ylcarbamate (3)

ethyl {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} quinolin-6-ylcarbamate (5)

propyl {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} quinolin-6-ylcarbamate (6)

N- {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} -N-quinolin-6-ylpropionamide (7)

ethyl {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} pyridin-4-ylcarbamate (8)

2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -N-quinolin-6-yl-2-thioxoacetamide (11)

Compounds (1), (4) and (11) are compounds in which the radical R7 is hydrogen. Compounds (2), (3), (5) and (6) - (8) contain an alkylcarbonyl group or an alkoxycarbonyl group as the group R7.

The following compounds (9), (10), (12), (13), (14) and (15) are compounds that have been studied for comparison. Compounds (9), (10), (14) and (15) are known from previous achievements. Compound (9) is described in Applicant's WO 02/10152, compound (10) is described in WO 03/022280, compound (13) is comprehensively described in the claims in WO 02/08225 A1, and compounds (12), (14) and ( 15) is presented in the claims in WO 99/51224 A1 and WO 01/22954.

2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -N- (2-methylquinolin-6-yl) -2-oxoacetamide (9)

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

2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxo-N-quinolin-8-yl-acetamide (12)

2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -N-isoquinolin-5-yl-2-oxoacetamide (13)

2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxo-N-pyridin-4-yl-acetamide (14)

2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -N- (2-methylquinolin-8-yl) -2-oxoacetamide (15)

Compounds with general formulas 1a and 1b in the scheme can be obtained in accordance with the following scheme:

Compounds of general formula 1c in which X = S can be prepared according to Scheme 2:

Compounds of general formula 1c in which Y = S can be prepared using methods known in the literature (W.-D. Malberg et al. Liebigs Ann. Chem. 10, 1983; 1649-1711).

Starting compounds II, III, and IV can be purchased commercially or prepared using known methods. Starting compounds II, III and IV are valuable intermediates for the preparation of indole derivatives of the invention with formula I.

To obtain the starting compounds and final compounds, one can recommend, for example, the following exemplary works on organic synthesis, the contents of which, therefore, intend to include in the description of this application:

- Houben-Weyl, Volume E 7a (Part 1) pp. 290-492, pp. 571-740

- Houben-Weyl, Volume E 7a (Part 2) pp. 191-156, 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, ss. 101-135, ss. 234-323

- Monograph "Comprehensive Organic Chemistry" (S.D. Barton, W.D. Ollis)

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

Due to his professional knowledge, a qualified specialist is familiar with solvents and excipients, with reaction parameters, such as reaction temperature and reaction time, which are used where necessary.

The following compounds, the inclusion of which in the following discussion is understandable based on their characteristic chemical structure, were synthesized in accordance with these general directions for stages 1, 2 and 3, as shown in Synthesis Schemes 1 and 2. The compounds of this invention were characterized analytically by determining their melting points and / or using 1H NMR spectroscopy and / or mass spectroscopy.

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

The invention will be explained in more detail using the following examples, not limited to.

Examples

Example 1 (Reaction according to Scheme 1, stage 1):

Obtaining 1- (4-chlorobenzyl) indole

A solution of 5.86 g (0.05 mol) of indole in 25 ml of dimethyl sulfoxide (DMSO) is added to a mixture of 1.32 g of sodium hydride (0.055 mol, suspension in mineral oil) in 50 ml of dimethyl sulfoxide. The resulting mixture was heated at 60 ° C for 1.3 hours; then allow to cool and 17.7 g (0.11 mol) of 4-chlorobenzyl chloride are added dropwise. The solution is heated to 60 ° C and left overnight; then it is poured into 200 ml of water with stirring. This mixture was extracted with a total volume of 75 ml of CH ₂ Cl ₂ , after which the organic phase was removed by drying with anhydrous sodium sulfate and filtered, and the filtrate was evaporated in vacuo.

Yield: 11.5 g (95% of theory).

Example 2 (Reaction according to Scheme 1, stage 2):

2- [1- (4-chlorobenzyl) -1H-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 at 0 ° C and in a nitrogen atmosphere is added dropwise to a solution of 1.12 ml of oxalyl chloride in 50 ml of ether. The mixture was heated under reflux for 2 hours and the solvent was then evaporated. 30 ml of DMF is then added to the precipitate, after which 1.93 g (13.9 mmol) of potassium carbonate are added and the suspension is cooled to 0 ° C; a solution of 1.57 g (10.7 mmol) of the amino component in 10 ml of DMF is then added dropwise. The reaction mixture was left stirring overnight at room temperature. At the end, it is stirred in ice water and the resulting precipitate is filtered with suction. The resulting crude product was chromatographed over 100 g of silica gel using the n-heptane / ethyl acetate = 4: 1 system.

