AT503733A1 - HALF SANDWICH RUTHENIUM (II) AND OSMIUM (II) COMPLEX COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF, AND THEIR USE IN THE TUMOR DISORDER CONTROL - Google Patents

Description

. * ·. ·· ·· ·· ·· ·

•···········. , .:·: 1

Semi-sandwich ruthenium (II) and osmium (II) complex compounds, process for their preparation and their use in the control of tumor diseases 5

The present invention relates to compounds comprising a polynuclear ruthenium (II) complex or osmium (II) complex, their preparation, and their use as medicaments for the treatment of cancers. 10

The potential utility of ruthenium complexes for the treatment of cancers has been described by M.J. Clarke, ACS Symp. Ser. 140 (1980) 157-180. 15 W001 / 30790 and WO 02/02572 and WO02006 / 018649 disclose ruthenium aromatic half-sandwich complexes in which the ruthenium is complexed with amino or diamino ligands in addition to the arene ligand and a halogen. In particular, the monomeric compounds proved to be active compounds in the growth inhibition of cancer cells.

WO 02/40494 discloses ruthenium half-sandwich complexes which, in addition to the arene ligand and another monodentate ligand, also have a phosphorus-containing ligand. 25

In WO 2004/096819, the ruthenium central metal is additionally chelated by a diamino compound, and WO 2004/005304 discloses ruthenium (II) half-sandwich complexes which have oxygen, sulfur or amino-containing bidentate ligands at this point.

Osmium complexes as well as their physiological behavior are described e.g. in Peacock et al. (Journal of the American Chemical Society (2006), 128 (5), 30 ·········································································. • • • • • • • • • • • «· ··········· 2 1739-1748) and Dorcier et al. (Organometallics (2005), 24 (9), 2114-2123), the compounds being described as being less active.

Despite the large number of possible ruthenium and osmium complexes, 5 the need for new, active compounds is very high.

It is therefore an object of the present invention to provide novel complex compounds of ruthenium and osmium which have high potency in the treatment of cancers. Surprisingly, it has now been found that ruthenium (II) or osmium (II) -10 half-sandwich complex, which additionally has cyclic α-hydroxy ketone, a hydroxyamino compound or a phosphorus-containing glucofuranoside as ligands, a very large activity in the growth inhibition of cancer cells have. This object is achieved by a complex compound of the general formula (I)

m

In which R 1, R 2, R 3, R 4, R 5, R6, R7, R8 and R9

Hydrogen, halogen, hydroxyl, carboxyl, nitro, amino, carbonyl and 5 substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, or alkylaryl or COOR 'with R' = alkyl aryl, alkylaryl is, X1, X2 * independently of one another are N, O, S, X3 = O, S or N-R10, where R10 = a linear or branched C-Moo-alkyl, a linear or branched C 1-10 -alkenyl containing one or more ether, thioether,

Amino, ester, amide or thioester functions within the chain and which may further be substituted by halogen, hydroxyl, carboxyl, and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl; Alkylaryl or COOR 'with R' = alkyl

Aryl, alkylaryl, Y, an anion or H20, DMSO, P (aryl) 3, a nitrogen-containing heterocycle having one or more nitrogen atoms in the ring or 25 P-glucofuranoside, Z is a physiologically acceptable anion, M = Ru or Os is m = 1-4, the dimeric, trimeric or tetrameric complexes being linked together via either R1, R2, R3 or R10, 30 4 q = 1, 2, 3 and $ = 0.1, 2 is.

Furthermore, the object is achieved by a compound of the general formula (II), 10

S + m (Z ^ sm / q (II) wherein R4, R5, R6, R7, R8 and R9 and Y; and, S, Z, q, M and m are as defined above, and R11 and R12 are independently O-R13, S -R13 or N-R13, where R13 is ···························································································. ···· ·· 5

Is hydrogen, carboxyl, carbonyl, substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, alkylaryl, or phosphate, and the monomeric complexes via R11 or R12 with one another to dimer, trimer or tetramers Units can be linked. R11 and R12 may also together form a 0,0 or S, S-acetal which may be substituted with substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, alkylaryl.

Furthermore, the object is achieved by a compound of general formula (III)

+

(III) ···· ······································································· ····· ·· 6 wherein R4, R5, R6, R7, R8 and R9 and as well as, S, Z, q, M and m are as defined above, and R14, R15, R16, R17, R18 and R19 are hydrogen , Carboxyl, carbonyl, substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, 5 substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, alkylaryl, and W is pyrazole, indazole, imidazole, benzimidazole, pyrazine or 1,2,4-triazole is. 10

If the alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkaryl or aryl groups at radicals R1, R2, R3, R4, R5, R6, R7, R8, R9, R13, R14, R15, R16, R17, R18 and R19 in the substituents in these groups are independently of each other preferably halogen, nitro, trihaloalkyl, ethoxyalkyl, hydroxy, alkyl, alkoxy, alkoxycarbonyl, alkylmercapto, amino, dialkylamino, dialkylaminocarbonyl and / or nitrile. Aryl or alkylaryl substituents on R1, R2 or R3 are preferably substituted by hydroxy, nitro, halogen, alkoxy, trihaloalkyl, or by alkyl or further aryl radicals. R4, R5, R6, R7, R8 and R9 are preferably hydrogen, linear or branched alkyl, aryl or COOR, very particularly preferably branched alkyl. Y is preferably selected from the group consisting of halogens, pseudohalogens, nitrate, carboxylate, sulfate, carbonate, hydrogen phosphate, 30 phosphate, tartrate, malonate, oxalate and R'OOO, where R " Is hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 6 -C 12 -cycloalkenyl, Ce-CU-aryl, or a heterocycle, is J • ··· ··· ···

