RS20060049A - Novel n-substituted indolyl-3-glycoxylic acid amides, use thereof as a medicament and method for the production thereof - Google Patents

Abstract

The invention relates to novel N-substituted indolyl-3-glyoxylic acid amides of general formula (I), the production thereof, and the use thereof as a medicament, especially for the treatment of tumors.

Description

NEW N-SUBSTITUTED AMIDES OF INDOLYL-3-GLYOXYL ACID,

THEIR USE AS A MEDICINE AND PROCEDURE FOR THEIR

OBTAINING

DESCRIPTION OF THE INVENTION

In the next few years, we can expect a dramatic increase in mortality in cancer and tumor patients. In 2001, approximately 10 million people worldwide suffered from cancer and over 6 million people died from this disease. Tumor development is a fundamental disease in higher organisms within flora and fauna. The generally accepted model of the treatment of carcinogenesis in several phases/steps implies that, due to the accumulation of a large number of mutations in individual cells, their behavior in terms of expansion and differentiation is modified in such a way that benign interphases eventually turn into a malignant state of metastasis. The term cancer or tumor covers a clinical picture that includes more than 200 different individual diseases. Oncosis can develop into a benign or malignant tumor. The most significant tumors are tumors of the lung, breast, stomach, canal (neck) of the uterus, prostate, head and tongue, large and small intestine, liver and blood (hematopoietic system). There are great differences regarding the course, prognosis, development and therapy of the mentioned disease. More than 90% of the recognized cases refer to solid tumors, which are usually in an advanced stage or in the stage of metastasis and can be treated with great difficulty or cannot be cured at all. The three pillars of cancer control are still surgical removal of the tumor, radiation treatment and chemotherapy. Despite great progress, it is still not possible to develop drugs that would lead to an increase in survival time or even a complete cure from solid tumors.

Therefore, there is reason to invent new drugs to control the development of cancer. First of all, a situation in which resistance is formed in an unwanted way, as happens with many antitumor agents, should be avoided.

Indolyl-3-glyoxylamides are often used as pharmacologically active compounds and as synthesis components in pharmaceutical hernia.

In WO03/022280, indoles of N-substituted alkyl- and aryl-3-glyoxylamides are described which have antitumor activity. However, examples of performing substitution on the nitrogen atom in glyoxylamide are not shown.

In documents WO99/51224 A1 and WO01/22954, N-substituted indol-3-yl derivatives with antitumor activity are described. However, examples of substitution are not shown.

In WO99/55696 A1, substituted hydroxyindoles are described as inhibitors of phosphodiesterase 4. The antitumor activity of the compounds of the invention is neither described nor suggested.

In WO 02/08225 A1, 2-(1H-indol-3-yl)-2-oxoacetamide derivatives are described which possess antitumor activity against solid tumors. However, examples of performing substitution on the nitrogen atom in glyoxylamide are not shown.

In patent application WO 00/67802, high chain fatty acid indole-3-glyoxylamides are described as potential antitumor agents. However, examples of implementation were not given nor were they confirmed with biological results.

In the publication of the application by W.-T. Lee et al. (J. Med. Chem. 2003, 46, 1706 hereafter), N-heterocyclic indolylglyoxylamides have been described as active compounds possessing antitumor activity.

WO 02/10152 A2 belonging to the applicant has already described the next class of indole derivatives for the treatment of tumors. In addition, the antiproliferative activity of the active compound, N-(2-methyl-6-quinolyl)-[1-(4-chlorobenzyl)-indol-3-yl]glyoxylamide was tested on different tumor cell lines.

The present invention relates to novel N-substituted indolyl-3-glyoxylamides, their preparation and use as drugs for the treatment of benign and malignant tumors in mammals, including humans.

In this application, N-substituted indolyl-3-glyoxylamides of the general formula I are described

in which

-represent hydrogen,

-unsubstituted or substituted alkyl,

-unsubstituted or substituted cycloalkyl.