Yield: 3.23 g (68.0%)

Melting point: 250 ° C

1 H NMR (DMSO-D 6) 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), 5.64 (s, 2H) ppm

Example 3 (Reaction according to Scheme 1, stage 3):

N- {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} -N-quinolin-6-yl-acetamide (2)

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

Yield: 4.04 g (61.5%)

Melting point: 122.9 ° C

1 H-NMR (600 MHz, DMSO-d6) δ = 9.02 (d, 1H), 8.54 (s, 1H), 8.44 (d, 1H), 8.21 (d, 1H), 8 , 17 (d, 1H), 8.10 (m, 1H), 7.88 (m, 1H), 7.65 (m, 1H), 7.58 (m, 1H), 7.44 (d, 2H), 7.33 (d, 2H), 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 Scheme 1, stage 3 (a)):

Methyl {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} quinolin-6-ylcarbamate (3)

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

Yield: 3.0 g (26.5%)

Melting point: 178.5 ° C

1 H NMR (600 MHz, DMSO-d6) δ = 9.02 (d, 1H), 8.58 (s, 1H), 8.47 (d, 1H), 8.17 (m, 3H), 7 84 (m, 1H), 7.63 (m, 2H), 7.44 (d, 2H), 7.34 (m, 4H), 5.60 (s, 2H), 3.65 (s, 3H).

MS (ESI) m / z 498.2 (MH ⁺ ), (Theor. 497.94)

Example 5 (Reaction according to Scheme 2, 3rd stage (b)):

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

3.68 g (9.1 mmol) of 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide are added under nitrogen atmosphere to a suspension of 4.00 g (9 , 1 mmol) 2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxo-N-quinolin-6-yl-acetamide in 200 ml of toluene, after which the mixture is heated at 75 ° C for 3 hours. The precipitate formed is filtered hot from the reaction solution and then washed with 100 ml of methylene chloride. The filtrate was concentrated in vacuo and the residue was chromatographed on flash silica gel (eluent: methylene chloride / methanol 99: 1). Product fractions were filtered on flash silica gel (eluent: n-heptane / ethyl acetate 1/1) after the solvent was removed again.

Yield: 0.46 g (11% of theory)

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

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

The following compounds of formula I were simplified by analogy with the synthesis route in Scheme 1 and in accordance with Examples 2 and 3.

Example 6:

2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -N- (1H-indazol-5-yl) -2-oxoacetamide (4)

Melting point: 203 ° C

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

Example 7

Ethyl {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} quinolin-6-ylcarbamate (5)

Melting point: 199 ° C

1 H-NMR (600 MHz, DMSO-d6) δ = 9.02 (m, 1H), 8.60 (s, 1H), 8.48 (d, 1H), 8.15 (m, 3H), 7 83 (m, 1H), 7.63 (m, 2H), 7.43 (d, 2H), 7.32 (m, 4H), 5.60 (s, 2H), 4.15 (q, 2H), 0.95 (t, 3H).

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

Example 8:

Propyl {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} quinolin-6-ylcarbamate (6)

Melting point 164 ° C

1 H-NMR (600 MHz, DMSO-d6) δ = 9.02 (m, 1H), 8.60 (s, 1H), 8.48 (d, 1H), 8.17 (m, 3H), 7 84 (m, 1H), 7.63 (m, 2H), 7.43 (d, 2H), 7.33 (m, 4H), 5.61 (s, 2H), 4.03 (t, 2H), 1.32 (m, 2H), 0.56 (t, 3H).

Example 9:

N- {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} -N-quinolin-6-ylpropionamide (7)

1 H-NMR (600 MHz, DMSO-d6) δ = 9.03 (m, 1H), 8.52 (s, 1H), 8.45 (d, 1H), 8.23 (d, 2H), 8 , 18 (d, 1H), 8.13 (m, 1H), 7.88 (m, 1H), 7.65 (m, 1H), 7.58 (m, 1H), 7.45 (d, 2H), 7.30 (m, 4H), 5.59 (s, 2H), 2.61 (q, 3H), 0.88 (t, 3H).

