RU2003105891A

RU2003105891A - INDOLE DERIVATIVES, METHOD FOR PRODUCING AND USING THEM, MEDICINAL PRODUCT AND METHOD FOR TREATING A TUMORAL DISEASE OF A MAMMAL

Info

Publication number: RU2003105891A
Application number: RU2003105891/04A
Authority: RU
Inventors: Беата АУЭ; Сильке БААСНЕР; Геральд БАХЕР; Экхард ГЮНТЕР; Бернд Никель; Дитмар Райхерт; Петер Эмиг
Original assignee: Центарис Гмбх
Priority date: 2000-07-28
Filing date: 2001-07-26
Publication date: 2004-10-20

Claims

1. Indole derivatives of the general formula 1

where R is hydrogen, linear or branched (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl substituted with at least one aryl substituent, wherein the aryl residue is unsubstituted or contains from one to five identical or different substituents, selected from the series: halogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, carboxyl, (C ₁ -C ₆ ) alkoxycarbonyl, preferably tert-butoxycarbonyl substituted with at least one fluorine atom, linear or branched (C ₁ -C ₆ ) alkyl, preferably trifluoromethyl, hydroxy, linear or branched (C ₁ -C ₆ ) alkoxy, preferably methoxy or ethoxy; benzyloxy or aryl (C ₁ -C ₆ ) alkyl, wherein the aryl residue is unsubstituted or contains from one to five identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or substituted with at least one fluorine atom linear or branched (C ₁ -C ₆ ) alkyl, preferably trifluoromethyl; R also means linear or branched (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, substituted or unsubstituted aryl (C ₁ -C ₆ ) alkyloxycarbonyl, preferably benzyloxycarbonyl, linear or branched (C ₁ -C ₆ ) alkoxycarbonyl linear, branched (C ₁ -C ₆ ) alkylcarbonyl, preferably acetyl, (C ₂ -C ₆ ) alkenyl, preferably allyl, (C ₂ -C ₆ ) alkynyl, preferably ethynyl or propargyl, or linear or branched cyano (C ₁ -C ₆ ) alkyl, preferably cyanomethyl;

R ₁ means a saturated, unsaturated or aromatic (C ₂ -C ₁₄ ) heterocycle containing at least one heteroatom selected from N, O and S, wherein said heterocycle is attached to the amide nitrogen atom directly or via (C ₁ -C ₆ ) an alkyl bridging group, and the (C ₁ -C ₆ ) alkyl residue may be unsubstituted or substituted with one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and 2 -, 4-, 5- or 6-pyrimidinyl residue, which in each case may be unsubstituted or contain od up to three identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy , (C ₁ -C ₆ ) alkoxy, benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl, provided that R ₁ is other than unsubstituted 2- or 4-pyrimidinyl or substituted with at least one methyl group 2-pyrimidinyl; and with the exception of 2-, 3-, 4- and 8-quinolyl and 2-, 3- and 4-quinolylmethyl radicals substituted by the following groups: (C ₁ -C ₆ ) alkyl, halogen, nitro, amino and (C ₁ - C ₆ ) alkylamino, or unsubstituted 2-, 3-, 4- and 8-quinolyl and 2-, 3- and 4-quinolylmethyl residues in which the cyclic carbon atoms of the pyridylmethyl fragment are unsubstituted or are substituted by the following groups: (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, nitro, amino and (C ₁ -C ₆ ) alkoxycarbonylamino;

