HK1057549B - Heteroaryl derivatives and the use thereof as pharmaceuticals - Google Patents

Description

Heteroaryl derivatives and their use as medicaments

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The present invention relates to novel heteroaryl derivatives of formula 1, their preparation and their use as medicaments, in particular for the treatment of tumors.

In one aspect, the present invention provides novel acridine derivatives of formula 1

Formula 1

Wherein

R、R₁、R₂、R₃To any acridine carbon atom C₁-C₉The same as aboveOr are different and independently of one another represent hydrogen, straight-chain or branched (C)₁-C₈) Alkyl radicals, (C)₃-C₇) Cycloalkyl, linear or branched (C)₁-C₈) Alkylcarbonyl, preferably acetyl, straight or branched (C)₁-C₈) Alkoxy, halogen, aryl- (C)₁-C₈) Alkoxy, preferably benzyloxy or phenylethoxy, nitro, amino, mono- (C)₁-C₄) Alkylamino, di- (C)₁-C₄) -alkylamino, (C)₁-C₈) -alkoxycarbonylamino group, (C)₁-C₆) -alkoxycarbonylamino- (C)₁-C₈) Alkyl, cyano, straight or branched cyano- (C)₁-C₆) Alkyl, carboxyl, (C)₁-C₈) Alkoxycarbonyl, substituted by one or more fluorine atoms (C)₁-C₄) Alkyl, preferably trifluoromethyl, carboxy- (C)₁-C₈) -alkyl or (C)₁-C₈) -alkoxycarbonyl- (C)₁-C₆) -alkyl, (C)₂-C₆) Alkenyl, preferably allyl, (C)₂-C₆) Alkynyl, preferably ethynyl or propargyl, straight-chain or branched cyano- (C)₁-C₆) -alkyl, preferably cyanomethyl, aryl, wherein the aryl group may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: halogen, straight or branched chain (C)₁-C₈) Alkyl radicals, (C)₃-C₇) Cycloalkyl, carboxyl, linear or branched (C)₁-C₈) Alkoxycarbonyl, preferably tert-butoxycarbonyl, trifluoromethyl, hydroxy, straight-chain or branched (C)₁-C₈) Alkoxy, preferably methoxy or ethoxy, benzyloxy, nitro, amino, mono- (C)₁-C₄) Alkylamino, di- (C)₁-C₄) Alkylamino, cyano, straight-chain or branched cyano- (C)₁-C₆) -an alkyl group,

z is oxygen or sulfur, the radical being substituted on the acridine heterocycle

Carbon atom C attachable to acridine ring skeleton₁-C₉The above step (1);

p, Q independently of one another represent oxygen, or each represent two hydrogen atoms (i.e. -CH)₂-)；

X is nitrogen or C-R₅Wherein R is₅Represents hydrogen or (C)₁-C₆) An alkyl group;

n, m independently of one another represent an integer from 0 to 3, with the proviso that: when n is 0, X represents CR₅R₆Wherein R is₅And R₆Independently of one another, represents hydrogen or (C)₁-C₆) -alkyl, and the nitrogen atom adjacent to C ═ Z is replaced by a hydrogen atom or (C-C)₆) -alkyl substitution;

