EP1581534A2

EP1581534A2 - Tumour-inhibiting annellated azepinone derivatives

Info

Publication number: EP1581534A2
Application number: EP03767828A
Authority: EP
Inventors: Bernhard Keppler
Original assignee: Faustus Forschungs Cie Translational Cancer Research GmbH
Current assignee: Faustus Forschungs Cie Translational Cancer Research GmbH
Priority date: 2002-12-23
Filing date: 2003-12-23
Publication date: 2005-10-05
Also published as: CA2551576A1; WO2004058766A2; JP2006515591A; DE10260618A1; US20060009445A1; DE10260618B4; WO2004058766A3; AU2003292264A1

Abstract

The invention relates to annellated azepinone derivatives, to a method for the production thereof, to metal complexes of the annellated azepinone derivatives, and to the use of the same for treating tumour diseases.

Description

Anti-tumor fused azepinone derivatives

The present invention relates to fused azepinone derivatives, a process for their preparation, metal complexes of fused azepinone derivatives, and their use for the treatment of tumor diseases.

The exact and gradual sequence of the individual steps of the cell cycle is an essential part of normal cell proliferation. The different forms of cyclin-dependent kinases (CDKs) are primarily responsible for the transition of the individual stages into one another. A deregulation of the activity of cyclin dependent kinases can be observed in many human tumors. These are based either on the overexpression of cyclins or on the lack of corresponding natural inhibitors due to genetic changes. Therefore, CDKs represent an attractive class of targets for the chemotherapeutic control of tumor diseases. However, there are so far only a few substances that are able to act as selective CDK inhibitors, with flavopiridol, roscovitins and the purvalanols being important compounds or connection classes are to be mentioned.

Annellated azepinones represent another important class of CDK inhibitors. The basic body of this class of compounds allows a number of modifications to optimize the structure with a view to the biological effectiveness. The class of indolo [3,2-d] benzazepinones in particular is a class of compounds whose potential as CDK inhibitors is currently being intensively investigated.

For example, substituted azepinones are described in WO 99/65910 as inhibitors of cyclin-dependent kinases. WO 01/60374 also discloses the use of suitably substituted azepinone derivatives for the production of medicaments which contain inhibitors for GSK-3β, CDK1 or CDK5. Both in WO 99/65910 and in WO 01/60374, the substitution pattern on the two aryl rings of the tetracyclic base body of the corresponding azepinone derivatives was varied. Replacing the lactam carbonyl group in the azepinone ring with a thioimidate or a hydroxyimidate group did not result in any improvement in biological activity (Schultz et al. J. Med. Chem. 1999, 42, 2909-2919).

The object of the present invention is to provide compounds for the treatment of cancer which are highly effective.

The object is achieved by a compound of the general formula (I) or (II)

in which

X is selected from the following groups (a), (b), (c)

and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, wherein

R ¹ , R ² and R ¹¹ -R ^{15 are} independently selected from the group consisting of hydrogen, halogen, hydroxyl and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, and

R ³ -R ¹⁰ and R ¹⁶ -R ^{20 are} independently selected from the group consisting of hydrogen, amino, nitro, cyano, formyl, carboxyl, SO ₃ H, SO ₃ M _b , where M is a physiologically compatible cation, hydroxy , Halogen and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl, alkynyl, alkoxy, alkylmercapto and dialkylamino, and

physiologically acceptable addition salts thereof.

Furthermore, the object of the present invention is achieved by a complex of the general formula (III)

[M _a ^{i +} Y _x ⁿ - LJ ^{[nx + z)] +} [i- (nx + z)] / n Y ^{n "} (III)

where L is a group of the general formula (IV),

(IV), wherein

R ¹ and R ^{2 are} as defined above,

R ³ -R ¹⁰ and R ¹⁶ -R ^{20 are} as defined above, and

M _a Ga, Fe, Ru, or La, Y is a physiologically acceptable anion, i is 2 or 3, n is 1 or 2, x is 0, 1, 2, or 3, z is 1, 2 or 3, nx + z <i,

and physiologically acceptable addition salts thereof.

The present invention further relates to a complex of the general formula (III ')

[MaLzf j7p Y ^{p "} n, wherein

j is 0, 1 or 2; p is 1 or 2, and

M _a , L and Y are as defined above.

The invention further relates to a compound of the general formula (VI)

wherein

R ²¹ and R ^{22 are} independently selected from the group consisting of hydrogen, halogen, hydroxyl and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl,

R ²³ to R ^{30 are} independently selected from the group consisting of hydrogen, amino, nitro, cyano, formyl, carboxyl, hydroxy, halogen, SO ₃ H, SO ₃ M _b , where M _{b is} a physiologically acceptable cation, and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl, alkynyl, alkoxy, alkylmercapto and dialkylamino,

where at least one of the groups R ^ ^b to R ^{M is} SO ₃ H or SO ₃ M _b , where M is a physiologically tolerated cation, and physiologically acceptable addition salts thereof.

The present invention further relates to a process for the preparation of a complex of the general formula (III)

[M _a i '+ - _v Yx n ^ - _| Tl [i- (nx + z)] + [i- (nx + z)] / n Y ^π (III)

where a compound L of the general formula (IV),

(IV) in which

, u, -nd- _D R1 ^η 6-R _D 2 ^z 0 ^{u are} as defined above,

is reacted with a compound of the general formula (V),

M _a Y _n (V),

in which M _a and Y are as defined above and m is 1, 2 or 3, and

i, n, x, and z are as defined above.

The present invention further relates to a process for the preparation of a complex of the general formula (IM ')

[M _a L ₂ ] ^{j +} j / p Y ^{p "} (MI '),

where a compound L of the general formula (IV),

(IV) in which

R ¹ and R ^{2 are} as defined above,

R ³ -R ¹⁰ and R ¹⁶ -R ^{20 are} as defined above,

is reacted with a compound of the general formula (V), M _a Y _q (V),

in which

M _{a is} as defined above,

Y is a physiologically acceptable anion,

q is 1, 2 or 3, and

j and p are as defined above.

Preferably, m or q is 3 when Y is a monovalent anion.