R ₂ means hydrogen, (C ₁ -C ₆ ) alkyl substituted by at least one halogen atom (C ₁ -C ₆ ) alkyl, substituted by at least one phenyl (C ₁ -C ₆ ) alkyl, wherein the phenyl moiety may be unsubstituted or contain from one to five identical or different substituents selected from the series: halogen, preferably chlorine, bromine or iodine, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, carboxyl, (C ₁ -C ₆₎ alkoxycarbonyl group substituted with at least one halogen atom, (C ₁ -C ₆₎ alkyl, preferably trifluoromethyl, hydroxy, (C ₁ -C ₆₎ alkoxy, preferably met Xi or ethoxy, phenyl (C ₁ -C ₆₎ alkoxy, preferably benzyloxy, nitro, amino, mono (C ₁ -C ₆₎ alkylamino, di (C ₁ -C ₆₎ alkylamino, mono (C ₃ -C ₆₎ cycloalkylamino , di (C ₃ -C ₆ ) cycloalkylamino, (C ₁ -C ₆ ) acylamino, phenyl (C ₁ -C ₆ ) alkylamino, arylcarbonylamino, heteroarylcarbonylamino, (C ₁ -C ₆ ) alkylsulfonamido, arylsulfonamido, maleimimido, succinimidido, phthalimido , benzyloxycarbonylamino (Z-amino), tert-butoxycarbonylamino (BOC-amino), 9-fluorenylmethoxycarbonylamino (Fmoc-amino), triphenylmethylamino (Tr-amino), 2 (4'-pyridyl) ethoxycarbonylamino (Ruos-amino), diphene lmetilsililamino (DPMS-amino), -NH-CH ₂ -COOH, -NH-CH (CH ₃₎ -COOH, (CH _z) ₂ CH-CH ₂ -CH ₂ -CH (NH -) - COOH, H ₃ C -CH ₂ -CH (CH _h) -CH (NH -) - COOH HOH ₂ C-CH (NH -) - COOH, phenyl-CH ₂ -CH (NH -) - COOH, ( 4-imidazolyl) -CH _2- CH (NH -) - COOH, HN = C (NH ₂ ) -NH (CH ₂ ) ₃ -CH (NH -) - COOH, H ₂ N (CH ₂ ) ₄ -CH (NH -) - COOH, H ₂ N-CO-CH ₂ -CH (NH -) - COOH, HOOC (CH ₂ ) ₂ -CH (NH -) - COOH;

2-, 3-, 4-, 5-, 6-, 7- and 8-quinolyl (C ₁ -C ₆ ) alkyl radical, with 2-, 3-, 4-, 5-, 6-, 7- and The 8-quinolyl residue may be unsubstituted or contain from one to six identical or different substituents selected from the range: halogen, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy;

2-, 3- and 4-pyridyl (C ₁ -C ₆ ) alkyl radical, wherein the 2-, 3- and 4-pyridyl radical may be unsubstituted or contain from one to four identical or different substituents selected from the series: halogen , (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy; an aryl carbonyl residue, wherein the aryl residue may be unsubstituted or contain from one to five identical or different substituents selected from the series: halogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, carboxyl, cyano, (C ₁ -C ₆ ) alkoxycarbonyl substituted by at least one fluorine atom (C ₁ -C ₆ ) alkyl, preferably trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) alkoxy, preferably methoxy or ethoxy, aryl (C ₁ -C ₄ ) alkoxy, preferably benzyloxy;

R ₃ and R ₄ can be attached to carbon atoms of the indole ring at C-2, C-4, C-5, C-6 or C-7 and independently mean the following groups: hydrogen, hydroxy, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₆ ) alkylcarbonyl, (C ₁ -C ₆ ) alkoxy, halogen, aryl (C ₁ -C ₄ ) alkoxy, preferably benzyloxy, nitro, amino, mono ( C ₁ -C ₄ ) alkylamino, di (C ₁ -C ₄ ) alkylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₆ ) alkoxycarbonylamino (C ₁ -C ₆ ) alkyl, cyano, linear or branched cyano (C ₁ -C ₆ ) alkyl, carbonyl, (C ₁ -C ₄ ) alkoxycarbonyl substituted with at least one fluorine atom (C ₁ -C ₄ ) alkyl, preferably trifluoromethyl, carboxy (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkoxycarbonyl (C ₁ -C ₆ ) alkyl;

Z ₁ means oxygen or sulfur atoms or two attached hydrogen and hydroxy atoms;

Z ₂ means an oxygen or sulfur atom;

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

2. Indole derivatives according to claim 1, characterized in that the substituents R, R ₂ , R ₃ , R ₄ , Z ₁ and Z ₂ have the meanings specified in claim 1, and