R₄represents a straight chain or branched chain (C)₁-C₂₀) -an alkyl group which may be saturated or unsaturated by having 1-3 double and/or triple bonds, and which may be unsubstituted or optionally substituted on the same or different carbon atoms by one, two or more aryl, heteroaryl, halogen, cyano, (C)₁-C₆) -alkoxycarbonylamino group, (C)₁-C₆) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino or di- (C)₁-C₄) -alkylamino substitution; (C)₆-C₁₄) -aryl, (C)₆-C₁₄) -aryl- (C)₁-C₄) -alkyl, or (C) containing one or more heteroatoms selected from N, O and S₂-C₁₀) -heteroaryl or (C)₂-C₁₀) -heteroaryl- (C)₁-C₄) -alkyl, wherein said (C)₁-C₄) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and wherein (C)₆-C₁₄) -aryl or (C)₂-C₁₀) -heteroaryl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: straight or branched chain (C)₁-C₈) Alkyl radicals, (C)₃-C₇) Cycloalkyl, halogen, cyano, (C)₁-C₆) -alkoxycarbonylamino group, (C)₁-C₆) -alkoxy, carboxy, (C)₁-C₈) Alkoxycarbonyl, linear or branched (C) substituted by one or more fluorine atoms₁-C₆) Alkyl, preferably trifluoromethyl, hydroxy, straight-chain or branched (C)₁-C₈) Alkoxy, preferably methoxy or ethoxy, where the adjacent oxygen atom may also pass through (C)₁-C₂) Alkylene, preferably methylene, bonded, benzyloxy, nitro, amino, mono- (C)₁-C₄) Alkylamino, di- (C)₁-C₄) -alkylamino, aryl, wherein the aryl group itself may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: straight or branched chain (C)₁-C₈) Alkyl radicals, (C)₃-C₇) Cycloalkyl, carboxyl, linear or branched (C)₁-C₈) Alkoxycarbonyl, trifluoromethyl, hydroxy, straight or branched (C)₁-C₈) Alkoxy, preferably methoxy or ethoxy, benzyloxy, nitro, amino, mono- (C)₁-C₄) Alkylamino, di- (C)₁-C₄) Alkylamino, cyano, straight-chain or branched cyano- (C)₁-C₆) -an alkyl group;

and structural isomers and stereoisomers, particularly tautomers, diastereomers and enantiomers, of the compounds of formula 1, and pharmaceutically acceptable salts, particularly acid addition salts thereof.

Thus, for example, a compound of the formula (1) having one or more chiral centers and present as a racemate may be separated into its optical isomers, i.e., enantiomers or diastereomers, by methods known per se. The separation can be carried out by chiral column separation, or by recrystallization from an optically active solvent, or derivatization with an optically active acid or base, or with an optically active reagent such as an optically active alcohol, followed by removal of the derivative group.

In addition, the acridine derivative of formula (1) can be converted into its salts, in particular for pharmaceutical use, into its physiologically acceptable salts with inorganic or organic acids. Acids suitable for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, acetic acid, tartaric acid, malic acid, embonic acid, malonic acid, trifluoroacetic acid or maleic acid.

In addition, if a sufficiently acidic group such as a carboxyl group is contained, the compound of formula (1) of the present invention can be converted into a salt thereof, particularly a physiologically acceptable salt thereof for pharmaceutical use, with an inorganic base or an organic base as necessary. Suitable bases for this purpose are, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lysine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

According to a preferred embodiment, the present invention provides an acridine derivative of formula 1, wherein R, R₁、R₂、R₃X, Z, P, Q, n and m have the abovementioned meanings, and

R₄represents a straight chain or branched chain (C)₁-C₂₀) -an alkyl group which may be saturated or unsaturated by having 1-3 double and/or triple bonds, and which may be unsubstituted or optionally substituted on the same or different carbon atoms by one, two or more aryl, heteroaryl, halogen, (C)₁-C₆) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino or di- (C)₁-C₄) -alkylamino substitution;

a phenyl ring or a naphthyl ring, each of which may be unsubstituted or mono-or polysubstituted, the same or different, by a substituent selected from the group consisting of: straight or branched chain (C)₁-C₈) Alkyl radicals, (C)₃-C₇) Cycloalkyl, halogen, cyano, (C)₁-C₆) -alkoxycarbonylamino group, (C)₁-C₆) -alkoxy, carboxy, (C)₁-C₈) Alkoxycarbonyl, linear or branched (C) substituted by one or more fluorine atoms₁-C₆) Alkyl, preferably trifluoromethyl, hydroxy, straight-chain or branched (C)₁-C₈) -an alkoxy group,preferably methoxy or ethoxy, where adjacent oxygen atoms may also pass through (C)₁-C₂) Alkylene, preferably methylene, bonded, benzyloxy, nitro, amino, mono- (C)₁-C₄) Alkylamino, di- (C)₁-C₄) -alkylamino, aryl, wherein the aryl group itself may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: straight or branched chain (C)₁-C₈) Alkyl radicals, (C)₃-C₇) Cycloalkyl, carboxyl, linear or branched (C)₁-C₈) Alkoxycarbonyl, trifluoromethyl, hydroxy, straight or branched (C)₁-C₈) Alkoxy, preferably methoxy or ethoxy, benzyloxy, nitro, amino, mono- (C)₁-C₄) Alkylamino, di- (C)₁-C₄) Alkylamino, cyano, straight-chain or branched cyano- (C)₁-C₆) -an alkyl group;