-unsubstituted or substituted aryl,

-unsubstituted or substituted heteroaryl,

-unsubstituted or substituted alkylaryl,

-unsubstituted or substituted alkylheteroaryl,

-amino, monoalkylamino, dialkylamino,

-halogen,

-alkyl substituted with one or more fluorine atoms, preferably a trifluoromethyl group,

-cyano, straight or branched cyanoalkyl,

-alkylcarbonyl,

-carboxyl. Alkoxycarbonyl, Carboxyalkyl, or Alkoxycarbonylalkyl,

-alkoxy,

-arylalkoxy. preferably benzyloxy.

-Alkoxycarbonylamino, Alkoxycarbonylaminoalkyl,

R2: - represents unsubstituted or substituted alkyl,

-unsubstituted or substituted alkylaryl,

-unsubstituted or substituted alkylheteroaryl,

R7: - sulfone of the formula -SO2-X1, where XI is N(alk)2, hydroxyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted alkylcycloalkyl, unsubstituted or substituted alkylheterocyclyl, unsubstituted or substituted alkylaryl, unsubstituted or substituted alkylheteroaryl;

-C(O)-X2, where X2 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted alkylaryl and unsubstituted or substituted alkylheteroaryl; -C(0)0-X3, where X3 is unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted alkylcycloalkyl, unsubstituted or substituted alkylheterocyclyl, and unsubstituted or substituted alkylheteroaryl, -C(0)NX4X5, where X4 and X5 are each independently hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted alkylcycloalkyl, unsubstituted or substituted alkylheterocyclyl, unsubstituted or substituted alkylaryl,

unsubstituted or substituted alkylheteroaryl,

or X4 and X5 together may be cycloalkyl or cycloheteroalkyl,

-C(S)NX6X7, where X6 and X7 each represent hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or

substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted alkylcycloalkyl, unsubstituted or substituted alkylheterocyclyl, unsubstituted or substituted alkylaryl,

unsubstituted or substituted alkylheteroaryl,

or X6 and X7 together may be cycloalkyl or cycloheteroaryl,

X: represents O, S, or geminally bonded hydrogen and hydroxyl,

Y: represents 0 or S

And

HET: represents a saturated, unsaturated or aromatic (C2-C14)-heterocycle comprising one or more heteroatoms selected from the group consisting of N, O and S, which may be directly attached to the amide nitrogen or via a (Cl-C6)-alkyl bridge and where the alkyl radical may be substituted or unsubstituted and where optionally one or two aryl or cycloalkyl groups may be attached to the heterocycle, and

where the heterocyclyl, aryl or cycloaryl groups may be unsubstituted or substituted and where the alkyl radical may in all cases be branched or straight and saturated or unsaturated,

and pharmaceutically acceptable salts thereof.

The heterocyclic substituent can in particular be 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, pyridmidine, pyridazine, pyrazine, benzofuran, indazole, carbazole, benzoxazole, benzimidazole, benzothiazole, benzotriazole, quinoline, isoquinoline, cinnoline, quinoxaline, quinazoline, phthalazine, pyridopyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, purine, pteridine, acridine and phenanthridine.

Within the meaning of the present invention, the term "alkyl" includes acyclic saturated or unsaturated hydrocarbons with 1 to 20 carbon atoms, which may be branched or unbranched and unsubstituted or mono- or polysubstituted chains.

Within the meaning of the present invention, the term "cycloalkyl" means cyclic hydrocarbons of 3-12 carbons, which may be saturated or unsaturated, unsubstituted or mono- or polysubstituted.

The term "aryl" means aromatic hydrocarbons having from 6 to 14 carbon atoms, which may be unsubstituted or mono- or polysubstituted, where the aryl substituents may be the same or different and may be present in any desired and possible position of the aryl group.

The term "heteroaryl" means a 5-, 6- or 7-membered cyclic aromatic radical comprising at least 1, when possible also 2, 3, 4, or 5 heteroatoms, where the heteroatoms may be the same or different and the heterocycle may be unsubstituted or mono- or polysubstituted. In the case of substitution on the heteroaryl group, the heteroaryl substituents may be the same or different and may be present at any desired and possible position of the heteroaryl. Preferred heteroatoms are nitrogen, oxygen and sulfur.