Example 10:

Ethyl {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} pyridin-4-ylcarbamate (8)

Melting point: 62 ° C

1H-NMR (600 MHz, DMSO-d6) δ = 8.74 (m, 2H), 8.52 (s, 1H), 8.12 (m, 1H), 7.60 (m, 1H), 7 55 (m, 2H), 7.40 (m, 2H), 7.30 (m, 4H), 5.57 (s, 2H), 4.10 (q, 2H), 0.95 (t, 3H).

Example 11 (Comparison Substance):

Preparation of 2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -N- (2-methylquinolin-6-yl) -2-oxoacetamide (9)

Yield: 14.8 g (77.3% of theory)

Melting point: 182-185 ° C

1 H NMR (COCl 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 (Comparison Substance):

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

Melting point: 200 ° C

1 H NMR (OMSO-D 6) 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), 7.3-7.38 (m, 4H); 5.63 (s, 2H) ppm.

Example 13 (Comparison Substance):

2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxo-N-quinolin-8-yl-acetamide (12)

Melting point: 178 ° C

Example 14 (Comparison Substance):

2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -N-isoquinolin-5-yl-2-oxoacetamide (13)

Melting point: 239-241 ° C

Example 15 (Comparison Substance):

2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxo-N-pyridin-4-yl-acetamide (14)

Melting point: 264 ° C

Example 16 (Comparison Substance):

2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -N- (2-methylquinolin-8-yl) -2-oxoacetamide (15)

Melting point: 200-202 ° C

The biological effects of the compounds of this invention

Conducting in vitro and in vivo tests on selected tumor models showed the presence of the following pharmacological activities.

Example 17: Antiproliferative effect on different cancer cell lines

The antiproliferative activity of substances 1, 2, 4, 9, 11, 12, 13, and 15 was tested in a proliferation test on resistant cancer cell lines (D. A. Scuderio et al. Cancer Res. 1988, 48, 4827-4833). The test used characterizes the activity of cellular dehydrogenase and allows you to determine the viability of cells, as well as indirectly determine the number of cells. The following cell lines were used: KB / HeLa cervical carcinoma cell line (ATCC CCL17), SKOV-3 ovarian adenocarcinoma cell line (ATCC HTB77), human glioblastoma cell line SF-268 (NCI 503138), and lung carcinoma cell line NCI-H460 (NCI 503473).

Table 1:
The ability of the compounds of the invention to inhibit proliferation in an XTT cytotoxic test performed on human cancer cell lines. Analysis of XTT proliferation, EC50 in μg / ml Example KB / HeLa SKOV-3 SF-268 NCI-H460 one 0.045 0.029 0.042 2 0.202 0.123 0.166 four 0.335 0.144 > 3.16 eleven 0.036 0.029 0.036 9 (C) 0.183 0.174 0.261 12 (C) > 3.16 > 3.16 > 3.16 > 3.16 13 (s) > 3.16 > 3.16 > 3.16 > 3.16 15 (C) > 3.16 but. > 3.16 but. C = Substance of comparison; n.o .: not defined

The results show that embodiments 1, 2, 4, and 11 are very potent inhibitors of the proliferation of selected tumor cell lines.

Example 18: Antiproliferative effect on cancer cell lines MDR

For the purpose of further characterization, substances 1, 2, 4, and 11 were studied with respect to their effect on the multidrug resistance of cell lines compared with non-resistant wild-type cell lines.

The following cell lines were studied: murine cells of the L1210 line, acute myeloid leukemia LT12 cell line, and resistance lines L1210 / mdr and LT12 / mdr. P388 mouse cells (methylcholanthrene-induced lymphoid neoplasm) and the doxorubicin-resistant P388 line were also included as a test system.

The results are summarized in Table 2 below:

Table 2:
Inhibitory effect of substances of the human cancer cell line in the test for XTT proliferation. Analysis of XTT proliferation, EC50 in μg / ml Example LT12 LT12 / mdr L1210 L1210VCR P388 P388ADR one 0.015 0.017 0.018 0.021 0.012 0.019 2 0.225 0.272 0.206 0.558 0.224 0.215 four 0.084 0.093 0.246 0.241 0.175 0.231 eleven 0.023 0.054 0.052 0.067 0.018 0.051 Paclitaxel (C) 0.005 0.34 0.048 > 3.16 0.035 > 3.16 Vincristine (C) 0.002 0.134 0.015 > 3.16 0.004 0.93 Doxorubicin (C) 0.029 > 3.6 0.269 > 3.16 0.204 > 3.16 Mitoxantrone (C) 0.006 3.1 0.09 2.1 0.053 0.608 Etoposide (C) 0.094 > 3.6 0.269 > 3.16 0.202 > 3.16 C = Example for comparison

Substances 1, 2, 4 and 11 show a very high inhibitory effect on all tested cell lines, while classical substances such as those that have a tubulin-inhibiting effect, for example paclitaxel or vincristine, and topoisomerase II inhibitors (doxorubicin, mitoxantrone and etoposide) , as you can see, have an effect on MDR1-resistant cell lines that is at least significantly less.