Furthermore, alkyl in the sense of the present invention preferably contain 1 to 10, more preferably 1 to 6 and in particular 1 to 3 carbon atoms, alkenyl or alkynyl preferably 2 to 10, more preferably 2 to 6 and in particular 2 to 3 carbon atoms, cycloalkyl or cycloalkenyl, preferably 3 to 10, more preferably 3 to 8 and especially 3 to 6 carbon atoms and aryl preferably 6 to 14, more preferably 6 to 10 and especially 6 carbon atoms.

If the following groups of R 1 and R ₂ ; R ₃ to R ₆ ; R to R ₁₀ ; Rn to R-ι; R-I6 to R ₂₀ ; R ₂ ι and R ₂₂ ; R ₂₃ to R ₂₆ ; R ₂₇ to R ₃₀ ; and X in the general formulas (I), (II), (IV) or (VI) are substituted, the substituents in these groups are independently of one another preferably halogen, hydroxyl, alkyl, alkoxy, alkoxycarbonyl, alkylmercapto, amino, dialkylamino, dialkylaminocarbonyl and / or nitrile, more preferably hydroxyl, amino and / or CC ₄ dialkylamino and in particular hydroxyl and / or CrC ₄ dialkylamino. Furthermore, 1 to 3 substituents, in particular 1 substituent, are preferably present.

Furthermore, substituted groups R ³ -R ¹⁰ , R ⁶ -R ²⁰ and X in the general formulas (I), (II) or (IV) and R ²³ -R ³⁰ in the general formula (VI) are preferred independently selected from the group consisting of haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkylene, alkoxycarbonyl, alkoxycarbonylalkylene, alkylmercapto, alkylmercaptoalkylene, dialkylamino, dialkylaminoalkylene, dialkylaminocarbonyl, dialkylaminocarbonylalkylene and alkyl nitrile.

Furthermore, R ¹ , R ² and R ¹¹ -R ¹⁵ in the general formulas (I), (II) or (IV) and R ²¹ and R ²² in the general formula (VI) are preferably selected independently of one another from the group consisting of Hydrogen, dC ₆ - alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, C ₆ - C ₄ aryl, halogen and hydroxyl , more preferably from hydrogen and C-rC ₆ alkyl and especially hydrogen.

Furthermore, R ³ -R ¹⁰ , R ¹⁶ -R ²⁰ in the general formulas (I), (II) or (IV) and R ²³ -R ³⁰ in the general formula (VI) are preferably selected independently of one another from the group consisting of Hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ -

Alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, C ₆ -C ₁₄ aryl,

Amino, nitro, cyano, formyl, carboxyl, S0 ₃ H, SO ₃ M, where M _{b is} a physiologically compatible cation, hydroxy, halogen, C 1 -C ₄ -haloalkyl, dd-hydroxyalkyl, d-Ot-alkyl nitrile, dd- Alkoxy, dd-alkoxy-dd-alkylene, dd-alkylmercapto, dC -alkylmercapto-CrC -alkylene, Cι-C ₄ -alkoxycarbonyl, dd-alkoxycarbonyl-C-rd-alkylene, di-dC ₄ -alkyl-amino, di- dC ₄ -alkylamino- dd-alkylene, di-dC -alkylaminocarbonyl and di-dC ₄ -alkylaminocarbonyl-

C 1 -C ₄ -alkylene, more preferably from hydrogen, nitro, halogen and dC ₆ - alkyl, and in particular from hydrogen and halogen.

Furthermore, R ¹ , R ² and R ¹ -R ¹⁵ in the general formulas (I), (II) or (IV) and R ²¹ and R ²² in the general formula (VI) are preferably selected independently of one another from the group consisting of Hydrogen, dC ₆ - alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, C ₆ - C ₁₄ aryl, halogen and hydroxyl , more preferably from hydrogen and dC ₆ - alkyl and especially hydrogen, and

R ³ -R ¹⁰ , R ¹⁶ -R ²⁰ in the general formulas (I), (II) or (IV) and R ²³ -R ³⁰ in the general formula (VI) independently of one another selected from the group consisting of hydrogen, CC ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkyny), C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ -Cycloalkenyl, C ₆ -C ₁ -aryl, amino, nitro, cyano, formyl, carboxyl, SO ₃ H, SO ₃ M _b , where M _{b is} a physiologically compatible cation, hydroxy, halogen, CC ₄ -haloalkyl, Cι- C ₄ hydroxyalkyl, C ₄ alkyl nitrile, d C ₄ alkoxy, CrC ₄ alkoxy dC ₄ alkylene, dC ₄ alkyl mercapto, CC ₄ alkyl mercapto C ₄ alkylene, dC ₄ alkoxycarbonyl , dd-alkoxycarbonyl-Ct-C ₄ -alkylene, di-dd-alkylamino, di-dd-alkylamino-dd-alkylene, di-dd-alkylaminocarbonyl and di-dd-alkylaminocarbonyl-dd-alkylene, more preferably from hydrogen , Nitro, halogen and -CC ₆ alkyl, and in particular from hydrogen and halogen.

R ¹ -R ⁶ and R ¹¹ -R ²⁰ in the general formulas (I), (II) or (IV) are particularly preferably hydrogen, and

R ⁷ -R ¹⁰ are independently selected from the group consisting of hydrogen, -CC ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₅ cycloalkyl, C ₃ - , C ₆ -cycloalkenyl, C ₆ -C ₁₄ -aryl, amino, nitro, cyano, formyl, carboxyl, SO ₃ H, SO ₃ M _b , where M is a physiologically compatible cation, hydroxy, halogen, dC ₄ -haloalkyl, dC ₄ -hydroxyalkyl, CrC ₄ -alky) nitrile, CC ₄ -alkoxy, Cd-alkoxy-dC ₄ -alkylene, Cι-C -alkylmercapto, C-ι-C ₄ -alkylmercapto-dC ₄ -alkylene, dd-alkoxycarbonyl , dC ₄ -alkoxycarbonyl-CrC ₄ -alkylene, di-dd-alkylamino, di-CrC ₄ -alkylamino-dC ₄ -alkylene, di-Cι-C ₄ -alkylaminocarbonyl and Di- d ~ C ₄ -alkylaminocarbonyl-d ~ d-alkylene,

wherein at least one of the substituents R ⁷ -R ^{10 is} not hydrogen.