2-, 4-, 5-or 6-pyrimidinyl, or 2-, 4-, 5-or 6-pyrimidinyl- (C)₁-C₄) -alkyl, wherein said (C)₁-C₄) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 2-, 4-, 5-or 6-pyrimidinyl radical may be unsubstituted or mono-or trisubstituted, identically or differently, by substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

3-, 4-, 5-or 6-pyridazinyl, or 3-, 4-, 5-or 6-pyridazinyl- (C)₁-C₄) -alkyl, wherein said (C)₁-C₄) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 3-, 4-, 5-or 6-pyridazinyl group may be unsubstituted or mono-or trisubstituted, identically or differently, by substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

2-, 3-, 5-or 6-pyrazinyl, or 2-, 3-, 5-or 6-pyrazinyl- (C)₁-C₄) -alkyl, wherein said (C)₁-C₄) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 2-, 3-, 5-or 6-pyrazinyl group may be unsubstituted or mono-tri-substituted, identically or differently, with substituents selected from: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, or 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl- (C)₁-C₄) -alkyl radicalWherein said (C)₁-C₄) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl group may be unsubstituted or mono-or pentasubstituted, identically or differently, with substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

2-, 4-, 5-, 6-, 7-, or 8-quinazolinyl, or 2-, 4-, 5-, 6-, 7-, or 8-quinazolinyl- (C)₁-C₄) -alkyl, wherein said (C)₁-C₄) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: hydrogen, (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 2-, 4-, 5-, 6-, 7-, or 8-quinazolinyl group may be unsubstituted or mono-or pentasubstituted, identically or differently, with substituents selected from: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group; 2-, 3-, 5-, 6-, 7-, or 8-quinoxalinyl, or 2-, 3-, 5-, 6-, 7-, or 8-quinoxalinyl-, (C₁-C₄) -alkyl, wherein said (C)₁-C₄) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 2-, 3-, 5-, 6-, 7-, or 8-quinoxalinyl group can be unsubstituted or mono-pentasubstituted, identically or differently, with substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl (phthalazinyl), or 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl- (C)₁-C₄) -alkyl, wherein said (C)₁-C₄) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl group may be unsubstituted or mono-or pentasubstituted, identically or differently, with substituents selected from: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

2-3-, 4-, 5-, 6-, 7-or 8-quinolyl, or 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl- (C)₁-C₄) -alkyl, wherein said (C)₁-C₄) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl group may be unsubstituted or mono-or hexasubstituted, identically or differently, with substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, preferably methyl, particularly preferably 2-methyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolinyl, or 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolinyl- (C)₁-C₄) -alkyl, wherein said (C)₁-C₄) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolinyl group may be unsubstituted or mono-or hexasubstituted, identically or differently, with substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

2-, 6-, 8-or 9- [9H ]]-purinyl, or 2-, 6-, 8-or 9- [9H ]]-purinyl- (C)₁-C₄) -alkyl, wherein said (C)₁-C₄) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and 2-, 6-, 8-or 9- [9H]-a purinyl group may be unsubstituted or mono-or trisubstituted, identically or differently, by substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

2-, 6-, 7-or 8- [7H]-purinyl, or 2-, 6-, 7-or 8- [7H]-purinyl- (C)₁-C₄) -alkyl, wherein said (C)₁-C₄) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and 2-, 6-, 7-or 8- [7H]-a purinyl group may be unsubstituted or mono-or trisubstituted, identically or differently, by substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-acridinyl, or 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-acridinyl- (C)₁-C₄) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-acridinyl group may be unsubstituted or mono-or octasubstituted, identically or differently, with substituents selected from: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-phenanthridinyl, or 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-phenanthridinyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: hydrogen, (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-phenanthridinyl group may be unsubstituted or mono-or octasubstituted identically or differently with substituents selected from the group consisting of: (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy (C)₆-C₁₀) -aryl- (C)₁-C₆) Alkoxy, preferably benzyloxyCarboxyl group, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