Most preferably, Y is a halogen, hydroxy, alkoxy, CN, SCN, or SH, or more preferably an H2O, Y is halo or hydroxy, preferably Y is chloro or bromo. 5 Z is preferably a halogen, pseudohalogen, nitrate, borate, hexafluorophosphate, carboxylate, sulfate, carbonate, hydrogen phosphate,

Tartrate, malonate, oxalate and R " COO, where R " Is 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 3 -C 10 aryl, or a heterocycle. I X1, X2 are preferably O. 15 X3 is preferably N-R10. R 10 is preferably a linear or branched C 1-50 -alkyl or alkenyl, more preferably a linear or branched C 1-30 -alkyl or alkenyl-and most preferably R 10 is C 1-12 -alkyl. 20

Preferably, two complexes of the general formula (I) are linked to one another via R10.

Furthermore, the aromatic ligand at the metal center in the general formulas (I), (II) or (III) is preferably substituted with linear or branched C 1-4 -mon-alkyl and more particularly the aromatic is substituted with methyl and isopropyl. The compound of the formula (I), (II) or (III) according to the invention can be in the form of an aqueous solution. t ···········································································

Furthermore, the object of the present invention is achieved by the use of a compound of the general formula (I), (II) or (III) for the treatment of tumor diseases. Furthermore, the object of the present invention is achieved by a process which makes the compounds of the formula (I), (II) or (III) available.

For this purpose, a compound of formula (IV)

wherein R4, R5, R6, R7, R8 and R9 are as defined above and D is a halogen 15, preferably chloride or bromide with a compound of general formula (V) wherein R1, R2, R3 and X1, X2, X3 as are defined above

20

········································································································································································································. VI), wherein R11 and R12 are as defined above

5 (VI) or with a compound of formula (VII) wherein R14, R15, R16, R17, R18 and R19 are as defined above

in a suitable solvent, if appropriate in the presence of a base, and then reacted with pyrazole, indazole, imidazole, benzimidazole, pyrazine or 20 1,2,4-triazole to prepare a compound of formula (III). As bases can be used hydroxide, carbonate, sulphate, alkoxide, hydride. Particularly preferred is sodium methoxide. 10

Furthermore, the object of the present invention is achieved by a medicament containing the compound (I) (II) or (III) according to the invention. The compounds of the formula (I), (II) or (III) can furthermore be used for the production of a medicament for the prophylaxis and / or treatment of cancer diseases.

In the following, the pharmaceutical according to the invention will be described in more detail. 10

The medicaments according to the invention are primarily administered intravenously, but also intramuscularly, intraperitoneally, subcutaneously or perorally. Also an external application is possible. Preferably, the administration is by intravenous injection or intravenous infusion. 15

The pharmaceutical preparations are prepared by processes known per se, the composition according to the invention being used as such or optionally in combination with suitable pharmaceutical carriers. If the pharmaceutical preparations 20 contain pharmaceutical excipients in addition to the active ingredient, the active ingredient content of these mixtures is 0.1 to 99.5, preferably 0.5 to 95 wt .-% of the total mixture.

The active substance may be used in any appropriate formulation, provided that the formation or maintenance of sufficient levels of active substance is ensured. This can be achieved for example by oral or parenteral administration in appropriate doses. Advantageously, the pharmaceutical preparation of the active ingredient is in unit dose form adapted to the desired administration. A unit dose may be, for example, a tablet, dragee, capsule, suppository, or measured volume of powder, granule, solution, solution, or the like. ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••

Emulsion or a suspension.

Under " unit dose " For the purposes of the present invention, a physically determined unit is understood which contains an individual amount of the active ingredient in combination with a pharmaceutical carrier and whose active substance content corresponds to a fraction or multiple 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 10 daily dose. If only a fraction, such as one half or one fourth, of the unit dose is needed for a single therapeutic administration, the unit dose is advantageously divisible, e.g. in the form of a tablet with a score. The pharmaceutical compositions of the present invention, when in unit dosage form and for applications e.g. are determined in humans, 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 of 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 substance (s) in amounts of from 0.1 to 5, preferably 1 to 3, 25 mg / kg body weight. For oral treatment, similar dosages may be used.

The therapeutic administration of the pharmaceutical preparation may be 1 to 4 times a day at fixed or varying times, e.g. each before meals and / or in the evening. However, it may be necessary to deviate from the stated dosages, depending on the type, the body weight and the age of the to ·········································································. •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• Pharmaceutical preparations and the period or interval within which the administration takes place. Thus, in some cases it may be sufficient to make do with less than the amount mentioned above 5, while in other cases, the above-mentioned amount of active ingredient must be exceeded. It may also be useful to administer the pharmaceutical preparations only once or at intervals of several days. 10 The determination of the required optimal dosage and mode of application of the active ingredients can be made by any specialist on the basis of his specialist knowledge.

The pharmaceutical preparations are generally composed of the composition according to the invention and non-toxic, pharmaceutically acceptable excipients which are used as admixture or diluent, for example in solid, semisolid or liquid form or as a wrapping agent, for example in the form of a capsule, a tablet coating, a sachet or a sachet container for the therapeutically active ingredient. A carrier can e.g. serve as a mediator for the ingestion of drug by the body, as a formulation aid, as a sweetener, as a flavoring, as a dye or as a preservative. For oral administration, e.g. Tablets, dragees, hard and soft capsules, e.g. from gelatin, dispersible powders, granules, aqueous and oily suspensions, emulsions, solutions or syrups.