The term "heterocyclyl" refers to a 3-, 4-, 5-, 6-, 7- or 8-membered cyclic organic radical comprising at least 1, preferably 2, 3, 4 or 5, heteroatoms, and these heteroatoms may be the same or different and the cyclic radical may be saturated or unsaturated but not aromatic and may be unsubstituted or mono- or polysubstituted. Preferred heteroatoms are nitrogen, oxygen and sulfur.

For the purposes of this invention, the terms "alkylcycloalkyl", "alkylheterocyclyl", "alkylaryl" or "alkyl-heteroaryl" mean that alkyl and cycloalkyl, heterocyclyl, aryl and heteroaryl have the previously defined meanings, and that the cycloalkyl, heterocyclyl, aryl or heteroaryl radical is attached via a C1-6-alkyl group to the compounds of general formula I.

In connection with the term "alkyl", the term substituted should be considered within the meaning of this invention as a designation for the substitution of a hydrogen radical with F, Cl, Br, J, CN, NH2, NH-alkyl, NH-cycloalkyl, NH-aryl, NH-heteroaryl, NH-alkylaryl, NH-alkylheteroaryl, NH-heterocyclyl, NH-alkyl-OH, N(alkyl)2, N(alkylaryl)2, , N(alkylheteroaryl)2, N(heterocyclyl)2,N(alkyl-OH)2NO, N02, SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkylaryl, S-alkylheteroaryl, S-heterocyclyl, S-alkyl-OH, S-alkyl-SH, S-alkyl, S-S-heterocyclyl, S-S-OH, S-S-SH. S-S-C(0)-NH-heterocyclyl, OH, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-alkylaryl, O-alkylheteroaryl, O-heterocyclyl, O-alkyl-OH, CHO, C(0)-alkyl, C(S)-alkyl, C(0)-aryl, C(S)-aryl, C(0)-alkylaryl, C(S)-alkylaryl, C(0)-heterocyclyl, C(0)-alkyl-OH, C(0)-alkylheteroaryl, C(0)-heterocyclyl, C02H, C02-alkyl, C02-cyclyl, C02-heterocyclyl, C02-aryl, C02-heteroaryl, C02-alkylaryl, C(0)-NH2, C(0)-NH-alkyl, C(0)NH-aryl, C(0)NH-heterocyclyl. C(0)NH-alkylheterocyclyl, C(0)N(alkyl)2, C(0)N(alkylaryl)2, C(0)N(alkylheteroaryl)2, C(0)N(heterocyclyl)2, SO-alkyl, SO2-alkyl, SO2NH2, SO3H, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, where the polysubstituted radicals can be either polysubstituted, for example, di- or trisubstituted, on different or on the same atoms, for example they can be trisubstituted on the same carbon atom in the case of CF3, - CH2CF3 or in different positions as in the case of -CH(OH)-CH-CH=CH-|CHC12. Polysubstitution can be performed on the same or different substituents.

In connection with aryl, heterocyclyl, heteroaryl, alkylaryl and cycloalkyl, mono- or polysubstituted within the meaning of this invention may mean mono- or polysubstitution, for example, di-, tri- or tetrasubstitution, on one or more ring hydrogen atoms by F, Cl, Br, J, CN, NH2, NH-alkyl, NH-cycloalkyl, NH-aryl, NH-heteroaryl, NH-alkylaryl, NH-alkylheteroaryl, NH-heterocyclyl, NH-alkyl-OH, N(alkyl)2, NC(0)alkyl, N(alkylaryl)2, N(alkylheteroaryl)2, N(heterocyclyl)2,N(alkyl-OH)2NO, N02, SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl, O-aryl, O-heteroaryl, O-alkylaryl, O-alkylheteroaryl, O-heterocyclyl, O-alkyl-OH, 0-C(0)-alkyl, CHO, C(0)-alkyl, C(S)-alkyl, C(0)-aryl, C(S)-aryl, C(0)-alkylaryl, C(S)-alkylaryl, C(0)-heterocyclyl, C(OS)-alkyl, C02H, C02-alkyl, C02-alkylaryl, C(0)-NH2, C(0)-NH-alkyl, C(0)NH-aryl, C(0)NH-heterocyclyl, C(0)N(alkyl)2, C(0)N(alkylaryl)2, C(0)N(alkylheteroaryl)2, C(0)N(heterocyclyl)2, SO-alkyl, S02-alkyl, SO-aryl, SO2-aryl, SO 2 -heteroaryl, SO 2 NH 2 , SO 3 H, CF 3 , CHO, CHS, alkyl, cycloalkyl, aryl, heteroaryl, and/or heterocyclyl, on one or different atoms (where one substituent may optionally be partially substituted). Polysubstitution can be performed on the same or different substituents.