R ¹ -R ⁸ and R ¹⁰ -R ²⁰ in the general formulas (I), (II) or (IV) are very particularly preferably hydrogen,

and R ⁹ is nitro, cyano, halogen or trifluoromethyl, in particular R ^{9 is} a nitro group or a halogen, bromine being very particularly preferred among the halogens. Furthermore, M _a in the general formulas (III), (III '), (V) or (V) is preferably Ga.

R ²¹ -R ²⁸ and R ³⁰ in the general formula (VI) are particularly preferably hydrogen or dC ₆ -alkyl, in particular hydrogen. R ²⁹ is particularly preferably SO ₃ H or SO ₃ M _b , where M _{b is} a physiologically compatible cation.

Furthermore, R ²¹ -R ²⁸ and R ³⁰ in the general formula (VI) are preferably hydrogen and R ²⁹ SO ₃ H or SO ₃ M _bl wherein M is a physiologically tolerated cation.

Furthermore, M is preferably sodium, potassium or ammonium.

Furthermore, X is preferably -CC ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl or C ₆ -C ₄ aryl , The substituents of X are preferably selected from hydroxyl, amino and dC ₄ dialkylamino.

XCC ₆ alkyl is particularly preferred. The substituents of X are particularly preferably selected from hydroxyl and dC ₄ dialkylamino.

In particular, X is dC ₆ alkyl and substituted by hydroxyl or dd-dialkylamino.

The connections KP1428, KP1436, KP1437, KP1438, KP1472 and KP1473 shown in the examples are particularly preferred. The compound KP1428 can contain CH ₃ OH from the synthesis. Furthermore, the compounds KP1437 and KP1438 can contain water and the compounds KP1472 and KP1473 from the synthesis CH ₃ CH ₂ OH.

Organic or inorganic addition salts can be formed with the following anions:

Chloride, bromide, phosphate, carbonate, nitrate, perchlorate, sulfate, citrate, lactate, Tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, glycollate, methanesulfonate, formate, malonate, naphthalene-2-sulfonate, salicylate and / or acetate.

H, sodium and / or potassium cations can be used as possible cations.

Y is preferably selected from the group consisting of halogens, pseudohalogens, nitrate, carboxylate, sulfate, carbonate, hydrogen phosphate, tartrate, malonate, oxalate and R ^" COO, where R ^{" is} hydrogen, Ci-Cβ-alkyl, C ₂ - Cβ-alkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, C ₆ -C ₁₄ aryl, or a heterocycle.

Y is particularly preferably a halogen, in particular chlorine.

The compounds or complexes according to the invention can contain water of crystallization or solvent molecules such as methanol or ethanol.

In the general formula (III), i is preferably 3. Furthermore, i is 2 or 3 if M _{a is} Ru or Fe, ie is in oxidation state II or III, and 3 if M _{a is} Ga, ie in oxidation state III present

In the general formula (III), n is preferably 1. Furthermore, x is preferably 0 or 1 and in particular 0. In a further preferred embodiment, z is 1 or 2 and in particular 2.

In the general formula (III '), j is preferably 0 or 1. More preferably, j is 0 or 1 if M _{a is} Ru or Fe, ie is in the oxidation state II or III, and 1 if M _{a is} Ga, ie in oxidation level III is present.

The compound according to the invention can be used for the prophylaxis and / or treatment of cancer.

The following is the medicament containing an invention Connection, described in more detail.

The medicament according to the invention is administered primarily intravenously, but also intramuscularly, intraperitoneally, subcutaneously or orally. External application is also possible. Administration by intravenous injection or intravenous infusion is preferred.

The medicament is produced by methods known per se, the compound according to the invention being used as such or, if appropriate, in combination with suitable pharmaceutical carriers. If the medicament according to the invention contains pharmaceutical carriers in addition to the active substance, the active substance content of this mixture is 0.1 to 99.5, preferably 0.5 to 95% by weight of the total mixture.

The medicament according to the invention can be used in any suitable formulation, provided that the formation or maintenance of sufficient active substance levels is ensured. This can be achieved, for example, by oral or parenteral administration in suitable doses. The pharmaceutical preparation of the active ingredient is advantageously in the form of unit doses which are tailored to the desired administration. A unit dose can be, for example, a tablet, a dragee, a capsule, a suppository or a measured volume of a powder, a granulate, a solution, an emulsion or a suspension.

For the purposes of the present invention, “unit dose” is understood to mean a physically determined unit which contains an individual amount of the active ingredient in combination with a pharmaceutical carrier and whose active ingredient content corresponds to a fraction or multiples of a single therapeutic dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half, a third or a quarter of a daily dose. When only a fraction, such as half or a quarter, of the unit dose is needed for a single therapeutic administration the unit dose is advantageously divisible, for example in the form of a tablet with a notch.

The pharmaceuticals according to the invention, if they are in unit doses and for applications e.g. are intended for humans, contain about 0.1 to 500 mg, preferably 10 to 200 mg and in particular 50 to 150 mg of active ingredient.

In general, in human medicine the active ingredient (s) are administered in a daily dose of 0.1 to 5, preferably 1 to 3 mg / kg body weight, optionally in the form of several, preferably 1 to 3, single doses to achieve the desired results. A single dose contains the active ingredient (s) in amounts of 0.1 to 5, preferably 1 to 3 mg / kg body weight. Similar doses can be used in oral treatment.

The therapeutic administration of the medicament according to the invention can take place 1 to 4 times a day at fixed or varying times, e.g. before meals and / or in the evening. However, it may be necessary to deviate from the doses mentioned, depending on the type, body weight and age of the individuals to be treated, the type and severity of the disease, the type of preparation and administration of the medicinal product, and the period or Interval within which the administration takes place. In some cases, it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient must be exceeded. It may also be useful to administer the medication only once or several days apart.

Any specialist, based on his or her specialist knowledge, can determine the required optimal dosage and type of application of the active ingredients.

The pharmaceuticals according to the invention generally consist of the compounds according to the invention and non-toxic, pharmaceutical compatible pharmaceutical carriers which are used as admixtures or diluents, for example in solid, semi-solid or liquid form or as enveloping agents, for example in the form of a capsule, a tablet cover, a sachet or another container for the therapeutically active ingredient. A carrier can serve, for example, as a mediator for the absorption of pharmaceuticals by the body, as a formulation aid, as a sweetener, as a taste corrector, as a color or as a preservative.