Tablets may contain inert diluents, e.g. Calcium carbonate, calcium phosphate, sodium phosphate or lactose; Granulating and distributing agents, e.g. Corn starch or alginates; Binding agent, e.g. Starch, gelatin or acacia gum; and lubricants, e.g. Aluminum or 99 »······················· 13

Magnesium stearate, talc or silicone oil. They may additionally be provided with a coating which may also be such as to cause a delayed dissolution and absorption of the drug preparation in the gastrointestinal tract, e.g. a better compatibility, 5 Protahierung or retardation is achieved. Gelatin capsules can be mixed with the drug with a solid, e.g. Calcium carbonate or kaolin, or an oily one, e.g. Olive, peanut, or paraffin oil, containing diluents. Aqueous suspensions may contain suspending agents, e.g. Sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum or acacia gum; Dispersing and wetting agents, e.g. Polyoxyethylene stearate, heptadecaethylene oxycatanol, polyoxyethylene sorbitol monooleate or lecithin; Preservatives, e.g. Methyl or propyl hydroxybenzoates; Flavoring agents; Sweeteners, e.g. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup. Oily suspensions may e.g. Peanut, olive, sesame, coconut or paraffin oil and thickening agents, e.g. Beeswax, hard paraffin or cetyl alcohol; sweeteners, flavorings and antioxidants.

Water-dispersible powders and granules may be mixed with dispersing, wetting and suspending agents, e.g. the above, as well as sweeteners, flavorings and colorants.

Emulsions can e.g. Olive, peanut, or paraffin oil in addition to 30 emulsifiers, e.g. Acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweetening and flavoring agents. ee ee ♦ • e • e • • • • • • e • e • • • • • • • • • • • • • # # # 9 9 · · · · · · ···· tt | 14 Aqueous solutions may contain preservatives, e.g. Methyl or propyl hydroxybenzoates; Thickener; Flavoring agents; Sweeteners, e.g. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup, as well as flavorings and colorants.

For parenteral administration of the drugs are sterile injectable aqueous solutions, isotonic saline or other solutions. 10 Any suitable solution may be used as a solvent for infusion. Preference is given to water and Haemaccel®. 15

In the following the invention will be explained by means of examples.

Example 1,1,3-Bis [3-benzyloxy-2-methyl-4 (1H) -pyridinon-1-yl] -propane 20 NaOH (1.40 g, 35.0 mmol) is added to a solution of 3-benzyloxy-2-methyl- Add 4-pyrone (10.00 g, 46 mmol) and 1.3-diaminopropane (1.14 g, 15 mmol) in a methanol-water mixture (2: 1, 210 mL) and reflux for 7 days. After cooling to room temperature, the product is extracted with dichloromethane (4x50mL), the solvent 25 is removed by rotary evaporation and a brown oil is obtained, which is dried under reduced pressure.

Example 2.1,4-Bis [3-benzyloxy-2-methyl-4 (1H) -pyridinon-1-yl] butane NaOH (1.40 g, 35.0 mmol) becomes a solution of 3-benzyloxy-2-methyl-4 pyrone (10.00 g, 46 mmol) and 1,4-diaminobutane (1.35 g, 15 mmol) in a methanol-water mixture (2: 1, 210 mL) and refluxed for 7 days. After cooling to room temperature, the product is extracted with dichloromethane (3x50mL), the solvent......... ········································· Rinse off with a brown oil. The pure product was obtained by slow crystallization from the oil, washing with acetonitrile (3 x 30 mL) and drying in vacuo. 5 Example 3.1.6-Bis [3-benzyloxy-2-methyl-4 (1H) -pyridinone-1-yl-hexane

NaOH (1.40 g, 35.0 mmol) is added to a solution of 3-benzyloxy-2-methyl-4-pyrone (10.00 g, 46 mmol) and 1.6 r diaminohexane (1.78 g, 15 mmol) in a methanol-water mixture (2: 1). 1, 210 mL) and boiled for 7 days at reflux. After cooling to room temperature, the product is extracted with dichloromethane (3x50 ml), the solvent is removed by rotary evaporation and a brown oil is obtained. The pure product was obtained by slow crystallization from the oil, washing with acetonitrile (3 x 30 mL) and drying in vacuo. Example 4.1,8-Bis [3-benzyloxy-2-methyl-4 (1H) -pyridinon-1-yl] octane

NaOH (1.40 g, 35.0 mmol) is added to a solution of 3-benzyloxy-2-methyl-4-pyridone (10.00 g, 46 mmol) and 1,8-diaminooctane (2.17 g, 15 mmol) in a methanol-water mixture (2: 1, 210 mL) and refluxed for 6 days. After cooling to room temperature, the product is extracted with dichloromethane (3 × 50 ml), the solvent is removed in a rotary evaporator and a brown oil is obtained. The pure product was obtained by slow crystallization from the oil, washing with ethyl acetate (3 x 30 mL) and drying in vacuo. 25 Example 5.1,12-Bis [3-benzyloxy-2-methyl-4 (1 H) -pyridinone-1-yl] dodecane

NaOH (1.40 g, 35.0 mmol) is added to a solution of 3-benzyloxy-2-methyl-4-pyridone (10.00 g, 46 mmol) and 1,12-diaminododecane (3.09 g, 15.0 mmol) in a methanol-water mixture (2: 1, 210 mL) and refluxed for 6 days. After cooling to room temperature, the product is extracted with dichloromethane (3 × 50 ml), the solvent is removed in a rotary evaporator and a brown oil is obtained. The pure product, a yellow oil, was obtained by column chromatography with methanol on silica gel by slow crystallization.