2-, 3-, 4-, 5-or 6-pyridyl, wherein the 2-, 3-, 4-, 5-or 6-pyridyl may be unsubstituted or mono-or tetrasubstituted, identically or differently, by substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

2-, 3-, 4-, 5-or 6-pyridyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 2-, 3-, 4-, 5-or 6-pyridyl group may be unsubstituted or mono-or tetrasubstituted, identically or differently, by substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₈) -an alkyl group;

2-, 3-, 4-or 5-thienyl, or 2-, 3-, 4-or 5-thienyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and 2-, 3-, 4-or 5-thienyl may be unsubstituted or mono-or trisubstituted, identically or differently, by substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

2-, 4-, or 5-thiazolyl, or 2-, 4-, or 5-thiazolyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 2-, 4-, or 5-thiazolyl group may be unsubstituted or mono-or disubstituted by the same or different substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

3-, 4-, or 5-isothiazolyl, or 3-, 4-, or 5-isothiazolyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 3-, 4-, or 5-isothiazolyl group may be unsubstituted or mono-or di-substituted, identically or differently, with a substituent selected from: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

2-, 4-, 5-, 6-, or 7-benzothiazolyl, or 2-, 4-, 5-, 6-, or 7-benzothiazolyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and 2-, 4-, 5-, 6-, or 7-benzothiazolyl may be unsubstituted or mono-or tetrasubstituted, identically or differently, by substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

1-, 2-, 4-, or 5-imidazolyl, or 1-, 2-, 4-, or 5-imidazolyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 1-, 2-, 4-, or 5-imidazolyl group may be unsubstituted or mono-tri-substituted by the same or different substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

1-, 3-, 4-, or 5-pyrazolyl, or 1-, 3-, 4-, or 5-pyrazolyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and 1-, 3-, 4-or 5-pyrazolyl may be unsubstituted or mono-or trisubstituted, identically or differently, by substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

1-, 2-, 3-, 4-, or 5-pyrrolyl, or 1-, 2-, 3-, 4-, or 5-pyrrolyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 1-, 2-, 3-, 4-or 5-pyrrolyl group may be unsubstituted or mono-or tetrasubstituted, identically or differently, by substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₈) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

1-, 3-, or 5- [ 1.2.4%]-triazolyl, or 1-, 3-, or 5- [ 1.2.4%]-triazolyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: hydrogen, (C)₁-C₆) -alkyl, halogen and oxo (═ O), and 1-, 3-, or 5- [1.2.4]-triazolyl may be unsubstituted or mono-or disubstituted by identical or different substituents selected from the group consisting of: (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

1-, 4-, or 5- [1.2.3]-triazolyl, or 1-, 4-, or 5- [1.2.3 [ ]]-triazolyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and 1-, 4-, or 5- [1.2.3]-triazolyl may be unsubstituted or mono-or disubstituted by identical or different substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

1-or 5- [1H]-tetrazolyl, or 1-, or 5- [1H]-tetrazolyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and 1-, or 5- [1H]-tetrazolyl may be unsubstituted or substituted with: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

2-or 5- [2H]-tetrazolyl, or 2-or 5- [2H]-tetrazolyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and 2-or 5- [2H]-tetrazolyl may be unsubstituted or substituted with: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

2-, 4-, or 6- [1.3.5]-triazinyl, or 2-, 4-, or 6- [1.3.5]-triazinyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: hydrogen, (C)₁-C₆) -alkyl, halogen and oxo (═ O), and 2-, 4-, or 6- [1.3.5]-triazinyl may be unsubstituted or mono-or disubstituted by identical or different substituents selected from: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

2-, 4-, or 5-oxazolyl, or 2-, 4-, or 5-oxazolyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 2-, 4-, or 5-oxazolyl group may be unsubstituted or mono-or disubstituted by identical or different substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

3-, 4-, or 5-isoxazolyl, or 3-, 4-, or 5-isoxazolyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 3-, 4-, or 5-isoxazolyl group may be unsubstituted or mono-or disubstituted by identical or different substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group;