R ₁ means a 2-, 4-, 5- or 6-pyrimidinyl residue or a 2-, 4-, 5- or 6-pyrimidinyl (C ₁ -C ₄ ) alkyl radical, wherein the (C ₁ -C ₄ ) alkyl radical may be unsubstituted or substituted by one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and a 2-, 4-, 5- or 6-pyrimidinyl residue, which is each case may be unsubstituted or contain from one to three identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkyl mino, hydroxy, (C ₁ -C ₆ ) alkoxy, benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one a fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl, provided that R ₁ is other than unsubstituted 2- or 4-pyrimidinyl or substituted at at least one methyl group of 2-pyrimidinyl;

A 3-, 4-, 5- or 6-pyridazinyl residue or a 3-, 4-, 5- or 6-pyridazinyl (C ₁ -C ₄ ) alkyl radical, wherein the (C ₁ -C ₄ ) alkyl radical may be unsubstituted or substituted by one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and a 3-, 4-, 5- or 6-pyridazinyl radical, which may be unsubstituted or contain from one to three identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino , hydroxy, (C ₁ -C ₆₎ alko B, benzyloxy, carboxy, (C ₁ -C ₆₎ alkoxycarbonyl, (C ₁ -C ₆₎ alkoxycarbonylamino or (C ₁ -C ₆₎ alkyl substituted by at least one fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

A 2-, 3-, 5- or 6-pyrazinyl residue or a 2-, 3-, 5- or 6-pyrazinyl (C ₁ -C ₄ ) alkyl radical, wherein the (C ₁ -C ₄ ) alkyl radical may be unsubstituted or substituted by one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and a 2-, 3-, 5- or 6-pyrazinyl radical, which may be unsubstituted or contain from one to three identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino , hydroxy, (C ₁ -C ₆₎ alkoxy, baa ziloksi, carboxy, (C ₁ -C ₆₎ alkoxycarbonyl, (C ₁ -C ₆₎ alkoxycarbonylamino or (C ₁ -C ₆₎ alkyl substituted by at least one fluorine atom, preferably trifluoromethyl, _{_(C6-C10)} aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

3-, 4-, 5-, 6-, 7- or 8-cinnolinyl or 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl (C ₁ -C ₄ ) alkyl radical, wherein (C ₁ -C ₄ ) the alkyl residue may be unsubstituted or substituted by one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and 3-, 4-, 5- , 6-, 7- or 8-cinnolinyl residue, which may be unsubstituted or contain from one to five identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono ( C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆ ) alk hydroxy, benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

2-, 4-, 5-, 6-, 7- or 8-quinazolinyl residue or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl (C ₁ -C ₄ ) alkyl residue, and ( The C ₁ -C ₄ ) alkyl radical may be unsubstituted or substituted by one or more identical or different substituents selected from the range: hydrogen, (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and 2-, 4- , 5-, 6-, 7- or 8-quinazolinyl residue, which may be unsubstituted or contain from one to five identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆ ) alkoxy, benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl radical; or 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl (C ₁ -C ₄ ) alkyl radical, wherein ( C ₁ -C ₄ ) the alkyl residue may be unsubstituted or substituted by one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and 2-, 3-, 5 -, 6-, 7- or 8-quinoxalinyl radical, which may be unsubstituted or contain from one to five identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydro Xi, (C ₁ -C ₆ ) alkoxy, benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

1-, 4-, 5-, 6-, 7- or 8-phthalazinyl residue or 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl (C ₁ -C ₄ ) alkyl residue, and ( C ₁ -C ₄ ) the alkyl residue may be unsubstituted or substituted by one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and 1-, 4-, 5 -, 6-, 7- or 8-phthalazinyl residue, which may be unsubstituted or contain from one to five identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆ ) alkoxy, benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl residue or 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl (C ₁ -C ₄ ) an alkyl residue, wherein the (C ₁ -C ₄ ) alkyl residue may be unsubstituted or substituted with one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and 2 -, 3-, 4-, 5-, 6-, 7- or 8-quinolyl residue, which may be unsubstituted or contain from one to six identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, preferably methyl, more preferably 2-methyl, halogen, nitro, amino, mono ( C ₁ -C ₆ ) alkylamino, N, N-di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₆ -C ₁₄ ) aryl (C ₁ -C ₆ ) alkoxy, preferably benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one halogen atom, preferably trifluoromethyl, (C ₆ -C ₁₄ ) aryl or (C ₆ -C ₁₄ ) aryl (C ₁ -C ₆ ) alkyl; with the exception of 2-, 3-, 4- and 8-quinolyl and 2-, 3- and 4-quinolylmethyl radicals substituted by the following groups: (C ₁ -C ₆ ) alkyl, halogen, nitro, amino and (C ₁ -C ₆ ) alkylamino, or unsubstituted 2-, 3-, 4- and 8-quinolyl and 2-, 3- and 4-quinolylmethyl radicals in which the cyclic carbon atoms of the pyridylmethyl fragment are unsubstituted or are substituted by the following groups: (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, nitro, amino and (C ₁ -C ₆ ) alkoxycarbonylamino;