Example 6.1.3-Bis [3-hydroxy-2-methyl-4 (1H) -pyridinon-1-yl] -propane Hydrogen was prepared by mixing 1,3-bis [3-benzyloxy-2-methyl-5 4 (1H) -pyridinon-1-yl] propane (1 g, 2.12 mmol) and palladium on charcoal (10% Pd) (100 mg) in glacial acetic acid (50 mL). The conversion was monitored by thin-layer chromatography until the starting material had disappeared. The catalyst and the insoluble product were filtered off and the product was dissolved with water. The solvent was removed by rotary evaporation and the product was dried under reduced pressure.

Example 7,1,4-Bis [3-hydroxy-2-methyl-4 (1H) -pyridinone-1-yl] butane Hydrogen was hydrogenated by a mixture of 1,4-bis [3-benzyloxy-2-methyl-4 ( 1H) -pyridinon-1-yl] butane (0.8 mg, 1.65 mmol) and palladium on charcoal 15 (10% Pd) (80 mg) in glacial acetic acid (30 mL). The conversion was monitored by thin-layer chromatography until the starting material had disappeared. The catalyst and the insoluble product were filtered off and the product was dissolved with water. The solvent was removed by rotary evaporation and the product was dried under reduced pressure. 20

Example 8,1,6-bis [3-hydroxy-2-methyl-4 (1H) -pyridinon-1-yl] hexane Hydrogen was replaced by a mixture of 1,6-bis [3-benzyloxy-2-methyl-4 ( 1H) -pyridinon-1-yl] hexane (1g, 1.95mmol) and palladium on charcoal (10% Pd) (100mg) in glacial acetic acid (30mL). The reaction was monitored by thin-layer chromatography until the educt disappeared. The catalyst was filtered off, the solvent was removed by rotary evaporation and the product was dried under reduced pressure.

Example 9.1,8-bis [3-hydroxy-2-methyl-4 (1H) -pyridinon-1-yl] octane. Hydrogen was replaced by a mixture of 1,8-bis [3-benzyloxy-2-methyl-4 ( 1H) -pyridinon-1-yl] octane (400 mg, 0.74 mmol) and palladium on charcoal (10% Pd) (40 mg) in glacial acetic acid (10 mL). The conversion was monitored by thin-layer chromatography until the starting material had disappeared. The catalyst was filtered off, the solvent was removed by rotary evaporation and the product was dried under reduced pressure. 5 Example 10,1,8-Bis [3-hydroxy-2-methyl-4 (1 H) -pyridinone-1-yl] octane

Hydrogen was hydrogenated by a mixture of 1,12-bis [3-benzyloxy-2-methyl-4 (1H) -pyridinone-1-yl] dodecane (84 mg, 0.14 mmol) and palladium on charcoal (10% Pd) (9 mg) in glacial acetic acid (10 mL). The conversion was monitored by thin-layer chromatography until the starting material had disappeared. The catalyst was filtered off, the solvent was removed by rotary evaporation and the product was dried under reduced pressure.

Example 11.1.3-Bis {chloro [3- (oxo-x0) -2-methyl-4- (1H) -pyridinonato * 04] 776-p-isopropyltoluene) ruthenium} propane 15 A solution of bis [(77 ® -p-isopropyltoluene) dichlororuthenium] (196.6 mg, 0.32 mmol) in methanol (15.0 mL) was added to a solution of 1,3-bis [3-hydroxy-2-methyl-4 (1H) -pyridinon-1-yl ] propane (124.5 mg, 0.43 mmol) and sodium methoxide (51.1 mg, 0.95 mmol) in methanol (15.0 mL). The reaction mixture was stirred at room temperature under argon atmosphere for 20 days. The unreacted starting materials were removed by filtration and the solvent was removed by rotary evaporation. The pure complex (orange-red solid) was obtained by extraction with dichloromethane / diethyl ether (2: 1, 30 mL), evaporation of the solvent and drying in vacuo. Example 12.1,4-Bis {chloro [3- (oxo-KO) -2-methyl-4- (1H) -pyridinonato / e04] 77®-p-isopropyltoluene) ruthenium} butane

A solution of bis [(77®-p-isopropyltoluene) dichlororuthenium] (108.7 mg, 0.18 mmol) in methanol (10.0 mL) was added to a solution of 1,4-bis [3-hydroxy-2-methyl-4 (1H ) -pyridinon-1-yl] butane (60.0 mg, 0.20 mmol) and 30% sodium methoxide (23.4 mg, 0.43 mmol) in methanol (10 mL). The reaction mixture was stirred at room temperature under argon atmosphere for 3 days. The unreacted starting materials were removed by filtration. Ee ee ee ee ee e e e e e e e e e e e e e ee e e e 18 e and the solvent was spun off. The pure complex (orange solid) was obtained by extraction with dichloromethane / diethyl ether (2: 1, 30 mL), evaporation of the solvent and drying in vacuo. Example 13.1,6-Bis (chloro [3- (oxo-x0) -2-methyl-4- (1H) -pyridinonato-x04] η6-p-isopropyltoluene) ruthenium} hexane

A solution of bis [(76-p-isopropyltoluene) dichlororuthenium] (153.3 mg, 0.25 mmol) in methanol (15.0 mL) was added to a solution of 1,6-bis [3-hydroxy-2-methyl-4 (1H) -pyridinon-1-yl] hexane (93.3 mg, 0.28 mmol) and 10% sodium methoxide (33.5 mg, 0.62 mmol) in methanol (15 mL). The reaction mixture was stirred at room temperature under argon atmosphere for 2 days. The unreacted starting materials were removed by filtration and the solvent was removed by rotary evaporation. The pure complex (orange solid) was obtained by extraction with dichloromethane / diethyl ether (2: 1, 15 30 mL), evaporation of the solvent and drying in vacuo.