1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, or 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl- (C)₁-C₆) -alkyl, wherein said (C)₁-C₆) -alkyl may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: (C)₁-C₆) -alkyl, halogen and oxo (═ O), and the 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl group can be unsubstituted or mono-to hexasubstituted, identically or differently, with substituents selected from the group consisting of: hydrogen, (C)₁-C₆) Alkyl, halogen, nitro, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) -alkylamino, hydroxy, (C)₁-C₆) -alkoxy, benzyloxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) An alkoxycarbonylamino group, or (C) mono-or polysubstituted by fluorine₁-C₆) -alkyl, preferably trifluoromethyl, (C)₆-C₁₀) -aryl and (C)₆-C₁₀) -aryl- (C)₁-C₆) -an alkyl group,

and isomers thereof, particularly tautomers, diastereomers and enantiomers, and pharmaceutically acceptable salts, particularly acid addition salts thereof.

According to a further embodiment, the present invention provides an acridine derivative of formula (1), characterized in that, R, R₁、R₂、R₃X, Z, P, Q, n and m have the abovementioned meanings, and R₄Represents phenyl which is unsubstituted or substituted by 1 to 5 identical or different (C)₁-C₆) Alkoxy substitution, in which the adjacent oxygen atoms may also pass through (C)₁-C₂) -an alkylene linkage.

According to a further embodiment, the present invention provides an acridine derivative of formula (1), characterized in that, R, R₁、R₂、R₃X, Z, P, Q, n and m have the abovementioned meanings, and R₄Represents 3, 5-dimethoxyphenyl.

According to a further embodiment, the present invention provides acridine derivatives of formula (1), characterized in that R₄Having the above meaning, R, R₁、R₂、R₃Each represents a hydrogen atom, Z represents an oxygen atom, and X represents a nitrogen atom, and P and Q each represent two hydrogen atoms (i.e., -CH)₂-, m is 0, and n is the integer 2.

According to a further embodiment, the present invention provides an acridine derivative of formula (1), characterized in that, R, R₁、R₂、R₃Each represents a hydrogen atom, Z represents an oxygen atom, X represents a nitrogen atom, and P and Q each represent two hydrogen atoms (i.e., -CH)₂-, m is 0, n represents the integer 2, and R₄Represents 3, 5-dimethoxyphenyl.

According to another aspect, the present invention provides a method for preparing an acridine derivative according to any one of claims 1 to 6, characterized in that an acridine carboxylic acid of formula (2)

Formula 2

R, R therein₁、R₂、R₃Having the above-mentioned meaning, Z represents an oxygen or sulfur atom and Y represents a leaving group such as halogen, hydroxy, (C)₁-C₆) -alkoxy, preferably methoxy or ethoxy, -O-tosyl, -O-mesyl or imidazolyl,

with amines of formula (3)

Formula 3

Wherein R is₄X, P, Q, m and n are as defined above,

if appropriate with diluents and auxiliaries, to form the desired acridine derivatives.

The synthesis route is as follows:

the compounds of formula 1 can be obtained according to the following reaction scheme 1:

reaction scheme 1

The starting materials (2) and (3) are commercially available or can be obtained by methods known per se. The starting materials (2) and (3) are useful intermediates for preparing the acridine derivative of the formula (1) of the present invention.

The solvents and auxiliaries used, if appropriate, and the reaction parameters used, such as reaction temperature and reaction time, are known to the person skilled in the art.

The acridine derivatives of formula (1) of the present invention are suitable for use as pharmaceuticals, in particular as antitumor agents, for the treatment of mammals, in particular humans, but also for the treatment of domesticated animals such as horses, cattle, dogs, cats, rabbits, sheep, poultry, etc.

According to another aspect, the present invention provides a method for controlling tumors in mammals, particularly humans, characterized in that a tumor-treating effective amount of at least one acridine derivative of formula (1) is administered to the mammal. The therapeutically effective dose of the acridinium derivatives of the present invention depends on, inter alia, the nature and stage of the tumorous disease, the age and sex of the patient, the type of administration and the duration of the treatment. Administration can be by oral, rectal, buccal (e.g., sublingual), parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), topical, or transdermal routes.