1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl residue or 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl (C ₁ -C ₄ ) an alkyl residue, wherein the (C ₁ -C ₄ ) alkyl residue may be unsubstituted or substituted by one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and 1 -, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl residue, which may be unsubstituted or contain from one to six identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydr hydroxy, (C ₁ -C ₆ ) alkoxy, benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

A 2-, 6-, 8- or 9- [9H] -purinyl residue or 2-, 6-, 8- or 9- [9H] -purinyl (C ₁ -C ₄ ) alkyl, wherein (C ₁ -C ₄ ) the alkyl residue may be unsubstituted or substituted by one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and 2-, 6-, 8- or 9- [ 9H] -purinyl residue, which may be unsubstituted or contain from one to three identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆ ) alkoxy, benzyloxy , carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

2-, 6-, 7- or 8- [7H] -purinyl residue or 2-, 6-, 7- or 8- [7H] -purinyl (C ₁ -C ₄ ) alkyl residue, wherein (C ₁ -C ₄ ) the alkyl residue may be unsubstituted or substituted by one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and 2-, 6-, 7- or 8- [7H] -purinyl residue, which may be unsubstituted or contain from one to three identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆ ) alkoxy, benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl residue or 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl (C ₁ -C ₄ ) alkyl radical, wherein the (C ₁ -C ₄ ) alkyl radical may be unsubstituted or substituted by one or more identical or different substituents selected from the group: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridilinyl radical, which may be unsubstituted or contain from one to eight the same or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alk amylamino, hydroxy, (C ₁ -C ₆ ) alkoxy, benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one a fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl radical or 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl (C ₁ -C ₆ ) alkyl radical, wherein the (C ₁ -C ₆ ) alkyl radical may be unsubstituted or substituted by one or more identical or different substituents selected from the range: hydrogen, (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl residue, which may be unsubstituted or contain from one up to eight identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ alkylamino, hydroxy, (C ₁ -C ₆ ) alkoxy, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkoxy, preferably benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl , (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

2-, 3-, 4-, 5- or 6-pyridyl residue, wherein the 2-, 3-, 4-, 5- or 6-pyridyl residue may be unsubstituted or contain from one to four identical or different substituents selected from series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆ ) alkoxy, benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with one or more fluorine atoms, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₁ -C ₆ ) aryl (C ₁ -C ₆ ) alkyl, with the proviso that Z ₁ , Z ₂ , R ₂ , R ₃ and R ₄ are as defined above or below, and R is (C ₂ -C ₆ ) alkenyl, preferably allyl, (C ₂ -C ₆ ) alkynyl, preferably ethynyl or propargyl, (C ₁ -C ₆ ) alkoxy (C ₁ - C ₆ ) alkyl or linear or branched cyano (C ₁ -C ₆ ) alkyl, preferably cyanomethyl, or provided that Z ₂ , R, R ₂ , R ₃ and R ₄ are as defined above or below, and Z ₁ means two attached hydrogen and hydroxy atoms;