Example 14.1,8-Bis {chloro [3- (oxo-O) -2-methyl-4- (1H) -pyridinonato-K04]; 76-p-isopropyltoluene) ruthenium} octane

A solution of bis [(^ ep-isopropyltoluene) dichlororuthenium] (76.0 mg, 20 0.12 mmol) in methanol (10.0 mL) was added to a solution of 1,8-bis [3-hydroxy-2-methyl-4 (1H) -pyridinon-1-yl] octane (50 mg, 0.14 mmol) and sodium methoxide (17.0 mg, 0.31 mmol) in methanol (10 mL). The reaction mixture was stirred at room temperature under argon atmosphere for 2 days. The unreacted starting materials were removed by filtration 25 and the solvent was removed by rotary evaporation. The pure complex was obtained by extraction with dichloromethane / diethyl ether (2: 1, 2 x 30 mL), evaporation of the solvent and drying in vacuo.

Example 15.1.12-Bis {chloro [3- (oxo-x0) -2-methyl-4- (1H) -pyridinonato * 04] 76-p-isopropyltoluene) ruthenium} dodecane 30 ·· ·· ·· · • · · · · · «t • · · • Μ · • · ····· • · · · · · ·" ·· "19

A solution of bis [(/ 6-p-isopropyltoluene) dichlororuthenium] (76.0 mg, 0.12 mmol) in methanol (10.0 mL) was added to a solution of 1,12-bis [3-hydroxy-2-methyl-4 ( 1H) -pyridinon-1-yl] -dododecane (58 mg, 0.14 mmol) and sodium methoxide (17.0 mg, 0.31 mmol) in methanol (10 mL). The reaction mixture was stirred at room temperature under argon atmosphere for 2 days. The unreacted starting materials were removed by filtration and the solvent was removed by rotary evaporation. The pure complex was obtained by extraction with dichloromethane / diethyl ether (2: 1, 2 x 30 mL), evaporation of the solvent and drying in vacuo. 10

Example 16,1,6-Bis {chloro [3- (oxo-x0) -2-methyl-4- (1H) -pyridinonato-x04] 76-p-isopropyltoluene) osmium} hexane

A solution of bis [(^ 6-p-isopropyltoluene) dichloroosmium] (197.7 mg, 0.25 mmol) in methanol (15.0 mL) was added to a solution of 1,6-bis [3-15-hydroxy-2-methyl-4 ( 1H) -pyridinon-1-yl] hexane (93.3 mg, 0.28 mmol) and sodium methoxide (33.5 mg, 0.62 mmol) in methanol (15 mL). The reaction mixture was stirred at room temperature under argon atmosphere for 2 days. The unreacted starting materials were removed by filtration and the solvent was removed by rotary evaporation. The pure complex (orange solid) was obtained by extraction with dichloromethane / diethyl ether (2: 1, 2 x 30 mL), evaporation of the solvent and drying in vacuo.

Example 17. [(r -6-p-isopropyltoluene) (3,5,6-bicyclophosphite-1,2-o-25-cyclohexylidene-D-glucofuranoside) ruthenium]

A solution of bis [(p6-p-isopropyltoluene) dichlororuthenium] (202 mg, 0.3 mmol) in CH 2 Cl 2 (2 mL) was added to a solution of 1,2-O-cyclohexylidene-D-glucofuranose 3,5,6-bicyclophosphite (200 mg, 0.7 mmol) in CH 2 Cl 2 (40 ml) and stirred at 50 ° C for 2 h. The solvent was removed by rotary evaporation and the solid was dried in vacuo. To remove traces of CH 2 Cl 2, the compound was dried at 70 ° C for 2 days and at 60 ° C in vacuo. ♦ · · · · · · · · · · · · · · · · · · ♦

• · · I · · · · · · · · · 20

Example 18. [(Λ76-ρ-1-sopropyltoluene) (3,5,6-bicyclophosphite-ethyl-1-thio-α-D-glucofuranoside) ruthenium]

A solution of bis [(/ 76-p-isopropyltoluene) dichlororuthenium] (185 mg, 0.3 mmol) in CH 2 Cl 2 (2 ml) became a solution of ethyl 1-thio-α-D-glucofuranose 3,5,6-bicyclophosphite (153 mg, 0.6 mmol) in CH 2 Cl 2 (40 mL) in CH 2 Cl 2 (40 mL) and stirred at 50 ° C for 2 h. The solvent was removed by rotary evaporation and the solid was dried at 60 ° C. in vacuo. 10 Example 19. [(r -6-p-isopropyltoluene) (3,5,6-bicyclophosphite-1,2-o-isopropylidenes-α-D-glucofuranoside) ruthenium]