According to a further aspect, the present invention provides a medicament for the treatment of tumors, characterized in that it comprises as active ingredient at least one acridine derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, if appropriate together with conventional pharmaceutically acceptable adjuvants, additives and carriers. These drugs may be solid, semi-solid, liquid or aerosol. Suitable solid formulations are, for example, capsules, powders, granules, tablets. Suitable semisolid formulations are, for example, ointments, creams, gels, pastes, suspensions, oil-in-water or water-in-oil emulsions. Suitable liquid formulations are, for example, sterile aqueous formulations for parenteral administration which are isotonic with the blood of the patient.

The present invention is illustrated in more detail by the following examples, but the present invention is not limited to the examples.

Examples

1- (3, 5-Dimethoxyphenyl) -4- (9-acridinylcarbonyl) piperazine (D-43411)

8g (35.84mmol) of acridine-9-carboxylic acid are placed in 300ml of DMF with stirring. To this mixture was added, with further stirring, 5.79g (57.34mmol) of N-methylmorpholine followed by the successive addition of 24.24g (46.59mmol) of Py-BOP (1-benzotriazolyltripropyrrolidinyl * hexafluorophosphate) and 7.96g (35.81mmol) of 1- (3, 5-dimethoxyphenyl) piperazine in 50ml of DMF. The mixture was stirred at room temperature for 12 hours, DMF was distilled off under reduced pressure and the residue was purified by means of a silica gel column (Kieselgel 60, from Merck AG, Darmstadt) using methylene chloride/methanol/(95: 5v/v) as mobile phase.

Yield: 12.9 (84.2% yield)

m.p.：172-175℃。

1. Antiproliferative effect in different tumor cell lines

In the proliferation assay, the anti-proliferative activity of substance D-43411 was determined using established tumor cell lines. In the test used, the cell dehydrogenation activity is determined, which enables the viability of the cells to be determined and indirectly the number of cells. The cell lines used were the human cervical cancer cell line KB/HeLa (ATCC/CCL17), the murine lymphocytic leukemia L1210(ATCC CCL-219), the human breast cancer cell line (MCF7/ATCC HTB22) and the ovarian adenocarcinoma cell line SKOV-3(ATCC HTB 77). They are established cell lines, well characterized, obtained from the ATCC and cultured.

The results shown in Table 1 demonstrate the highly potent antiproliferative effect of D-43411 in the cell lines SKOV-3, L-1210 and HeLa/KB. Since the MCF7 line grew particularly slowly, the effect of D-43411 was very small during the 48 hour test period (18% inhibition at 3.16. mu.g/ml; therefore determined to be > 3.16).

TABLE 1 in vitro cytotoxicity in tumor cell lines (values determined from 5 concentrations)

2. Method of producing a composite material

XTT assay for determining cellular dehydrogenase activity

Adherently growing tumor cell lines HeLa/KB, SKOV-3 and MCF7 and suspension growing L1210 leukemia lines were grown in an incubator with a gas inlet at 37 ℃ under standard conditions with 5% CO₂And 95% air humidity. On day 1 of the test, adherent cells were detached using trypsin/EDTA and pelleted by centrifugation. The cell pellet was then resuspended in RPMI medium at the appropriate cell concentration and transferred to a 96-well microtiter plate. The microtiter plates were then incubated overnight in an incubator with a gas inlet. The test substances were made up as stock solutions in DMSO and diluted with culture medium to the desired concentration on day 2 of the test. The substances in the medium were then added to the cells and cultured in an incubator with a gas inlet for 45 hours. Cells not treated with test substance were used as control.

For the XTT assay, 1mg/ml XTT (3' - [1- (phenylaminocarbonyl) -3, 4-tetrazolium]Sodium bis (4-methoxy-6-nitro) benzenesulfonate) was dissolved in RPMI-1640 medium without phenol red. In addition, a solution of 0.383mg/ml PMS (N-methyl dibenzopyrazine methyl sulfate) in Phosphate Buffered Saline (PBS) was prepared. On day 4 of the test, 75 μ l/well of XTT-PMS compound was pipetted into a cell plate that had been incubated with the test for 45 hours. For this purpose,the XTT solution was mixed with the PMS solution at a ratio of 50: 1(v/v) just prior to use. The cell plates were then incubated in an incubator with a gas inlet for 3 hours and the Optical Density (OD) was measured in a luminometer_490nm)。

Using the obtained OD_490nmPercent inhibition relative to control was calculated. Antiproliferative activity was assessed using regression analysis.