Example 19: Inhibition of tubulin polymerization

Substances 1, 4, 9, 11, 12, 13, and 15 were studied with respect to their ability to inhibit bovine tubulin polymerization in an in vitro test (DMBollag et al. Cancer Res. 1955, 55, 2325-2333). This test is carried out using tubulin, which was purified during the polymerization - depolymerization process and which polymerizes upon addition of GTP and heating. Table 3 gives the EC ₅₀ values at which inhibition of the polymerization of tubulin containing 30% bound proteins occurs (maximum allowable amount).

Table 3:
Inhibition of tubulin polymerization. Mean values of two independent experiments Example Inhibition of tubulin polymerization, EC ₅₀ in μg / ml one 0.71 four 1.26 eleven 0.97 9 (C) 1.16 12 (C) > 10 μM 13 (s) > 10 μM 15 (C) > 10 μM Vincristine 0.35 C - an example for comparison

The results show that substances 1, 4, 9, and 11 have a very strong inhibitory effect on tubulin polymerization, while compounds 12, 13, and 15 have no effect.

Example 20: Inhibition of topoisomerase II

The ability of a substance to inhibit topoisomerase II was studied in two in vitro tests.

- Analysis of cDNA to determine the activity of topoisomerase II

In this quantitative assay, which was described by P. Arimondo (Anti-Cancer Drug Design 2000, 15 (6), 413-421), "DNA is treated with human DNA topoisomerase II in the absence and presence of the components of the assay. In this system, the compound 1 of this invention was tested at three different concentrations (100, 31.6 and 10 μM). For comparison, the positive control and standard compounds m-amsacrine (m-amsa), paclitaxel (Taxol) and vincristine were used, in each case the concentration was 100 μM.

Analysis:

2 μl of 10x standard assay buffer, 1 μl of cDNA (200 ng), 0.5 μl of human II topoisomerase (1 unit) and 15.5 μl of H ₂ O are pipetted to 1 μl of a pre-injected analyte (concentrated 20 times per 100% DMSO) and mix reagents. Samples with the reaction mixture are placed in a thermostat, which is preheated to 37 ° C and incubated at 37 ° C for 10 minutes. The incubation was stopped after adding 4 μl of 5x stop buffer and the substance was further extracted with CIA. After that, 20 μl of the supernatant was applied to a 1% agarose gel containing 0.25 μg of ethidium bromide in 1 ml and subjected to separation at 100 V for 1 h. At the end, the gel was photographed in UV light (see Figure 1) . The inhibition of decatenation (extension) of cDNA is quantified using the GelPRO ^® Analyzer Software (see Figure 2).

- pRYG release assay to determine topoisomerase II activity

This analytical system was used to further identify the inhibitory properties of the compounds of this invention with respect to topoisomerase II. In this system, compound 1 of this invention was tested at three different concentrations (100, 31.6 and 10 μM). For comparison, standard compounds m-amsacrine (m-amsa), paclitaxel (Taxol) and vincristine at concentrations of 316 and 100 μM were used.

The analysis was carried out as follows.

2 μl of a 10x standard assay buffer, 0.5 μl of pRYG cDNA (125 ng), 0.5 μl of human II topoisomerase (1 unit) and 16 μl of H ₂ O are pipetted to 1 μl of a pre-injected analyte (concentrated 20 times in 100% DMSO) and mix the reagents. Samples with the reaction mixture are placed in a thermostat, which is preheated to 37 ° C and incubated at 37 ° C for 30 minutes. The incubation is stopped after adding 4 μl of 5x stop buffer. After that, 10 μl of the sample was applied to a 1.2% agarose gel containing 0.25 μg of ethidium bromide in 1 ml and separated at 100 V for 2.5 hours. Finally, the gel was photographed in UV light (see Figure 3). Inhibition pRYG release was quantified using analyzer software GelPRO ^® (see. Figure 2).