For oral use e.g. Tablets dragees, hard and soft capsules, e.g. come from gelatin, dispersible powders, granules, aqueous and oily suspensions, emulsions, solutions or syrups.

Tablets can contain inert diluents, e.g. Calcium carbonate, calcium phosphate, sodium phosphate or lactose; Granulation and

Distribution means, e.g. Corn starch or alginates; Binders, e.g. Strength,

Gelatin or acacia; and lubricants, e.g. Aluminum or

Magnesium stearate, talc or silicone oil. You can also be provided with a coating, which can also be such that it delayed dissolution and absorption of the drug preparation in the

Gastrointestinal tract so that e.g. better tolerance,

Contracting or retardation is achieved. Gelatin capsules can

Drug mixed with a solid, e.g. Calcium carbonate or kaolin, or an oily, e.g. Olive, peanut, or paraffin oil, diluent included.

Aqueous suspensions can include suspending agents, e.g.

Sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth or acacia; Dispersing and wetting agents, for example polyoxyethylene stearate, heptadecaethyleneoxycatanol, polyoxyethylene sorbitol monooleate or lecithin; Preservatives, for example methyl or propyl hydroxybenzoates; Flavoring agents; Sweeteners, for example sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup, contain. Oily suspensions can include peanut, olive, sesame, coconut or

Paraffin oil and thickeners such as e.g. Beeswax, hard paraffin or

Cetyl alcohol; also sweeteners, flavoring agents and antioxidants.

Water-dispersible powders and granules may contain the compound of the invention in admixture with dispersing, wetting and suspending agents e.g. the above, as well as with sweeteners, flavorings and colorants.

Emulsions can e.g. Olive, peanut, or paraffin oil in addition to emulsifiers, such as Acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweeteners and flavoring agents.

Aqueous solutions can contain preservatives, e.g. Methyl or propyl hydroxybenzoates; Thickener; Flavoring agents; Sweeteners, e.g. Contain sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup, as well as flavorings and colorings.

Sterile injectable, aqueous solutions, isotonic saline solutions or other solutions are used for parenteral use of the medicinal substances.

The following examples illustrate the invention. Reaction of ethyl anthranilate with ethyl succinate (11 (JACS, 1958, 80, 2172):

(1)

A mixture consisting of 14.7 g of ethyl succinate, 10.3 g of ethyl anthranilate and 2.14 g of sodium hydride was heated under reflux in 140 ml of dry toluene for 3 hours with stirring. The reaction mixture was left to stand overnight, and then 75 mL of 10% hydrochloric acid was slowly added. The precipitate that formed was filtered off and recrystallized three times from ethanol. Yield: 4.5 g (29.5%), m.p .: 210-213 ° C; IR: 1673 cm ^"1 (conjugated ester), 1648 cm ^{" 1} (amide), 1623 cm ^"1 (C = C); λ _max (ethanol) 228-229 nm (ε = 29260), 239 nm (ε = 19580 ) sh, 293-296 nm (ε = 12200). Anal. calculation for C ₁₂ H ₁₃ NO ₄ (235.24): C, 63.15; H, 5-30; N, 5.67. Found: C, 63.31; H , 5.45; N, 5.78.

2.3.4.5-Tetrahvdro-1H-1-benzazepine-2.5-dione (Aren. Pharm. 1991, 324, 579):

494 mg (2 mmol) 1 were heated to 150 ° C. with 0.07 ml (3.9 mmol) water in 10 ml DMSO while stirring under N ₂ . After 1 h it was poured into 50 ml of water and extracted 10 times with 10 ml of CH ₂ CI ₂ each. The united org. Phases were washed with water, dried over Na ₂ SO ₄ and i. Vak. evaporated. Recrystallization of the residue from ethanol gave colorless crystals. Yield 85%, m.p .: 187-188 ° C (EtOH). C ₁₀ H ₉ NO ₂ (175.2); IR: 3220 (NH), 1660 cm ^"1 (C = O); H NMR (DMSO-d ₆ ) δ (ppm): 10.05 (bs; 1 H, NH), 7.81 (dd; 1 H, J = 1.5 / 8 Hz, H _ar omat), 7.53 (ddd; 1 H, J = 1.5 / 7/8 Hz, H _aromat ), 7.19-7.13 (m; 2H _aromat ), 2.63-2.93 (m, AA ^' BB ^' ; 4H, CH ₂ CH ₂ ) .El MS: m / z (%) = 175 (93%, M ⁺ ).

9-bromo-7,12-dihvdro-indolor3,2-dimbenzazepin-6 (5H) -one (3) (Aren. Pharm. 1992, 325, 297):

Bromophenylhydrazine (7 mmol) was added to a suspension of 2 (1.05 g, 6 mmol) in glacial acetic acid (10 ml), followed by stirring at 70 ° C. for 1 h. After cooling, 0.5 ml of conc. H ₂ SO ₄ stirred at 70 ° C for 1 h. The mixture was allowed to cool, poured into 50 ml of 10 percent. Sodium acetate solution and suctioned off the precipitate. Yellow crystals. Yield: 58%. M.p .:> 330 ° C (1,4-dioxane). C ₁₆ HnBrN ₂ O (327.2). IR: 3220 (NH); 1640 cm ^"1 (C = O). ¹ H NMR: δ (ppm): 11.75 (s; 1 H, NH), 10.05 (s; 1 H, NH), 7.89 (d; 1H, J = 1.5 Hz, C-8-H), 7.74 (bd; 1 H, J = 7.5 Hz, Ar-H), 7.41-7.34 (m; 2H, Ar-H), 7.30-7.21 (m; 3H, Ar-H), 3:50 (s, 2H, CH _2). 9-Bromo-7.12-dihvdroindolor3,2-cflri1benzazepine-6- (5HHhion (4) J. Med. Chem. 1999. 42. 2909):

(3) (4)