If the compounds of the invention of the general formula I have at least one asymmetric center, they can be present in the form of their racemates, in the form of pure enantiomers and/or diastereoisomers or in the form of mixtures of these enantiomers and/or diastereoisomers, and in the form of substances and in the form of pharmaceutically acceptable salts of these compounds. The mixtures may be present in any mixing ratio for the stereoisomers.

If possible, the compounds according to the invention can be present in the form of tautomers.

Compounds of the general formula I according to the invention, such as, for example, a primary, secondary or tertiary amine, if they have a sufficiently basic group, can be translated into salts with inorganic or organic acids. Pharmaceutically active salts of compounds of the general formula I of the invention can preferably be formed 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 acid, succinic acid, tartaric acid, racemic acid, malic acid, embonic acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid. Among other things, the salts formed are hydrochlorides, hydrobromides, sulfates, phosphates, methanesulfonates, sulfoacetates, tosylates, carbonates, hydrogencarbonates, formates, acetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates (salts of malic acid), embonates, mandelates, fumarates, lactates, citrates and glutamates. The stoichiometry (stoichiometric ratio) of the salts formed from the compounds of the invention can be whole or non-whole multiples of unity.

If they contain a sufficiently acidic group such as a carboxyl group, the compounds of the general formula I can be converted with inorganic or organic bases into their physiologically acceptable salts. Examples of suitable inorganic bases are sodium hydroxide, potassium hydroxide, calcium hydroxide, and organic bases,

ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylenediamine and lysine.

The stoichiometry of the salts formed from the compounds of the invention may be whole or non-whole multiples of unity.

Preference is also given to solvates and especially hydrates of the compounds of the invention which can be obtained by crystallization from a solvent or from an aqueous solution. In these cases, it is possible for one, two, three or any number of solvates or water molecules to combine with the compounds of the invention to form solvates and hydrates.

The most preferred are the compounds of the general formula I, which are included in the following selection:

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

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

(2)

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

(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl {2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxoacetyl}-quinolin-6-ylcarbamate (4)

N-{2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxoacetyl}-4-methyl-N-quinolin-6-yl-benzenesulfonamide (5)

The compounds, indolyl-3-glyoxylamides of general formula I of the invention are useful for the treatment of mammals, including humans. Non-human mammals can be domestic animals such as horses, cows, dogs, cats, rabbits, sheep and the like.

A further aspect of the invention provides a method for treating a tumor in a mammal, including humans, which comprises administering to the mammal at least one indolyl-3-glyoxylamide of general formula I, in a dose effective for treating the tumor.

The therapeutically effective dose of certain indolyl-3-glyoxylamide from the invention given for the purpose of treatment depends, among other things, on the nature and condition of the tumor, the age and gender of the patient, the method of administration and the duration of the treatment. Medicines according to the invention can be applied in the form of liquid, semi-solid and solid pharmaceutical forms, in the form of aerosols, powders, epipastics, tablets, coated tablets, emulsions, foams, solutions, suspensions, gels, creams, pastes, pills, lozenges, capsules or suppositories (suppositories).

The pharmaceutical form according to the invention, among other things, includes at least one ingredient, depending on the pharmaceutical form used, where appropriate excipients are, among other things, solvents, solution activators, solvents, emulsifiers, humectants, anti-foaming agents, gelling agents, thickening agents, film-forming agents, binders, buffers, salt-forming agents, drying agents, flow regulators, fillers, preservatives (dispersion stabilizers), antioxidants, agents for coloring, agents for easier removal from the mold, lubricants (lubricants), disintegrants, agents for masking tastes and smells. The choice of excipients, as well as the amount to be applied, depends on the chosen pharmaceutical form and is based on formulations known to experts.