2-, 3-, 4-, 5- or 6-pyridyl (C ₁ -C ₆ ) alkyl radical, wherein the (C ₁ -C ₆ ) alkyl radical may be unsubstituted or substituted with one or more identical or different substituents selected from series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and a 2-, 3-, 4-, 5- or 6-pyridyl residue, which may be unsubstituted or contain from one to four identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆₎ alkoxy, benzyloxy, carboxy, (C ₁ -C ₆₎ alkoxy Arbon, (C ₁ -C ₆₎ alkoxycarbonylamino or (C ₁ -C ₆₎ alkyl substituted by at least one fluorine atom, preferably trifluoromethyl, _{_(C6-C10)} aryl or (C ₆ -C ₁₀₎ aryl ( C ₁ -C ₆ ) alkyl;

A 2-, 3-, 4- or 5-thienyl residue or a 2-, 3-, 4- or 5-thienyl (C ₁ -C ₆ ) alkyl radical, wherein the (C ₁ -C ₆ ) alkyl radical may be unsubstituted or substituted by one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and a 2-, 3-, 4-, or 5-thienyl residue, which may be unsubstituted or contain from one to three identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆ ) alkoxy, benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

A 2-, 4- or 5-thiazolyl residue or a 2-, 4- or 5-thiazolyl (C ₁ -C ₆ ) alkyl radical, wherein the (C ₁ -C ₆ ) alkyl radical may be unsubstituted or substituted with one or more identical or various substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= 0), and a 2-, 4- or 5-thiazolyl residue, which may be unsubstituted or contain from one to two identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆ ) alkoxy, benzyloxy, arboksi, (C ₁ -C ₆₎ alkoxycarbonyl, (C ₁ -C ₆₎ alkoxycarbonylamino or (C ₁ -C ₆₎ alkyl substituted by at least one fluorine atom, preferably trifluoromethyl, _{_(C6-C10)} aryl, or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

A 3-, 4- or 5-isothiazolyl residue or a 3-, 4- or 5-isothiazolyl (C ₁ -C ₆ ) alkyl radical, wherein the (C ₁ -C ₆ ) alkyl radical may be unsubstituted or substituted with one or more identical or various substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and a 3-, 4-, or 5-isothiazolyl residue, which may be unsubstituted or contain from one to two identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆ ) alkoxy, no nzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

A 2-, 4-, 5-, 6- or 7-benzothiazolyl residue or a 2-, 4-, 5-, 6- or 7-benzthiazolyl (C ₁ -C ₆ ) alkyl residue, wherein (C ₁ -C ₆ ) the alkyl residue may be unsubstituted or substituted by one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and 2-, 4-, 5-, 6- or 7 -benzothiazolyl residue, which may be unsubstituted or contain from one to four identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy , (C ₁ -C ₆ ) alkoxy, benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

A 1-, 2-, 4- or 5-imidazolyl residue or a 1-, 2-, 4- or 5-imidazolyl (C ₁ -C ₆ ) alkyl radical, wherein the (C ₁ -C ₆ ) alkyl radical may be unsubstituted or substituted with one or more identical or different substituents selected from the group: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and a 1-, 2-, 4- or 5-imidazolyl residue, which may be unsubstituted or contain from one to three identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino hydroxy, (C ₁ -C ₆ ) alkoxy, benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

A 1-, 3-, 4- or 5-pyrazolyl residue or a 1-, 3-, 4- or 5-pyrazolyl (C ₁ -C ₆ ) alkyl radical, wherein the (C ₁ -C ₆ ) alkyl radical may be unsubstituted or substituted with one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and a 1-, 3-, 4- or 5-pyrazolyl residue, which may be unsubstituted or contain from one to three identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino , hydroxy, (C ₁ -C ₆₎ alkoxy, baa ziloksi, carboxy, (C ₁ -C ₆₎ alkoxycarbonyl, (C ₁ -C ₆₎ alkoxycarbonylamino or (C ₁ -C ₆₎ alkyl substituted by at least one fluorine atom, preferably trifluoromethyl, _{_(C6-C10)} aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

1-, 2-, 3-, 4- or 5-pyrrolyl residue or 1-, 2-, 3-, 4- or 5-pyrrolyl (C ₁ -C ₆ ) alkyl residue, wherein (C ₁ -C ₆ ) the alkyl residue may be unsubstituted or substituted by one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and 1-, 2-, 3-, 4-, or 5-pyrrolyl residue, which may be unsubstituted or contain from one to four identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆ ) alk xy, benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