(i) P ₂ S ₅ , NaHCO _a , THF, N ₂ , reflux

A solution of 3 (327 mg, 1 mmol) in THF (30 mL) was stirred at 50 ° C under a protective nitrogen atmosphere. Phosphorus pentasulfide (250 mg, 1.12 mmol) and sodium hydrogen carbonate (370 mg, 4.4 mmol) were added in succession. After heating under reflux in a nitrogen blanket for 3 hours, the reaction mixture was allowed to cool to room temperature and then transferred to ice (50 g). The mixture was stirred until the ice had completely melted, and the precipitate which formed was filtered off with suction, washed with water and recrystallized from ethanol / toluene. Yield: 67% pale yellow crystals: mp:> 330 ° C; IR: 3430, 3140 cm ^"1 (NH); H NMR (400 MHz) 3.91 (s, 2H, CH ₂ ), 7.30 (dd, 1 H, 1.5 / 8.6 Hz), 7.39-7.45 (m, 4H), 7.79 (d, 1 H, 7.1 Hz), 7.86 (d, 1 H, 1.5 Hz), 11.92 (s, 1 H, NH), 12.07 (s, 1 H, NH). 9-Bromo-6- (met ylthio) -7.12-dihvdroindolor3.2-cπrn-benzazepine (5) J. Med. Chem. 1999. 42. 2909):

(4) (5)

(i) NaH, THF, CH ₃ IN 2 'reflux

Sodium hydride (24 mg, 1 mmol, 60% suspension in oil) was added to a solution of 4 (343 mg, 1 mmol) in THF (20 mL). After heating to reflux in a protective nitrogen atmosphere for 1 hour, the mixture was cooled to room temperature and a solution of iodomethane (170 mg, 1.2 mmol) in THF (2 mL) was added. The mixture was heated under reflux for a further 2 hours, cooled again to room temperature, and then the reaction mixture was transferred to ice (150 ml). After stirring for 15 minutes, the precipitate was filtered off, washed with water and crystallized from ethanol. Yield: 44% colorless crystals; M.p .: 199 ° C; IR: 3420 (NH), 1615 cm ^"1 (C = N); ¹ H NMR (400 MHz) 2.35 (s, 3H, CH ₃ ), 3.51 (s, 2H, CH ₂ ), 7.26-7.32 (, 2H ), 7.36-7.43 (m, 3H), 7.80- 7.82 (m, 1 H), 7.97 (d, 1 H, 1.5 Hz), 11.82 (s, 1 H, NH). KP1428:

(KP1428)

(5)

(i) H ₂ NNHCSNH ₂ , CH ₃ OH

To 5 (714 mg, 2 mmol) in methanol (35 mL) was added thiosemicarbazide (220 mg) in methanol (55 mL). The solution was filtered and stored at room temperature. After 4 days, the precipitate formed was filtered off, washed with methanol and air-dried. Yield: 490 mg. Ber. For Cι ₈ Hι _β N ₅ BrOS,%: C, 50.01; H, 4.20; N, 16.20. Found,%: C, 50.12, H, 4.55; N, 15.63. MS (ESI): m / z = 400 [M ⁺ ].

KP1436:

(5) (KP1436)

(i) H ₂ NNH ₂ -H ₂ O, CH ₃ OH Hydrazine hydrate (0.2 mL) was added to 5 (714 mg, 2 mmol) in dry ethanol (50 mL). The solution was filtered and then stored at room temperature. After 2 days, the precipitate formed was filtered off, washed with ethanol and air-dried. Yield: 236 mg. Ber. for Cι ₆ Hι ₃ N ₄ Br,%: C, 56.32; H, 3.84; N, 16.42. Found,%: C, 56.19, H, 3.80; N, 16.22. MS (ESI): m / z = 341 [M ⁺ ].

KP1437:

(KP1437)

(KP1436)

(i) 2-hydroxybenzaldehyde, methanol

2-Hydroxybenzaldehyde was added to KP1436 in boiling methanol (30 mL) and the solution was warmed until all of the starting material was dissolved. The next day the precipitate was filtered off, washed with methanol and air dried. Yield: 150 mg. Ber. for C ₂₃ Hι ₉ N ₄ O ₂ Br,%: C, 59.62; H, 4.13; N, 09/12. Found:%: C, 60.23, H, 4.17; N, 12/12 MS (ESI): m / z = 445 [M ⁺ ]. KP1438:

(KP1436)

(i) 2-hydroxybenzaldehyde,

GaCI _3> methanol

KP1436 (170 mg, 4.9 mmol) was heated to boiling in methanol (30 mL) and 2-hydroxybenzaldehyde (60 mg, 4.9 mmol) in methanol (1 mL) was added. The reaction mixture was refluxed for 15 minutes. After the starting material had completely dissolved, KP1437 began to crystallize out. At this point a solution of GaCI ₃ (2.45 mmol) in ethanol (0.3 mL) was added. The solution thus obtained was heated to reflux for 20 minutes and then left to stand at room temperature. The next day the precipitate was filtered off, washed with cold methanol and dried in vacuo. Yield: 90 mg. The yield can be improved to 140 mg if the reaction is carried out in the presence of 0.05 g of triethylamine. Ber. for C ₆ H ₃₂ N ₈ GaBr ₂ ClO ₂ -2.5H ₂ O,%: C, 53.19; H, 3.59; N, 10.79. Found,%: C, 52.89, H, 3.60; N, 10.63. MS (ESI): m / z = 957 [M ⁺ -Cl].

9-bromo-6-N- (2-N \ N'4Dimethylaminoethylamino) -7.12 ~ dihydroindolo- [3,2-d] [1] benzazepine (KP1472)

(9-bromo-6-N- (2-N ', N'-dimethylaminoethylamino) -7,12-dihydrobenzo [2,3] azepino [4,5-b] indole)

Batch 1, 50 g of 9-bromo-6 (methylthio) -7,12-dihydroindolo [3,2-d] [1] benzazepine

(M = 357.2 g mol ^"1 => 4.2 mmol)

500 μl N, N-dimethylethylenediamine (95%; d = 0.803 g cm ^'3 ; M = 88.15 g mol ^"1 => 4.3 mmol)

50 ml ethanol (abs.)