Medicines according to the invention can be applied in a suitable form suitable for application to the skin, epicutaneously as a solution, suspension, emulsion, foam, ointment, paste, or salve; through the mucosa of the tongue and oral cavity, buccally, lingually or sublingually in the form of tablets, lozenges, film tablets, lozenges or mouthwash; through the stomach and intestinal mucosa, enterally in the form of tablets, film tablets, capsules, solutions, suspensions or emulsions; through the rectal mucosa, rectally in the form of suppositories, rectal capsules or ointments; through the nasal mucosa, nasally in the form of drops, ointment or spray, through the bronchial and alveolar epithelium, through the lungs or by inhalation in the form of an aerosol or inhalant; through the conjunctiva, conjunctivally in the form of eye drops, eye ointment, eye tablets, flakes or eye lotion; through the genital mucosa, intravaginally in the form of vaginalette, ointment or douche; intrauterine in the form of a uterine pessary; through a different urethra, intraurethral in the form of irrigation fluid, ointment or through a probe; into an artery, intra-arterially in the form of an injection; into a vein, intravenously as an injection or infusion; into the skin, intracutaneously in the form of an injection or implant; under the skin, subcutaneously in the form of an injection or implant; into the muscle, intramuscularly in the form of an injection or implant; into the abdominal cavity, intraperitoneally in the form of injection or infusion.

The therapeutic effect of the compounds of the invention of the general formula I can be prolonged by appropriate measures with regard to practical therapeutic requirements. This goal can be achieved by chemical and/or pharmaceutical means. Examples of achieving prolongation of the effect are the use of implants and liposomes, forms with delayed release of the active substance, suspensions of nanoparticles and "target drugs" of compounds according to the invention, formation of salts and complexes of low solubility, or the use of crystalline suspensions.

The compounds according to the invention can be used as individual substances or in combination with other cytotoxic substances such as, for example, cisplantin, carboplatin, doxorubicin, ifosfamide, cyclophosphamide, 5-FU, methotrexate and especially in combination with signal transduction inhibitors, such as, for example, Herceptin, Glivec or Iressa.

Special attention is given to drugs that include at least one compound from the following group of indolyl-3-glyoxyl derivatives:

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

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

(2)

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

(1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl {2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxoacetyl}-quinolin-6-ylcarbamate (4)

N-{2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxoacetyl}-4-methyl-N-quinolin-6-yl-benzenesulfonamide (5)

These compounds can be present not only in the form of free bases but also in the form of physiologically acceptable acids.

In addition, the invention also includes a process for the preparation of compounds of the formula I according to the invention.

Compounds (I) according to the invention can be synthesized according to the scheme shown below:

According to the general procedure for phases 1 and 2, on which synthetic scheme 1 is based, the following compounds are synthesized, which follow from the list of corresponding chemical names in the following text. Analytical characterization of compounds according to the invention was performed on the basis of melting point values or on the basis of 1H-NMR spectroscopy and mass spectrometry.

Chemicals and solvents used were purchased from usual suppliers (Acros,

Avocado, Aldrich, Fluka, Lancaster, Mawbridge, Merck, Sigma, TCI, etc.) or are synthesized.

The invention will be explained in detail by means of the following examples but will not be limited thereto.

The presented compounds of the invention from 1-5 are synthesized on the basis of the following general rule:

General regulation

1.2 mmol of 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-quinolin-6-ylacetamide is added to a mixture of 1.2 mmol of sodium hydride (60% suspension of mineral oil) in 50 ml of dimethylformamide or THF while cooling with ice. After stirring for 25 min at room temperature, 1.3 mmol of the corresponding acyl chloride was added and the ice was removed. After 3 h, the reaction solution was poured into a mixture of ice and water and extracted three times with 100 ml of ethyl acetate. The combined organic phases are then dried over sodium sulfate and concentrated to dryness. The crude product thus obtained is then purified by recrystallization or column chromatography.