1-, 3- or 5- [1.2.4] triazolyl residue or 1-, 3- or 5- [1.2.4] triazolyl (C ₁ -C ₆ ) alkyl residue, and (C ₁ -C ₆ ) alkyl residue may be unsubstituted or substituted by one or more identical or different substituents selected from the range: hydrogen, (C ₁ -C ₆ ) alkyl, halogen and oxo (= O), or 1-, 3- or 5- [1.2.4] a triazolyl residue, which may be unsubstituted or contain from one to two identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆ alkoxy, benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom, preferably trifluoromethyl, (C ₆ - C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

1-, 4- or 5- [1.2.3] triazolyl residue or 1-, 4- or 5- [1.2.3] triazolyl (C ₁ -C ₆ ) alkyl residue, and (C ₁ -C ₆ ) alkyl the residue may be unsubstituted or substituted by one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and 1-, 4- or 5- [1.2.3] triazolyl a residue which may be unsubstituted or contain from one to two identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di ( C ₁ -C ₆₎ alkylamino, hydroxy, (C ₁ -C ₆₎ Alcock and, benzyloxy, carboxy, (C ₁ -C ₆₎ alkoxycarbonyl, (C ₁ -C ₆₎ alkoxycarbonylamino or (C ₁ -C ₆₎ alkyl substituted by at least one fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

1- or 5- [1H] -tetrazolyl residue or 1- or 5- [1H] -tetrazolyl (C ₁ -C ₆ ) alkyl residue, wherein the (C ₁ -C ₆ ) alkyl residue may be unsubstituted or substituted with one or more the same or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and 1- or 5- [1H] -tetrazolyl residue, which may be unsubstituted or contain a substituent from the series: hydrogen , (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆ ) alkoxy, benzyloxy, carboxy , (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alk xicarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

A 2- or 5- [2H] -tetrazolyl residue or a 2- or 5- [2H] -tetrazolyl (C ₁ -C ₆ ) alkyl radical, wherein the (C ₁ -C ₆ ) alkyl radical may be unsubstituted or substituted with one or more the same or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and a 2- or 5- [2H] -tetrazolyl residue, which may be unsubstituted or contain a substituent from the series: hydrogen , (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆ ) alkoxy, benzyloxy, carboxy , (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alk xicarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

2-, 4- or 6- [1.3.5] -triazinyl residue or 2-, 4- or 6- [1.3.5] -triazinyl (C ₁ -C ₆ ) alkyl radical, wherein (C ₁ -C ₆ ) the alkyl residue may be unsubstituted or substituted by one or more identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and 2-, 4- or 6- [1.3. 5] a triazinyl radical, which may be unsubstituted or contain from one to two identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ - C ₆ ) alkoxy, benzyloxy, carboxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonylamino, or (C ₁ -C ₆ ) alkyl substituted with at least one fluorine atom, preferably trifluoromethyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

A 2-, 4- or 5-oxazolyl residue or a 2-, 4- or 5-oxazolyl (C ₁ -C ₆ ) alkyl radical, wherein the (C ₁ -C ₆ ) alkyl radical may be unsubstituted or substituted with one or more identical or various substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and a 2-, 4- or 5-oxazolyl residue, which may be unsubstituted or contain from one to two identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆ ) alkoxy, benzyl and, carboxy, (C ₁ -C ₆₎ alkoxycarbonyl, (C ₁ -C ₆₎ alkoxycarbonylamino or (C ₁ -C ₆₎ alkyl substituted by at least one fluorine atom, preferably trifluoromethyl, _{_(C6-C10)} aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

A 3-, 4- or 5-isoxazolyl residue or a 3-, 4- or 5-isoxazolyl (C ₁ -C ₆ ) alkyl radical, wherein the (C ₁ -C ₆ ) alkyl radical may be unsubstituted or substituted with one or more identical or various substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen or oxo (= O), and a 3-, 4- or 5-isoxazolyl residue, which may be unsubstituted or contain from one to two identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxy, (C ₁ -C ₆ ) alkoxy, no ziloksi, carboxy, (C ₁ -C ₆₎ alkoxycarbonyl, (C ₁ -C ₆₎ alkoxycarbonylamino or (C ₁ -C ₆₎ alkyl substituted by at least one fluorine atom, preferably trifluoromethyl, _{_(C6-C10)} aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl;