9-Bromo-6 (methylthio) -7,12-dihydroindolo [3,2-d] [1] benzazepine (1,50 g) was weighed into a 100 ml round-bottomed flask with a gas tap, dissolved with ultrasound assistance in absolute ethanol (50 ml) and pipetted in N, N-dimethylethylenediamine (0.5 ml) using a piston-operated pipette (Eppendorf). The flask was then sealed with a rubber septum under argon and placed in the drying cabinet (57-61 ° C). After 14 days it was removed from the drying cabinet and the reaction mixture was filtered through a glass suction filter. The mixture was then slowly evaporated to about% at an oil bath temperature of 57-60 ° C. while drawing in air through an inlet tube with cotton plugs, the product precipitating out as a fine crystalline precipitate. The mixture was then cooled in a freezer (-20 ° C.) before being filtered off in a suction filter, washed 3 times with 10 ml of cooled (-20 ° C.) ethanol (96%) and sucked dry.

Yield: 1.1 g of colorless crystalline product (58.9% of theory); Product contains one equivalent of ethanol).

Ethanol was removed in vacuo before NMR measurement. δ _H (400.13 MHz; d ₆ -DMSO):

11, 61 [1H (N12); s]; 7.84 [1H (C8); s]; 7.68 [1H (C1); d; ³ J (H _C2 ) = 7.53 Hz]; 7.36 [1H (C11); d; ³ J ( _C ιo) = 8.53 Hz]; 7.25 [1H (C3); dd; ³ J (H _C ) = 8.53 Hz; J (H _C4 ) = 8.03 Hz]; 7.23 [1H (C10); d; ³ J (H _C n) = 8.53 Hz];

7.14 [1H (N13); t; ³ J (H _C H) = 5.02 Hz]; 7.13 [1H (C4); d; ³ J (H _C3 ) = 8.03 Hz]; 7.03 [1H (C2); dd; ³ J (H _C ι) = 7.53 Hz; ³ J (H _C3 ) = 8.53 Hz]; 3.32 [2H (C7); s]; 3.28 [2H (C14); dt; ³ J (H _N13 ) = 5.02 Hz; ³ J (H _C ι ₅ ) = 6.53 Hz]; 2.15 F6H (C17 + C18); s];

δ _c (100.63 MHz; d ₆ -DMSO):

155.52 (C6); 147.25 (C4a); 136.78 (C11a), 136.24 (C12a); 129.09 (C7b);

128.36 (C4); 128.23 (C3); 127.42 (C1); 124.49 (C10); 122.59 (C12b); 121, 07 (C2);

121.00 (C8); 113.96 (C11); 112.01 (C9); 109.31 (C7a); 58.61 (C15);

46.12 (C17 + C18); 39.90 (C14); 28.66 (C7);

Elemental analysis (C ₂ oH ₂ - | N ₄ Br-C ₂ H ₆ O):

w-% C w-% H w-% N theoretical 59.60 6.14 12.64 found 59.68 5.85 12.93

9-bromo-6- (2-hydroxyethylamino) -7,12-dihydroϊndolo [3,2-d] [1] benzazepine (KP1473)

(9-bromo-6- (2-hydroxyethylamino) -7,12-dihydro-benzo [2,3] azepino [4,5-b] indole)

EtOH _abs , 60 ° C

Batch 1, 50 g of 9-bromo-6 (methylthio) -7, 12-dihydroindolo [3,2-d] [1] benzazepine

(M = 357.2 g mol ^"1 => 4.2 mmol) 270μl 2-aminoethanol (99%; d = 1.015 g cm ^"3; M = 61.08 g mol ^"1 => 4.4 mmol )

50ml ethanol (abs.)

9-bromo-6 (methylthio) -7,12-dihydroindolo [3,2-d] [1] benzazepine (1,50 g) was dissolved in absolute 100 ml (50 ml) in a 100 ml round bottom flask with a gas tap with ultrasound support. Ethanolamine was pipetted in using a piston-operated pipette (Eppendorf). The flask was then sealed with a rubber septum under argon and placed in the drying cabinet (57-60 ° C). After 14 days, was taken out of the dry box and filtered through a sintered glass suction filter ^'. The mixture was then slowly evaporated to dryness at 57-60 ° C. oil bath temperature while sucking in air through an inlet pipe with cotton plugs. The product obtained in this way (overgrown crystals) was suspended in 5 ml of cold ethanol, immediately filtered off through a glass internal suction filter and washed again briefly with 5 ml of ethanol (96%). Then it was further dried under vacuum. Weight: 0.8 g (47.4% of theory); The product contains one equivalent ethanol)

δ _H (400.13 MHz; d ₆ -DMSO):

11, 62 [1H (N12); s]; 7.82 [1H (C8); s]; 7.68 [1H (C1); d; ³ J (H _C2 ) = 8.03 Hz]; 7.36 [1H (C11); d; ³ J (cιo) = 8.53 Hz]; 7.35 [1H (N13); t; ³ J (H _C ι) = 5.02 Hz]; 7.25 [1H (C3); dd; ³ J (H _C2 ) = 8.53 Hz; ³ J (H _C4 ) = 8.03 Hz]; 7.23 [1H (C10); d; ³ J (H _C n) = 8.53 Hz]; 7.11 [1H (C4); d; ³ J (H _C3 ) = 8.03 Hz]; 7.04 [1H (C2); dd; ³ J (H _C ι) = 8.03 Hz; ³ J (H _C3 ) = 8.53 Hz]; 4.94 [1H (O); s]; 4.36 [1H (EtOH-OH); t; ³ J (H _Et oH-CH ₂ ) = 5.02 Hz]; 3.52 [2H (C15); t; ³ J (H _C ι ₄ ) = 5.52 Hz]; 3.45 [2H (EtOH-CH2); dq; ³ J (HHOH-OH) = 5.02 Hz; ³ J (H _Et0 H-cH3) = 7.03 Hz]; 3.32 [2H (C7); s]; 3.26 [2H (C14); dt; ³ J (H _C ι ₅ ) = 5.52 Hz; ³ J (H _N13 ) = 5.02 Hz]; 1.06 [3H (EtOH-CH3); t; ³ J (H _{E to} H-cH ₂ ) = 7.03 Hz];

δ _c (100.63 MHz; d ₆ -DMSO): 156.06 (C6); 147.02 (C4a); 136.81 (C11a); 136.21 (C12a); 129.06 (C7b);

128.28 (C4); 128.23 (C3); 127.47 (C1); 124.54 (C10); 122.66 (C12b); 121, 21 (C2); 120.99 (C8); 1 14.00 (C1 1); 112.05 (C9); 109.31 (C7a); 60.82 (C15); 56.91 (EtOH-CH2); 44.93 (C14); 28.66 (C7); 19.43 (EtOH-CH 3);