Taking all the facts into account, we can conclude that it was shown that compound 1 according to this invention significantly inhibits topoisomerase II in both analytical systems. The results obtained with compound 1 are comparable to the inhibition values obtained with the topoisomerase II inhibitor m-amsacrine. As expected, neither paclitaxel nor vincristine showed an inhibitory effect in the two determinations.

Example 21: Cell Cycle Analysis

The cell cycle encompasses the development of a cell from one cell generation to another. During the resting phase (GO) and the pre-synthesis phase (G1), the cell has a diploid set of chromosomes (2 s). In the synthesis phase (S), the amount of DNA is increased by replication. The phase ends when the premitotic phase (G2M) sets in, in which the cell has a double set of chromosomes (4 s) and a doubled DNA content. In the next phase of mitosis (M), which is short in duration, the replicated chromosomes are equally distributed between two daughter cells, each of which again has a diploid DNA content and is in phase G01, which means that the cell cycle can start again.

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

The percentage of cells stopped in the G2 / M phase of the cell cycle after they were treated with standard substances or selected test substances are shown in Table 4. The results were analyzed using special software (ModFit ™).

Table 4:
The concentration required to inhibit 50% of the cells in the G2 / M phase. Example EC50 in nM (50% of cells in G2 / M) one 25.2 2 125.3 four 252 eleven 41.8 14 (C) > 1000 Paclitaxel 26.9 Mitoxantrone 25.3

Substances 1, 2, 4, and 11 of this invention exhibit activities that are comparable to those of standard paclitaxel and mitoxantrone compounds.

Example 22: Demonstration of apoptosis CDD ^plus nucleosome ELISA test

Fission of nuclei is a late consequence of apoptosis. The changes that can be observed in this regard may be a characteristic sign that DNA strands are cleaved by endonucleases and, as a result, nucleosome particles are fragmented.

The CDD ^plus Nucleosome ELISA test described by Roche Molecular Biochemicals was used to demonstrate nucleosome particles.

For this, the effects of compounds 1 and 2 on the U-937 cell line at different concentrations (1 nM-10 μM; 24 hours of treatment) were studied. (See FIGS. 5 and 6).

In this test, it was possible to observe a concentration-dependent increase in the content of nucleosomes in cell lysates for compounds 1 and 2. It was impossible to demonstrate any significant increase in the supernatant of cell culture, which is a fact in favor of the death of apoptotic cells that occurred after exposure to compounds 1 and 2 .

Example 23: Demonstration of the solubility in water of the compounds of the invention under saturation conditions

The solubility of substances 1, 2, 10 and 14 in water was determined under saturation conditions, as described below. A maximum of 1% DMSO was added to dissolve the substances, as well as to achieve wetting of the samples. Used the HPLC-UV method to verify the content. The results are summarized in Table 5 below.

Table 5:
Solubility values for saturation of substances 1, 2, 10, 14 Connection Name Solubility in water at saturation [μg / ml] one 25.0 2 28.5 10 (s) 0.038 14 (C) 0.35

1) the number of dead animals is compared with the total number

Example 24: In vivo Activity

In a human xenograft model (melanoma, MEXF-462), the in vivo activity and tolerance of compound 2 of the invention were studied in comparison with the same values for substances 10 and 14. The results are summarized in table 6 below.

The activity of compounds 2, 10 and 14 in vivo (melanoma, MEXF-462).

Table 6:
The activity of compounds 2, 10 and 14 in vivo (melanoma, MEXF-462) Substance Dose, mcg / kg Application Death, n ¹ Optimum T / C% (day) 2 80 inward 0/6 mice 0.0% (18), complete remission in all 6 animals 10 (s) 70 inward 5/6 mice are dead 2.3% (7) 10 (s) 55 inward 2/6 mice are dead 0.8% (14) 14 (C) 32 inward 3/5 mice are dead 14.6% (7) 14 (C) 16 inward 3/5 mice are dead 0.7% (18)

1) The number of dead animals compared to the total number

In this xenograft model, Compound 2 was observed to cause complete remission of tumor diseases in the treated animals, while at the same time it was well tolerated. A comparable antineoplastic effect was also observed in the case of compounds 10 and 14, but these substances were less tolerated.

Example 25: In vivo Activity

In another human xenograft model (mammary gland, MAXF857), the in vivo activity and tolerance of compound 2 of the invention were compared with those of substance 10. The results are shown in the table below.

Effect of compounds 2 and 10 on breast cancer MAXF857.

