DE19701692A1 - Anticancer pharmaceutical composition - Google Patents

Abstract

A pharmaceutical comprises one or more metal complexes of formula (I) {R<1>(CH2)mC(O)-CR<3>C(O)R<2>}2M(X)2-n (I) M = titanium, zirconium or hafnium; R<1> = H, 1-8C alkyl or phenyl which is optionally substituted by one or more F, Cl, Br, NO2, 1-4C alkyl, 1-4C alkoxy or CF3 groups; R<2> = 1-8C alkyl or phenyl which is optionally substituted by one or more F, Cl, Br, NO2, 1-4C alkyl, 1-4C alkoxy or CF3 groups; R<3> = H, 1-4C alkoxycarbonyl or phenyl; X = a mono- (n = 0) or di- (n = 1) de-protonated pentose or hexose, which is optionally substituted by one or more H, NH2, 1-3C alkylamino, thiol, 1-3C alkylthiol, COOH, 1-3C alkoxycarbonyl, acetoxy, 1-3C alkyl or 1-3C alkoxy groups; one or more OH groups may also be replaced by H; m = 0 or 1 but is not 0 when R<1> = H, and n = 0 or 1. If the ligand X<-> or X<2-> contains an NH2 group, then (I) may also be present as the hydrogen halide. Also claimed are aqueous solutions containing (I).

Description

Technical field

The invention relates to metal complexes having an antineoplastic effect and these drugs.

State of the art

There are currently two metal complexes, cis-diammine dichloroplatin (II) and cisplatin (INN = Inter national nonproprietary name) and cis-diammine (cyclobutane-1,1-dicarboxylato) platinum (II), Carboplatin (INN) used in the clinic as cancer chemotherapy drugs. Cisplatin has proven to be an extremely potent anti-tumor agent particularly in the treatment of Testicular tumors but also z. B. ovarian tumors and small cell bronchial carcinomas proven. A disadvantage of cisplatin is its relatively high toxicity. Are particularly serious its nephrotoxicity and permanent hearing loss. Kidney and Hearing damage becomes apparent after the administration of a single therapeutic dose found considerable frequency. In addition to the nephro- and haematotoxic effects for the patients above all the long-lasting severe nausea and the associated Nausea extremely unpleasant.

The spectrum of action of carboplatin largely resembles that of cisplatin. Is carboplatin Compared to cisplatin, less kidney damage, although with the same therapeuti efficiency, myelotoxicity is more important as a dose-limiting factor. In addition, carboplatin is less nauseating.

There have been numerous other platinum complexes and complex compounds of others recently Transition metals proposed as cytostatic agents. In DE-OS 28 01 355 become a brown amorphous complex, which is formed by reacting ascorbic acid with a Titanium (III) - and a copper (II) compound (molar ratio 36: 1: 6) was obtained curative and prophylactic effects against u. a. Attributed to leukemia. It has been reported that Titanocene, zirconocene and hafnocene dichloride inhibiting against the Ehrlich ascites Mouse tumor [P. Köpf-Maier, B. Hesse, H. Köpf, J. Cancer Res. Clin. Oncol. 96, 43 (1980)]. In EP-OS 49 486 and EP-OS 73 502 bis (β-diketonato) tin, Titanium, zirconium and hafnium complexes with antineoplastic activity are described.  

Presentation of the invention

It has now surprisingly been found that the metal complexes of the general formula (I)

[{R ¹ (CH ₂ ) _m C (O) CR ³ C (O) R ² } ₂ M (X) _2-n ] (I),

wherein
M titanium, zircon or hafnium,
R ¹ is hydrogen, C ₁ -C ₈ alkyl or phenyl substituted by fluorine, chlorine, bromine, nitro, C ₁ -C ₄ - may be substituted alkyl, C ₁ -C ₄ alkoxy or trifluoromethyl mono- or polysubstituted,
R ² C ₁ -C ₈ alkyl, C ₁ -C ₄ alkoxy or phenyl, which is replaced by fluorine, chlorine, bromine, nitro, C ₁ - C ₄ alkyl, C ₁ -C ₄ alkoxy or trifluoromethyl one or more times can be substituted
R ^{3 is} hydrogen, C ₁ -C ₄ alkoxycarbonyl or phenyl,
X⁻ ^{/ 2} ⁻ single (for n = 0) or double (for n = 1) deprotonated pentoses or hexoses caused by hydrogen, amino, C ₁ -C ₃ alkylamine, thiol, C ₁ -C ₃ alkylthiol, carboxyl , C ₁ - C ₃ alkoxycarbonyl, acetoxy, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy can be mono- or polysubstituted, ie one or more OH groups can be hydrogen atoms or the groups mentioned above be replaced
m is the number 0 or 1, but not 0 if R ^{1 is} hydrogen, and
n is the number 0 or 1
mean and, insofar as a ligand X⁻ / X ^2- contains an amino group whose hydrohalides have an interesting cytostatic activity with a favorable therapeutic range and are suitable as a chemotherapeutic agent for the treatment of cancer.