Elemental analysis (C ₁₈ Hι ₆ N ₃ OBr-C ₂ H ₆ O):

w-% C w-% H w-% N

Theoretical 57.70 5.33 10.09 Found 57.71 5.32 10.14

Sodium 6 (5H) -oxo-7,12-dihydroindolo [3,2-d] [1] benzazepine-9-sulfonate (KP1474)

(Sodium-6-oxo-5,12-dihydro-7H-benzo [2,3] azepino [4,5-b] indol-9-sufonat)

Batch 0.50 g dihydro-1 H-benz [b] azepine-2,5-dione (M = 175.19 g mol ^" ^■ 1 '_ =.>. 2.85 mmol)

0.57 g of 4-hydrazinobenzenesulfonic acid hemihydrate (98%; M = 197.22 g mol ^" =

2,8528mmol)

0.24 g sodium acetate (98.5%, M = 82.034 g mol ^"1 => 2.88 mmol)

4.5 ml acetic acid (99.8%; d = 1,049g cm ^"3 )

250 μl H ₂ SO ₄ (95-97%; d = 1.84 g cm ^"3 ; M = 98.079 g mol ^{" 1} => 4.50 mmol)

0.79 g sodium acetate (98.5%, M = 82.03 g mol ^"1 => 9.48 mmol) 325 ml methanol (pA) 7.6 ml H ₂ O.

Dihydro-1 H-benz [b] azepine-2,5-dione and sodium acetate were weighed into a 10 ml round bottom flask and suspended in 3 ml of glacial acetic acid with ultrasound support. Solid 4-hydrazinobenzenesulfonic acid hemihydrate was added with stirring. The mixture was then refluxed under an argon atmosphere for 75 minutes at an oil bath temperature of 133 ° C. The starting materials went into solution almost completely. The reaction mixture, which was still hot, was then filtered through a sintered glass funnel (P4), rinsing being carried out with 1.5 ml of acetic acid. After cooling to room temperature, 250 μl of sulfuric acid were added using a piston-operated pipette while stirring. A fine, light precipitate begins after a very short ultrasound treatment to fail. The hot oil bath was then suspended and the mixture was refluxed under argon for a further 75 minutes. After cooling to room temperature, the product was filtered off in a glass suction filter, washed with 3 ml of glacial acetic acid, then 3 times with 5 ml of THF and finally 3 times with 5 ml of diethyl ether. The product (approx. 1 g), which had been sucked dry for some time and, based on experience, contains some impurities which are difficult to identify, was dissolved in 300 ml of methanol with 7 ml of H ₂ O. For this purpose, a solution of 3 equivalents of sodium acetate in 25 ml of methanol was poured with 0.6 ml of H ₂ O. The resulting precipitate was filtered off and discarded. The filtrate was evaporated to dryness and the residue was suspended in 30 ml of dry methanol under ultrasound. After refluxing for 10 minutes, the white product in the mixture cooled to room temperature was filtered off in a glass suction filter, washed 3 times with 5 ml of cold methanol and finally 3 times with 5 ml of diethyl ether. It was then dried in vacuo.

Yield: 0.62 g of white powder

δ _H (400.13 MHz; d ₆ -DMSO):

11.69 [1H (N12); s]; 10.12 [1 H (N5); s]; 7.91 [1H (C8); s]; 7.76 [1H (C1); d; ³ J (H _C ) = 7.5 Hz]; 7.51 [1H (C10); d; ³ J (H _C n) = 8.5 Hz];

7.39 [1H (C11); d; ³ J ( _C ιo) = 8.5 Hz]; 7.37 [1H (C3); dd; ³ J (H _C2 ) = 7.5 Hz;

³ J (H _c4 ) = 7.5 Hz];

7.28 [1H (C2); dd; ³ J (H _C ι) = 7.5 Hz; ³ J (H _C3 ) = 7.5 Hz;]; 7.27 [1H (C4); d; ;

³ J (H _C3 ) = 7.5 Hz]; 4.12 [0.5H (O _Me oH); s]; 3.49 [2H (C7); s]; 3.18 [1.5H (C _Me oH); s];

δ _c (100.63 MHz; d ₆ -DMSO):

172.27 (C6); 140.67 (C9); 138.15 (C11a); 136.33 (C12b); 134.12 (C12a); 128.96 (C3); 127.75 (C1); 126.10 (C7b); 124.57 (C2); 123.62 (C4a); 123.17 (C4); 121, 39 (C10); 116.07 (C8); 11, 31 (C11); 108.97 (C 7a); 49.35 (C _Me o _H ); 32.56 (C7);

δ _N (40.55 MHz; based on NH ₄ CI; d ₆ -DMSO): 108 (N12); 117 (N5); Anti-tumor effect:

The tumor-inhibiting effect was tested in the XTT assay using the example of various cell lines in vitro. The incubation period was 48 hours (IC ₅₀ values in μM).

IC ₅ o values azepinone derivatives

KP 1428 KP1437 KP1438 line

CCRF-CEM 5.47 1, 66 0.54

K-562 48.4 1, 56 0.61

MOLT-4 2.63 2.9 0.35

COLO 205 13.3 5.25 1.85

HCT-15 24.1 0.74 0.15

HCT-116 26.4 2.56 1.32

HT-29 9.46 6.61 1.64

SW-620 22.8 3.83 2.57

MCF-7 20.7 10.4 6.32

OVCAR 3 2.59 6.82 4.08

NCI-H460 14.4 9.51 5.35

NCI-H226 30.1 7.19 2.04

SK-MEL-5 19.4 10 0.64

SK-MEL-28 18.5 7.98 0.44

Hep 3B 0.935

Hep G2 0.385

Claims

Expectations:

1. Compound of the general formula (I) or (II)

in which

X is selected from the following groups (a), (b), (c)

and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl,

wherein

R ¹ , R ² and R ¹¹ -R ^{15 are} independently selected from the group consisting of hydrogen, halogen, hydroxyl and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, and R ³ -R ¹⁰ and R ¹⁶ -R ^{20 are} independently selected from the group consisting of hydrogen, amino, nitro, cyano, formyl, carboxyl, SO ₃ H, SO ₃ M _b , where M is a physiologically compatible cation, hydroxy , Halogen and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl, alkynyl, alkoxy, alkylmercapto and dialkylamino, and

physiologically acceptable addition salts thereof.