A solution of bis [(p6-p-isopropyltoluene) dichlororuthenium] (123 mg, 0.2 mmol) in CH 2 Cl 2 (1 ml) was added to a solution of 1,2-O-isopropylidenedi-D-glucofuranose 3,5,6-bicyclophosphite (100 mg, 0.4 mmol) in CH 2 Cl 2 (20 mL) 15 and stirred at 50 ° C for 2 h. The solvent was removed by rotary evaporation and the solid was dried in vacuo. To remove traces of CH 2 Cl 2, the compound was dried at 70 ° C for 2 days and at 60 ° C in vacuo. 20 Example 20. [(Ru (r 6-arene) (N, 0-ligand) (K1-azole)] (CF 3 SO 3)

To a solution of 1 equivalent of the complex [Ru (ri6-arene) (N, 0-ligand) Cl] in tetrahydrofuran was added equivalents of AgCF3SO3 and the mixture stirred at room temperature for two hours. Thereafter, 1 equivalent of azole (pyrazole, indazole, imidazole, benzimidazole and 25 derivatives thereof, 1,2-bis (1,2,4-triazol-1-yl) ethane was added to the reaction solution and again stirred for two hours at room temperature The residue was evaporated to dryness and taken up in dichloromethane and the product was precipitated with diethyl ether, separated and washed twice with diethyl ether and dried in vacuo. · · · · · · ·

• · · · · · 21 ··

Example 21. [(Ru (Ti6-arenes) (N, 0-ligand) -azole)] (CF 3 SO 3) 2 To a solution of 2 equivalents of complex [Ru (q6-adenes) (N, 0-ligand) Cl] in tetrahydrofuran, 2 equivalents of AgCF 3 SO 3 were added 5, and the mixture was stirred for 2 hours at room temperature. Thereafter, equivalents of azole pyrazole, indazole, imidazole, benzimidazole and derivatives thereof of 1,2-bis (1,2,4-triazole-Myl) ethane were added to the reaction solution and again stirred at room temperature for two hours by centrifugation from the solid freed and the supernatant freed of solvent in vacuo. The residue evaporated to dryness was taken up in dichloromethane and the product was precipitated with diethyl ether, separated and washed twice with diethyl ether and dried in vacuo. 15

Example 22. (Quinolin-8-olato-K / V1, K08) chloro [(1,2,3,4,5,6-r /) -1-isopropyl-4-methylbenzene] osmium (I) 734 mg 8-hydroxyquinoline and 289 mg of sodium methylate are suspended in 20 ml of methanol, the resulting reaction mixture is stirred at RT for 10 minutes. With vigorous stirring, 2 g of [(r) 6-p-cym) OsCl 2] 2 are added and the resulting suspension, containing orange precipitate, stirred for two hours. Then about half of the solvent is removed under reduced pressure and the intermediate product is precipitated with 20 ml of diethyl ether. The solid is filtered through a G4 glass filter crucible, washed with 5 ml of diethyl ether and dried briefly in a high vacuum.

Subsequently, the filter cake is extracted six times with 10 ml of dichloromethane and the combined organic phases are concentrated in vacuo until incipient crystallization. By adding 30 ml of diethyl ether, the product is completely precipitated, the precipitate is stirred for an hour 30. Then the reaction mixture is passed over a G4

Filtered glass filter crucible and the solid washed with 10 ml of diethyl ether. The product is dried under high vacuum. ·· ·· ·· · e · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···· ♦ · · · · et # ·· · 22

Example 23. (Quinoline-e-olato-K / VVO 3 -il-imidazole-KA / 3) [(1,2,3,4,5,6- / 7) -1-isopropyl-4-methylbenzene] osmium ( II) chloride 200 mg of [(r 6-p-Cym) OsCl (quin)] and 27 mg of imidazole are suspended in 3 ml of 5 methanol, the reaction mixture is stirred for 18 hours at RT. Then, the resulting clear solution is filtered through Celite and concentrated in vacuo to 0.5 ml. By adding 5 ml of diethyl ether, the product is precipitated, the resulting suspension is stirred for a further five hours. Subsequently, the reaction mixture is filtered through a G4 glass filter crucible 10 and the product washed twice with 2 ml of diethyl ether. The high vacuum is dried to freedom from solvents.

Example 24. (Quinolin-8-olato-K / V1, KO®) (1H-imidazole-K / S ^) [(1,2,3,4,5,6- / 7) -1-isopropyl-4 -methylbenzene] osmium (II) trifluoromethanesulfonate A suspension of 250 mg of [(n6-p-cym) OsCl (quin)] and 127.5 mg of silver triflate in 5 ml of methanol is stirred at RT for 30 minutes. Then 33.8 mg of imidazole are added and the suspension is stirred for a further 30 minutes. The solvent is removed on a vacuum and the residue is dried for one hour under high vacuum. Then the solid is resuspended in 20 ml of dichloromethane and filtered through Celite from the white solid. The filtrate is concentrated in vacuo to 0.5 ml, with vigorous stirring 5 ml of diethyl ether are added. The resulting yellow-brown oil is stirred until a yellow precipitate begins to precipitate, then it is stirred for a further 18 hours. Via a G4 glass filter crucible 25, the product is filtered off, washed twice with 2 ml of diethyl ether and dried under high vacuum.