Table 7:
In vivo activity of compounds 2 and 10 (mammary gland, MAXF857) Substance Dose, [mcg / kg] Application Death, n ¹ Optimum T / C% (day) 2 80 inward 0/6 mice 9.6% (10) 10 (s) 40 inward 2/6 mice are dead 6.5% (10)

1) The number of dead animals compared to the total number

While compounds 2 and 10 were found to have a comparable antineoplastic effect, substance 10 was significantly worse tolerated (2.6 mice were dead) than substance 2.

Claims (14)

1. Indole derivatives of the general formula I

where R: is unsubstituted or substituted with quinolyl, pyridopyrazinyl, indazolyl or pyridyl and which is directly bonded to the nitrogen amide group R1: unsubstituted or substituted alkyl aryl, R2: hydrogen R3-R6: hydrogen, R7: (C ₁ -C ₆ ) -alkylcarbonyl or (C ₁ -C ₆ ) -alkoxycarbonyl, and X, Y: oxygen or sulfur, with the proviso that when R is an unsubstituted or substituted 2-, 3-, 4-, 5- and 6-pyridyl group and R1-R6 are as defined above, R7 is not an acetyl radical or a tert-butyloxycarbonyl group; and their physiologically tolerant salts. 2. Indole derivatives according to claim 1, characterized in that R is: unsubstituted or substituted with 5-, 6-, 7-quinolyl, unsubstituted or substituted with 2-, 3-, 6-, 7- and 8-pyridopyrazinyl, unsubstituted or substituted 3-, 4-, 5-, 6- and 7-indazolyl; unsubstituted or substituted with 2-, 3-, 4-, 5- and 6-pyridyl. 3. Indole derivatives according to claim 1 or 2, characterized in that R7 is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, acetyl or propionyl. 4. Derivatives of indole according to claim 1, characterized in that they are selected from the following group: N- {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} -N-quinolin-6-yl-acetamide (2) methyl {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} quinolin-6-ylcarbamate (3) ethyl {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} quinolin-6-ylcarbamate (5) propyl {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} quinolin-6-ylcarbamate (6) N- {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} -N-quinolin-6-ylpropionamide (7) ethyl {2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxoacetyl} pyridin-4-ylcarbamate (8). 5. Indole derivatives according to claim 1, characterized in that R1 is 4-chlorobenzyl, R2-R6 is hydrogen, and X and Y are oxygen or sulfur. 6. Indole derivatives of the general formula I, where R: substituted 6-quinolyl, substituted or unsubstituted 7-quinolyl directly linked to the amide nitrogen, where 2-methyl-6-quinolyl is excluded and where, when X is a sulfur atom, R may also be unsubstituted 6-quinolyl; unsubstituted or substituted 2-, 3-, 6-, 7- and 8-pyridopyrazinyl, unsubstituted or substituted 3-, 4-, 5-, 6- and 7-indazolyl, R1: unsubstituted or substituted alkyl aryl, R2: hydrogen R3-R6: hydrogen, and R7: hydrogen, X, Y: oxygen or sulfur, and their physiologically tolerant salts. 7. Indole derivatives according to claim 6, characterized in that they are selected from the following group: 2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -N-quinolin-6-yl-2-thioxoacetamide (11) 2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -2-oxo-N-pyrido [2,3-b] pyrazin-7-yl-acetamide (1) 2- [1- (4-chlorobenzyl) -1H-indol-3-yl] -N- (1H-indazol-5-yl) -2-oxoacetamide (4). 8. Indole derivatives according to claims 6-7, characterized in that R1 is 4-chlorobenzyl, R2-R6 is hydrogen, and X and Y are oxygen or sulfur. 9. A pharmaceutical composition having an apoptosis inducing effect, characterized in that it contains an effective amount of at least one of the indole derivatives described in claims 1-8. 10. The composition according to claim 9, characterized in that the indole derivative is in the composition of microparticles or nanoparticles. 11. The composition according to claim 9 or 10, characterized in that it further comprises a pharmaceutically acceptable carrier and / or excipient and is in the form of tablets, sugar coated tablets, capsules, infusion solutions or ampoules, suppositories, plasters, preparations in in the form of powders that can be used for inhalation, suspensions, creams and ointments. 12. The use of indole derivatives, characterized according to claims 1 to 8, to obtain a pharmaceutical composition for the treatment of tumor diseases. 13. The use according to claim 12 for the treatment of tumor diseases in the case of drug resistance in relation to other active compounds. 14. The use according to claim 12 for the treatment of tumor diseases in the case of metastatic carcinomas.

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