Example 1:

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

1H-NMR (DMSO-Cl6) d = 8.94-8.95 (m, 2H), 8.70 (s, 1H); 8.35 (d, IH), 8.08-8.09 (m. 2H), 8.03 (d, IH), 7.85 (dd, IH), 7.73 (d, 2H), 7.62 (d, IH), 7.55-7.58 (m, IH). 7.41-7.46 (m, 3H), 7.27-7.36 (m, 6H), 5.60 (s, 2H) ppm.

Example 2 : N.r2.[i-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxoacetyl}-2-phenyl-N-quinolin-6-yl-acetamide (2)

MS: m/e = 558.0 (M+H+)

Example 3:

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

MS: m/e = 560.0 (M+H+)

Example 4:

(1R, 2S, 5R)-2-Isopropyl-5-methylcyclohexyl {2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxoacetyl}-quinolin-6-ylcarbamate (4)

MS: m/e -622.0 (M+H+)

Example 5: N-{2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxoacetyl}-4-methyl-N-quinolin-6-yl-benzenesulfonamide (5)

MS: m/e = 594 (M+H+)

Biological data:

Inhibition of selected tumor cell lines

The antiproliferative activity of substance 1 was tested in a proliferation assay using established tumor cells (D.A. Scuderio et al., Cancer Res. 1988, 48, 4827-4833). The mentioned test determines the activity of cellular dehydrogenase and determines cell viability and, indirectly, the number of cells. The cell lines used are KB/HeLa (ATCC CCL17) human cervical carcinoma cell line, SKOV-3 (ATCC HTB77) adenocarcinoma cell line, SF-268 (NCL 503138) human glioblastoma cell line and NCL-H460 (NCL 503473) lung carcinoma cell line.

Table 1: Inhibition of proliferation by substances of the invention in the XTT cytotoxicity test on human tumor cell lines

Example 7:

Antiproliferative effect on MDR tumor cell lines:

Suspect 1 was further characterized by testing against multidrug-resistant cell lines compared to non-resistant wild-type cell lines.

The cell lines being tested are the L1210 mouse cell line, the LT 12 cell line from individuals suffering from acute myeloid leukemia, and the L1210/mdr AND LT12/mdr resistant lines. Other test systems used here are the mouse P388 cell line (methylcholanthrene-induced lymphoid neoplasm) and the doxorubicin-resistant P388 cell line.

The collected results are shown in table 2:

Table 2: Inhibitory effect of substance (1) in the XTT proliferation assay on human tumor cell lines

Claims (10)