Example 25. (Quinolin-8-olato-KA / 1, KOe) [(1,2,3,4,5,6- / 7) -1-isopropyl-4-methylbenzene] (1H-pyrazole-K / V ^ osmiunhOI) trifluoromethanesulfonate A suspension of 250 mg of [(n6-p-cym) OsCl (quin)] and 127.5 mg of silver triflate in 5 ml of methanol is stirred at RT for 30 minutes. Then 33.8 mg of pyrazole are added and the suspension is stirred for a further 30 minutes. ;

• * · · · • · ····· • · · · ····

The solvent is removed on a vacuum and the residue is dried for one hour under high vacuum. Then the solid is resuspended in 5 ml of dichloromethane and filtered through Celite from the white solid. The filtrate is concentrated in vacuo to 0.5 ml, with vigorous stirring 5 ml of diethyl ether are added. The resulting yellow solution is again concentrated in vacuo. After half of the solvent is removed, a yellow precipitate begins to precipitate. 3 ml of diethyl ether are added and the suspension is stirred for 18 hours. Then the product is filtered off through a G4 glass filter crucible, washed twice with 2 ml of 10 diethyl ether and dried under high vacuum.

Example 26. (1 / - / - Benzimidazole KA / 3) (Quinoline-8-olato-K / S / 1, K08) [(1,2,3,4,5,6- / 7) -1 - isopropyl 4-methylbenzene] osmium (II) trifluoromethanesulfonate A suspension of 250 mg of [(r 6-p-Cym) OsCl (quin)] and 127.5 mg of 15 silver triflate in 5 ml of methanol is stirred at RT for 30 minutes. Then 58.6 mg of benzimidazole are added and the suspension is stirred for a further 30 minutes. The solvent is removed on a vacuum and the residue is dried for one hour under high vacuum. The residue is then resuspended in 5 ml of dichloromethane and filtered through Celite from white solid 20. The filtrate is concentrated in vacuo to 0.5 ml, with vigorous stirring 5 ml of diethyl ether are added. The resulting yellow precipitate is stirred for 18 hours at RT, then the solid is filtered through a G4 glass filter crucible. The product is washed twice with 2 ml of diethyl ether and dried under high vacuum. 25

Example 27. (IH-benzimidazole-K / N, X-quinoline-β-olato-KA / VO8) [(1,2,3,4,5,6- / 7) -1-isopropyl-4-methylbenzene] osmium ( ll) hexafluorophosphate A solution consisting of 100.4 mg of silver hexafluorophosphate in 2 ml of 30 methanol is added dropwise to a suspension of 200 mg of [(q6-p-cymene) OsCl (quin)] in 10 ml of methanol. The orange solid goes into solution, it forms a white solid and after stirring for 30 minutes at RT 46.9 mg of benzimidazole dissolved in 2 ml of methanol are added. There will be two more 24 ••• ff ··

Stirred for hours, then filtered from the white solid and the filtrate was concentrated strongly on a rotary evaporator. The batch is stored overnight at 4 ° C. The precipitated crystals are carefully washed with a little cold diethyl ether and dried under high vacuum. 5

Example 28. (Quinolin-8-olato-KW1 .KO ^ .e-DimethyM H-benzimidazole-1 ^) ((1,2,3,4,5,6-rj) -1-isopropyl-4-methylbenzene] osmium (II) hexafluorophosphate

To a suspension of 200 mg of [(n6-p-cym) OsCl (quin)] in 10 ml of methanol 10, a solution consisting of 100.4 mg of silver hexafluorophosphate in 2 ml of methanol is added dropwise. The orange solid goes into solution, it forms a white solid and after stirring for 30 minutes at RT 58 mg of 5,6-dimethylbenzimidazole dissolved in 2 ml of methanol are added. The mixture is stirred for a further two hours, then filtered off from the white solid and the filtrate 15 concentrated on a rotary evaporator to half. The batch is stored overnight at 4 ° C. The precipitated crystals are carefully washed with a little cold diethyl ether and dried under high vacuum. For the compounds of Examples 11 to 16, data were obtained in vitro in two cell lines, which showed increasing activity with increasing chain length in the ruthenium complexes (Figure 2). The comparison of the compounds of Examples 13 (Ru) and 16 (Os), each with the same spacer, gave an approximately 3x higher activity for the Ru compound. The results are shown in FIGS. 1 and 2. 30

Claims (19)