2. A compound according to claim 1, wherein X is selected from the following groups (a), (b) and (c)

3. complex of the general formula (III),

[M _a ^{i +} Y _x ^{n "} LJ ^{[i" (nx + z)] +} [i- (nx + z)] / n Y ^{n ~} (III)

where L is a group of the general formula (IV),

(IV), wherein

R ¹ and R ^{2 are} as defined above,

R ³ -R ¹⁰ and R ¹⁶ -R ^{20 are} as defined above, and

and physiologically acceptable addition salts thereof.

4. Complex of the general formula (III ')

[M _a L ₂ ] ^{j +} j7p Y ^p - (111 '),

where L is a group of the general formula (IV),

wherein

R ¹ and R ^{2 are} as defined in claim 1,

R ³ -R ¹⁰ and R ¹⁶ -R ^{20 are} as defined in claim 1,

_Ma Ga, Fe, La and Ru, and

j is 0, 1 or 2, p is 1 or 2,

Y is a physiologically acceptable anion, and physiologically acceptable addition salts thereof.

5. The complex of claim 3 or 4, wherein Y is selected from the group consisting of halogen, pseudohalogen, nitrate, carboxylate, sulfate and R ^' OOO, where R "is hydrogen, CC ₆ alkyl, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl, C ₃ - C ₆ cycloalkyl, C ₃ -C _e cycloalkenyl, C ₆ -C ₁₄ aryl, or a heterocycle.

6. The complex of claim 5, wherein Y is chlorine

7. The compound or complex according to one of claims 1 to 6, wherein R ¹ -R ⁶ and R ¹¹ -R ²⁰ in the general formulas (I), (II) or (IV) are hydrogen and R ⁷ -R ¹⁰ are independently selected from the group consisting of hydrogen, amino, nitro, cyano, formyl, carboxyl, SO ₃ H, S0 ₃ M _b , where M is a physiologically compatible cation, hydroxyl, halogen-substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl, alkynyl, alkoxy, alkylmercapto and dialkylamino, where at least one substituent R ⁷ -R ^{10 is} not hydrogen.

8. The compound or complex according to claim 7, wherein R ⁷ -R ^{10 are} independently selected from the group consisting of hydrogen, dC ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, C ₆ -C ₁₄ aryl, amino, nitro, cyano, formyl, carboxyl, SO ₃ H, S0 ₃ M, where M _{b is} a physiologically compatible cation, Hydroxy, halogen, dC ₄ -haloalkyl, dC -hydroxyalkyl, dC ₄ -alkyl nitrile, dC ₄ -alkoxy, Cι-C ₄ - alkoxy-dC ₄ -alkylene, dC ₄ -alkylmercapto, dC ₄ -alkylmercapto-dC ₄ -alkylene, dC ₄ -alkoxycarbonyl, dC ₄ -alkoxycarbonyl-dC ₄ -alkylene, Di-CrC ₄ -alkylamino, Di-dC -alkylamino-C-ι-C -alkylene, Di-C C ₄ -alkylaminocarbonyl and Di- CC ₄ -alkylamino-carbonyl-C ₁ -C ₄ -alkylene.

9. The compound or complex according to claim 8, wherein R ¹ -R ⁸ and R ¹⁰ - R ²⁰ in the general formulas (I), (II) or (IV) are hydrogen, and R ^{9 is} nitro, cyano, halogen or Is trifluoromethyl.

10. The compound or complex of claim 9, wherein R ^{9 is} nitro or halogen.

11. The compound or complex of claim 10, wherein the halogen is bromine.

12. The compound of claim 1, wherein the compound of general formula (I)

13. The compound of claim 1, wherein the compound of general formula (I)

14. The compound of claim 1, wherein the compound of general formula (II)

15. The compound of claim 1, wherein the compound of general formula (II)

16. The compound of claim 1, wherein the compound of general formula (II)

17. Compound of the general formula (VI)

wherein

R and R are independently selected from the group consisting of hydrogen, halogen, hydroxyl and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl

R, 23 to R ₅ 30 are independently selected from the group consisting of hydrogen, amino, nitro, cyano, formyl, carboxyl, hydroxy, halogen, S0 ₃ H, SO ₃ M _b , where M is a physiologically acceptable cation, and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl, alkynyl, alkoxy, alkylmercapto and dialkylamino,

where at least one of the groups R ²³ to R ^{30 is} SO ₃ H or SO ₃ M _b , where M _{b is} a physiologically tolerated cation,

and physiologically acceptable addition salts thereof.

18. A compound according to claim 17, wherein R ^{29 is} SO ₃ H, or S0 ₃ M _b , wherein M is a physiologically acceptable cation.

19. A compound according to any one of claims 17 or 18, wherein R ²¹ to R ²⁸ and R ^{30 is} hydrogen.

20. Medicament containing a compound or a complex according to any one of claims 1 to 19.

21. Use of a compound or a complex according to any one of claims 1 to 19 for the prophylaxis and / or treatment of

Tumor diseases.

22. Process for the preparation of a complex of the general formula (III)

[M _a ^{i +} Y _x ^{n "} L _z ] ^{[Knx + z)] +} [i- (nx + z)] / n Y ^π" (III)

where a compound L of the general formula (IV),

(IV) in which

R -R ¹⁰ and R -R ^ are as defined in claim 1, is reacted with a compound of the general formula (V),

M _a aY ^■ , (V),

in which

M _a and Y are as defined in claim 3 and m is 1, 2 or 3, and

i, n, x, and z are as defined in claim 3.

23. Process for the preparation of a complex of the general formula (IM ')

where a compound L of the general formula (IV)

(IV), wherein

R ¹ and R ^{2 are} as defined in claim 1, R ³ -R ¹⁰ and R ²⁰ -R ^{16 are} as defined in claim 1,

is reacted with a compound of the general formula (V),

M _a Y _q (V),

in which

M _{a is} as defined in claim 3,

Y is a physiologically acceptable anion, and

q is 1, 2 or 3,

and j and p are as defined in claim 4.