1. N-substituted indolyl-3-glyoxylamide of general formula I in which: R1.R3-R6: -represent hydrogen, -unsubstituted or substituted alkyl, -unsubstituted or substituted cycloalkyl, -unsubstituted or substituted aryl, -unsubstituted or substituted heteroaryl, -unsubstituted or substituted alkylaryl, -unsubstituted or substituted alkylheteroaryl, -amino, monoalkylamino, dialkylamino, -halogen, -alkyl substituted with one or more fluorine atoms, preferably a trifluoromethyl group. -cyano, straight or branched cyanoalkyl, -alkylcarbonyl, -carboxyl, alkoxycarbonyl, carboxyalkyl. or alkoxycarbonylalkyl, -alkoxy, -arylalkoxy, preferably benzyloxy, -alkoxycarbonylamino, alkoxycarbonylaminoalkyl, R2: - represents unsubstituted or substituted alkyl, -unsubstituted or substituted alkylaryl, -unsubstituted or substituted alkylheteroaryl, R7 represents a sulfone of the formula -SO2-X1, where XI is N(alk)2, hydroxyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted alkylcycloalkyl, unsubstituted or substituted alkylheterocyclyl, unsubstituted or substituted alkylaryl, unsubstituted or substituted alkylheteroaryl; -C(0)-X2, where X2 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted alkylaryl and unsubstituted or substituted alkylheteroaryl, -C(0)0-X3, where X3 is unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted alkylcycloalkyl, unsubstituted or substituted alkylheterocyclyl, and unsubstituted or substituted alkylheteroaryl, -C(0)NX4X5, where X4 and X5 are each hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted alkylcycloalkyl, unsubstituted or substituted alkylheterocyclyl, unsubstituted or substituted alkylaryl, unsubstituted or substituted alkylheteroaryl, or X4 AND X5 together may be cycloalkyl or cycloheteroalkyl, -C(S)NX6X7, where X6 and X7 each independently represent hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted alkylcycloalkyl, unsubstituted or substituted alkylheterocyclyl, unsubstituted or substituted alkylaryl, unsubstituted or substituted alkylheteroaryl, or X6 and X7 together can be cycloalkyl or cycloheteroaryl, X: represents 0, S, or geminally bonded hydrogen and hydroxyl, Y: represents O or S and HET: one or more heteroatoms selected from the group consisting of, saturated, unsaturated or aromatic (C2-C14)-heterocycle comprising N, O and S, which may be directly attached to the amide nitrogen or via a (C1-C6)-alkyl bridge and where the alkyl radical may be substituted or unsubstituted and where optionally one or two aryl or cycloalkyl groups may be fused to form a heterocycle, and where the alkyl radical in all cases it may be branched or unbranched and saturated or unsaturated, and where heterocyclyl, aryl or cycloaryl groups may be unsubstituted or substituted or pharmaceutically acceptable salts thereof. 2. N-substituted indolyl-3-glyoxylamide of the general formula I according to claim 1, characterized in that HET can be 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, pyridimidine, pyridazine, pyrazine, benzofuran, indazole, carbazole, benzoxazole, benzimidazole, benzothiazole, benzotriazole, quinoline, isoquinoline, cinnoline, quinoxaline, quinazoline, phthalazine, pyridopyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, purine, pteridine, acridine and phenanthridine. 3. N-substituted indolyl-3-glyoxylamide of general formula I as in claims 1-2, characterized by neutralization of its base compounds with inorganic or organic acids or neutralization of its acid compounds with inorganic or organic bases. 4. N-substituted indolyl-3-glyoxylamide of the general formula I according to patent claims 1-3, characterized in that it has at least one asymmetric carbon atom in the form of a racemate, in the form of pure enantiomers and/or diastereomers or in the form of a mixture of these enantiomers and/or diastereomers, in the form of a tautomer. solvates and hydrates. 5. N-substituted indolyl-3-glyoxylamide of the general formula I according to patents claims 1-4, especially one of these compounds N-{2-[l-(4-chlorobenzyl)-lH-indol-3-yl]-2-oxoacetyl}-N-quinolin-6-yl-benzamide (1) N-{2-[l-(4-chlorobenzyl)-lH-indol-3-yl]-2-oxoacetyl}-2-phenyl-N-quinolin-6-yl-acetamide (2) Phenyl {2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxoacetyl}-quinolin-6-ylcarbamate (3) (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl {2-[1-(4-chlorobenzyl)-1 H-indol-3-yl]-2-oxoacetyl}-quinolin-6-ylcarbamate (4) N-{2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxoacetyl}-4-methyl-N-quinolin-6-yl-benzenesulfonamide (5) 6. N-substituted indolyl-3-glyoxylamide of the general formula I according to patent claims 1-5, characterized in that it is used as an active compound in medicine. 7. Use of an N-substituted indolyl-3-glyoxylamide of the general formula I according to claims 1-5 for the manufacture of a medicament for the treatment of tumors in mammals, including humans. 8. Process for obtaining N-substituted indolyl-3-glyoxylamides of the general formula I according to patent claims 1-5, characterized in that the reaction takes place according to the following scheme: 9. A drug characterized by the fact that as an active constituent it contains at least one N-substituted indolyl-3-glyoxylamide of the general formula I according to patent claims 1-5, if possible with the usual pharmaceutically acceptable excipients, additives and auxiliaries. 10. A method for the treatment of benign and malignant tumors in mammals, including humans, characterized in that it comprises administering at least one N-substituted indolyl-3-glyoxylamide of the general formula I according to claims 1-5 to mammals in a dose that is effective for tumor treatment.