1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl residue or 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl (С ₁ -С ₆ ) an alkyl residue, wherein the (C ₁ -C ₆ ) alkyl residue may be unsubstituted or substituted with one or more identical or different substituents selected from the series: (C ₁ -C ₆ ) alkyl, halogen and oxo (= O), or 1 -, 2-, 3-, 4-, 5-, 6- or 7-indolyl residue, which may be unsubstituted or contain from one to six identical or different substituents selected from the series: hydrogen, (C ₁ -C ₆ ) alkyl, halogen, nitro, amino, mono (C ₁ -C ₆₎ alkylamino, di (C ₁ -C ₆₎ alkylamino, hydroxy, (C ₁ - ₆₎ alkoxy, benzyloxy, carboxy, (C ₁ -C ₆₎ alkoxycarbonyl, (C ₁ -C ₆₎ alkoxycarbonylamino or (C ₁ -C ₆₎ alkyl substituted by at least one fluorine atom, preferably trifluoromethyl, _(C6- -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl.

3. Indole derivatives according to claim 1 or 2, characterized in that the substituents R, R ₂ , R ₃ , R ₄ , Z ₁ and Z ₂ have the meanings specified in claim 1, and R ₁ means quinolyl substituted at least one linear or branched (C ₁ -C ₆ ) alkyl or (C ₁ -C ₂ ) alkoxy group.

4. Indole derivatives according to one of claims 1 to 3, characterized in that the substituents R, R ₂ , R ₃ , R ₄ , Z ₁ and Z ₂ are as defined in claim 1, and R ₁ means 2-methyl- 6-quinolyl.

5. Indole derivatives according to one of claims _{1 to} ₄ , characterized in that the substituents R, R ₂ , R ₃ , R ₄ , Z ₁ and Z ₂ are as defined in claim 1, and R ₁ means 2-methyl- 6-quinolyl, R ₂ means 4-chlorobenzyl, R ₃ and R ₄ in each case mean a hydrogen atom, and Z ₁ and Z ₂ mean an oxygen atom.

6. Derivatives of indole according to one of claims 1 to 5, characterized in that they are intended for use as a medicine.

7. The use of an indole derivative of the general formula (1) according to one of claims 1 to 5 as a medicine for the treatment of a tumor of a mammal.

8. The method of obtaining the indole derivative of the general formula (1) according to one of claims 1 to 5, which consists in the fact that the intermediate derivative of indole of the general formula (2)

where R ₂ , R ₃ and R ₄ have the meanings defined in claim 1, are reacted with a compound of the general formula (3)

where Z ₁ and Z ₂ mean the values defined in claim 1, a Y ₁ and Y ₂ independently mean the corresponding leaving group, such as halogen, (C ₁ -C ₆ ) alkoxy, -O-tosyl, -O-mesyl or - N1-imidazole, and then react with an amine of the general formula (4) or (5)

where R and R ₁ are as defined in claim 1, with the formation, respectively, of the desired compound of general formula (1) or a compound of general formula (6)

where R ₁ , R ₂ , R ₃ , R ₄ , Z ₁ and Z ₂ have the meanings specified in claim 1, if necessary, using diluents or excipients, after which the compound of general formula (6) is reacted with a compound of general formula (7)

where R is as defined in claim 1, and Y3 is the corresponding electrophilic leaving group, such as halogen, (C ₁ -C ₆ ) alkoxy, -O-tosyl, -O-mesyl or -N1-imidazole, with the formation of the desired compound (1) optionally using diluents or excipients, wherein R is other than hydrogen.

9. A method of treating a tumor disease of a mammal, characterized in that the mammal is administered at least one indole derivative according to one of claims 1 to 5 in a dose effective for treating a tumor disease.

10. A drug, characterized in that it contains at least one derivative of indole according to one of claims 1 to 5 as an active component, if necessary in a mixture with standard pharmaceutically acceptable excipients, additives and carriers.