Example I

Tablets containing 50mg of active compound

Consists of the following components:

(1) active Compound 50.0mg

(2) Lactose 98.0mg

(3) Corn starch 50.0mg

(4) Polyvinylpyrrolidone 15.0mg

(5) Magnesium stearate 2.0mg

In total: 215.0mg

Preparation:

the components (1), (2) and (3) are mixed and granulated with the aqueous solution of (4). Mixing the desired granules with (5). The mixture was tabletted.

Example II

Capsules containing 50mg of active compound

Consists of the following components:

(1) active Compound 50.0mg

(2) Dried corn starch 58.0mg

(3) Lactose powder 50.0mg

(4) Magnesium stearate 2.0mg

In total: 160.0mg

Preparation:

grinding (1) and (3). The milled material was added to the mixture of (2) and (4) with vigorous mixing. The powder mixture was filled into size 3 hard gelatin capsules on a capsule filling machine.

Claims (19)

1. Acridine derivatives of formula 1

Formula 1

Wherein

R、R₁、R₂、R₃To any acridine carbon atom C₁-C₉The above, identical or different, and independently of one another represent hydrogen, straight-chain or branched (C)₁-C₈) Alkyl radicals, (C)₃-C₇) Cycloalkyl, linear or branched (C)₁-C₈) Alkylcarbonyl, straight or branched chain (C)₁-C₈) Alkoxy, halogen, aryl- (C)₁-C₈) Alkoxy, nitro, amino, mono- (C)₁-C₄) Alkylamino, di- (C)₁-C₄) -alkylamino, (C)₁-C₈) -alkoxycarbonylamino group, (C)₁-C₆) -alkoxycarbonylamino- (C)₁-C₈) Alkyl, cyano, straight or branched cyano- (C)₁-C₆) Alkyl, carboxyl, (C)₁-C₈) Alkoxycarbonyl, substituted by one or more fluorine atoms (C)₁-C₄) Alkyl, carboxy- (C)₁-C₈) -alkyl or (C)₁-C₈) -alkoxycarbonyl- (C)₁-C₆) -alkyl, (C)₂-C₆) -alkenyl, (C)₂-C₆) Alkynyl, straight-chain or branched cyano- (C)₁-C₆) -alkyl, aryl, wherein the aryl group may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: halogen, straight or branched chain (C)₁-C₈) Alkyl radicals, (C)₃-C₇) Cycloalkyl, carboxyl, linear or branched (C)₁-C₈) Alkoxycarbonyl, trifluoromethyl, hydroxy, straight or branched (C)₁-C₈) Alkoxy, benzyloxy, nitro, amino, mono- (C)₁-C₄) Alkylamino, di- (C)₁-C₄) Alkylamino, cyano, straight-chain or branched cyano- (C)₁-C₆) -an alkyl group,

z is oxygen or sulfur, the radical being substituted on the acridine heterocycle

Carbon atom C bound to the acridine ring skeleton₉The above step (1);

p, Q each represents two hydrogen atoms, i.e. -CH₂-；

X is nitrogen;

n＝2；

m＝0；

R₄is represented by (C)₆-C₁₄) -aryl, wherein (C)₆-C₁₄) -an aryl group may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: straight or branched chain (C)₁-C₈) Alkyl radicals, (C)₃-C₇) Cycloalkyl, halogen, cyano, (C)₁-C₆) Alkoxy, linear or branched (C) substituted by one or more fluorine atoms₁-C₆) -an alkyl group;

or a pharmaceutically acceptable salt of the compound of formula 1.