Claims 1. A compound of the formula (I) 5 + wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8 and R 9 are hydrogen, halogen, hydroxyl, carboxyl, nitro, amino, carbonyl and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl , Alkenyl and alkynyl, or alkylaryl or COOR 'where R' = alkyl, aryl, alkylaryl, X, X, X independently = N, O, S, X3 = O, S or N-R10, where R10 = a linear or branched C 1-10 alkyl, a linear or branched C 1-10 alkenyl, which may possess one or more ether, thioether, amino, ester, amide or thioester functions within the chain and which are further substituted by halogen, hydroxyl , Carboxyl, and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, or alkylaryl or COOR 'with R' = alkyl, aryl, alkylaryl, Y, an anion or H 2 O , DMSO, P (aryl) 3, a nitrogen-containing it is a heterocycle having one or more nitrogen atoms in the ring or P-glucofuranoside, Z is a physiologically acceptable anion, M is Ru or Os, m is 1-4, the dimeric, trimeric or tetrameric complexes either via R1, R2, R3 or R10 are linked together, q = 1, 2, 3 and s = 0,1, 2. 2. A compound according to claim 1, wherein X1 and X2 are O and X3 N-R10. 3. A compound according to any one of claims 1 to 2, wherein Y is chlorine or bromine. 27 • 4. A compound according to any one of claims 1 to 3, wherein R5 and R8 are alkyl. 5. A compound according to any one of claims 1 to 4, wherein R5 is methyl and R8 isopropyl. 6. A compound according to any one of claims 1 to 5, wherein R is a C3-C12 alkyl. 10 7. A compound according to any one of claims 1 and 6, wherein m is 2 and s is 0. 8. A compound of the formula (II) 15 (li) S + (Zq ') sm / qm hydrogen, halogen, hydroxyl, carboxyl, nitro, amino, carbonyl and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, or alkylaryl or COOR 'with R' = alkyl is aryl, alkylaryl, Y, an anion or H 2 O, DMSO, P (aryl) 3, a nitrogen-containing heterocycle having one or more nitrogen atoms in the ring or P-glucofuranoside, Z is a physiologically acceptable anion , M = Ru or Os, m = 1-4, the dimeric, trimeric or tetrameric complexes being linked together via either R11 or R12, q = 1, 2, 3 and s = 0.1, 2. and R11 and R12 are independently 0-R13, S-R13 or N-R13, wherein R13 is hydrogen, carboxyl, carbonyl, substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, alkylaryl , or phosphate is, ···· ♦♦ ····························································································· ·· ·· ·· ···· ·· 29 A compound according to claim 8 wherein R 11 and R 12 together form a 0,0 or S, S-acetal substituted with substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, Alkylaryl are substituted. A compound according to any one of claims 8 or 9 wherein R 8 is methyl and R 5 is isopropyl and R 12 is thioethyl. 0 A compound according to any one of claims 8 to 10, wherein M is ruthenium. 12. A compound of the formula (III) (III) ·············································································· 30 Wherein R4, R5, R6, R 7, R 8 and R 9 are hydrogen, halogen, hydroxyl, carboxyl, nitro, amino, carbonyl and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, or alkylaryl or COOR 'with R' = Alkyl aryl, alkylaryl, Z is a physiologically acceptable anion, 10 M = Ru or Os, m = 1-4, q = 1.2, 3 and 15 s = 0.1, 2. and R 14, R 15, R 16, R 17, R 18 and R 19 are hydrogen, carboxyl, carbonyl, substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, 20 substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, alkylaryl, and W pyrazole, indazole, Imidazole, benzimidazole, pyrazine or 1,2,4-triazole. A compound according to claim 12, wherein R 14, R 15, R 16, R 17, R 18 and R 19 are hydrogen and M is ruthenium. 14. A compound according to claim 12, wherein M is osmium. 15. A medicament containing a compound according to at least one of claims 1 to 14. φφ • φφ • φ ·φφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφ • φφφφφ · φφφφφφφφφ · 31 16.Use of a compound according to any one of claims 1 to 14 for the manufacture of a medicament for the prophylaxis and / or treatment of cancer. 17. A process for preparing a compound according to any one of claims 1 to 7 wherein a ruthenium complex of the formula (IV) wherein R4, R5, R6, R7, R8 and R9 are hydrogen, halogen, hydroxyl, carboxyl, nitro, amino, carbonyl and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, or Alkylaryl or COOR 'with R' = alkyl aryl, alkylaryl, and D is a halogen, with a compound of general formula (V), R. 20 ♦ · ♦ • · · • · «• · ♦ • · · ··· < · · • · • · · · • · · • · · · · · · ♦ • · · • · · · • · · · · · · • · · · · · · · · · 32 wherein R1, R2, R3 are hydrogen, halogen, hydroxyl, carboxyl, nitro, amino, carbonyl and substituted or unsubstituted cycloalkyl, 5 cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, or alkylaryl or COOR 'with R '= Alkyl aryl, alkylaryl, X 1, X 2 = independently of one another are N, O, S, X 3 = O, S or N-R 10, where R 10 = a linear or branched C 1-30 -alkyl, a linear or branched one Ci.ioo alkenyl, which may possess one or more ether, thioether, 15 amino, ester, amide or thioester functions within the chain and which further comprises halogen, hydroxyl, carboxyl, and substituted or unsubstituted cycloalkyl, cycloalkenyl, Aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, or alkylaryl or COOR 'with R' = alkyl 20 aryl, alkylaryl, may be reacted. 18. A process for preparing a compound according to any one of claims 8 to 11 wherein a ruthenium complex of the formula (IV), 33 ► ·················· Wherein R4, R5, R6, R7, R8 and R9 are hydrogen, halogen, hydroxyl, carboxyl, nitro, amino, carbonyl and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, or Alkylaryl or 10 COOR 'with R' = alkyl aryl, alkylaryl, and D is a halogen, with a compound of general formula (VI), wherein R11 and R12 are 15 • I 5 are independently 0-R13, S-R13 or N-R13, wherein R13 is hydrogen, carboxyl, carbonyl, substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, alkylaryl, or phosphate is, is being implemented. 10 19.A process for preparing a compound according to any one of claims 11 to 14, wherein a ruthenium complex of the formula (IV) 15th wherein R4, R5, R6, R7, R8 and R9 are hydrogen, halogen, hydroxyl, carboxyl, nitro, amino, carbonyl and substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, or alkylaryl or COOR 'with R' = alkyl, aryl, alkylaryl, and D is a halogen, ♦ · • · · • · · · · · ····· • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •. ················································· 35 with a compound of general formula (VII), 5 OH R R 19 18! Wherein R14, R15, R16, R17, R18 and R19 are hydrogen, carboxyl, carbonyl, substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, substituted or unsubstituted, linear or branched alkyl, alkenyl and alkynyl, alkylaryl, and the product obtained subsequently reacted with pyrazole, indazole, imidazole, benzimidazole, pyrazine or 1,2,4-triazole. 15 20 25