2. The acridine derivative of claim 1, characterized in that R, R₁、R₂、R₃X, Z, P, Q, n and m have the meanings given in claim 1, and

R₄represents a phenyl ring or a naphthyl ring, each of which may be unsubstituted or mono-or polysubstituted, identically or differently, by substituents selected from the group consisting of: straight or branched chain (C)₁-C₈) Alkyl radicals, (C)₃-C₇) Cycloalkyl, halogen, cyano, (C)₁-C₆) Alkoxy, linear or branched (C) substituted by one or more fluorine atoms₁-C₆) -an alkyl group.

3. The acridine derivative of claim 1, wherein R, R₁、R₂、R₃Together with each other independently of one another, from acetyl, benzyloxy, phenylethoxy, trifluoromethyl, allyl, ethynyl, propargyl and cyanomethyl.

4. The acridine derivative of claim 1, wherein R, R₁、R₂、R₃At least one of which is selected independently of one another from aryl groups, which may be identically or differently mono-or polysubstituted by substituents selected from the group consisting of: t-butyloxycarbonyl, methoxy or ethoxy.

5. The process of claim 1Acridine derivative, wherein the (C)₆-C₁₄) Aryl groups may be substituted identically or differently by substituents selected from trifluoromethyl, methoxy and ethoxy.

6. The acridine derivative of claim 1, wherein said adjacent oxygen atoms may be connected by a methylene group.

7. The acridine derivative of claim 1, wherein for R₄The aryl group may be substituted with a methoxy group or an ethoxy group.

8. The acridine derivative of claim 1, which is an acid addition salt.

9. The acridine derivative of claim 1, wherein R₄Represents a phenyl ring or a naphthyl ring, each of which may be unsubstituted or mono-or polysubstituted by substituents selected from the group consisting of: trifluoromethyl, methoxy, ethoxy.

10. The acridine derivative of any one of claims 1-9, characterized in that R, R₁、R₂、R₃And Z has the meaning given in any one of claims 1 to 9, P, Q representing two hydrogen atoms, respectively-CH₂-, X is nitrogen, n ═ 2, m ═ 0, and R₄Represents phenyl which is unsubstituted or substituted by 1 to 5 identical or different (C)₁-C₆) Alkoxy substitution, in which the adjacent oxygen atoms may also pass through (C)₁-C₂) -an alkylene linkage.

11. The acridine derivative of any one of claims 1-9, characterized in that R, R₁、R₂、R₃And Z has the meaning given in any one of claims 1 to 9, P, Q representing two hydrogen atoms, respectively-CH₂-, X is nitrogen, n ═ 2, m ═ 0, and R₄Represents 3, 5-dimethoxyphenyl。

12. The acridine derivative of any one of claims 1-9, characterized in that R₄Has the meaning given in any of claims 1 to 9, R, R₁、R₂、R₃Each represents a hydrogen atom, and Z represents an oxygen atom.

13. The acridine derivative of any one of claims 1-9, characterized in that R, R₁、R₂、R₃Each represents a hydrogen atom, Z represents an oxygen atom, and R₄Represents 3, 5-dimethoxyphenyl.

14. Use of an acridine derivative according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment of mammalian tumours.

15. Method for producing acridine derivatives according to one of claims 1 to 13, characterized in that acridine carboxylic acid of formula (2)

Formula 2

R, R therein₁、R₂、R₃Having the meaning given in any one of claims 1 to 13, Z represents an oxygen or sulphur atom and Y represents a leaving group,

with amines of formula (3)

Formula 3

Wherein R is₄Having the definition of any of claims 1 to 13, P, Q representing two eachA hydrogen atom being-CH₂-, X is nitrogen, n is 2, m is 0,

the desired acridine derivative is formed.

16. The method according to claim 15, wherein Y in the acridine carboxylic acid of formula (2) is halogen, hydroxy, (C) is₁-C₆) Alkoxy, -O-tosyl, -O-mesyl or imidazolyl.

17. The method according to claim 16, wherein Y in the acridine carboxylic acid of formula (2) is methoxy or ethoxy.

18. The process of any one of claims 15-17, wherein the reaction is carried out with the use of a diluent and an adjuvant.

19. A medicament, characterized in that it comprises at least one acridine derivative according to any one of claims 1 to 13 as active ingredient together with customary pharmaceutically acceptable adjuvants, additives and carriers.