The invention therefore relates to medicaments comprising one or more of the metal complexes of the above general formula (I), in which M, R ¹ , R ² , R ³ , X⁻ / X ^2- , m and n have the meanings given above, in particular to fight cancer.

Medicaments containing one or more metal complexes of the general formula (I ') are particularly preferred,

[{R ^{1 '} (CH ₂ ) _m' C (O) CR ^{3 '} C (O) R ^2' } ₂ M '(X') _2-n ] (I '),

wherein
M 'titanium, zircon or hafnium,
R ^{1 'is} hydrogen, C ₁ -C ₆ alkyl or phenyl, which can be mono- or polysubstituted by fluorine, chlorine, bromine, nitro, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy or trifluoromethyl,
R ^{2 '} C ₁ -C ₆ alkyl, C ₁ -C ₂ alkoxy or phenyl, which can be substituted by C ₁ -C ₂ alkoxy,
R ^{3 'is} hydrogen, C ₁ -C ₂ alkoxycarbonyl or phenyl,
X'⁻ ^{/ 2} ⁻ single (for n = 0) or double (for n = 1) deprotonated pentoses or hexoses, which are replaced by hydrogen, amino, thiol, carboxyl, C ₁ -C ₂ alkoxycarbonyl, acetoxy, methyl or C ₁ -C ₂ alkoxy can be mono- or polysubstituted, ie one or more OH groups can be replaced by hydrogen atoms or the groups mentioned above,
m 'is the number 0 or 1, but not 0 if R ^{1' is} hydrogen, and
n is the number 0 or 1
mean and, insofar as a ligand X'⁻ / X ' ^2- contains an amino group, its hydrohalides.

Medicaments containing one or more metal complexes of the general formula (I ″) are particularly preferred,

[{R ^{1 ''} (CH ₂ ) _{m ''} C (O) CR ^{3 ''} C (O) R ^{2 ''} } ₂ M '' (X '') _2-n ] (I ''),

wherein
M '' titanium, zircon or hafnium,
R ^{1 ″ is} hydrogen, C ₁ -C ₄ -alkyl or phenyl, which may be substituted by C ₁ -C ₂ -alkoxy,
R ^{2 ''} C ₁ -C ₄ alkyl or phenyl,
R ^{3 '' is} hydrogen or phenyl,
X''⁻ ^{/ 2} ⁻ single (for n = 0) or double (for n = 1) deprotonated pentoses or hexoses,
m "is the number 1 if R ^{1" is} hydrogen and the number 0 if R ^{1 "is} phenyl,
n is the number 0 or 1
mean.

Particular embodiments of the invention are medicaments containing compounds of the formulas (I), (I ') and (I'') above, in which the variables R1, R1' and R1 '', R2, R2 'and R2'', R3, R3 'or R3'', X⁻ ^{/ 2} ⁻, X'⁻ ^{/ 2} ⁻ or X''⁻ ^{/ 2} ⁻, m, m' or m '' and n have the meanings given above, M, M 'and M'', however, each only mean titanium.

Drugs containing (D-arabinosato-O ^x , O ^y ) bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) titanium (IV) with x = 1, y = 2 or x = are particularly preferred 3, y = 4, bis (D-arabinosato-O ^x ) bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) titanium (IV) with x = 1, 2, 3, 4 or 5, Bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) (D-xylosato-O ^x , O ^y ) titanium (IV) with x = 1, y = 2 or x = 3, y = 5 , Bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) bis (D-xylosato-O ^x ) titanium (IV) with x = 1, 2, 3, 4 or 5, bis (1-phenylbutane -1,3-dionato-O ¹ , O ³ ) (D-ribosato-O ^x , O ^y ) titanium (IV) with x = 1, y = 2 or x = 2, y = 3 or x = 3 , y = 4, bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) bis (D-ribosato-O ^x ) titanium (IV) with x = 1, 2, 3, 4 or 5, ( D-Fructosato-O ^x , O ^y ) bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) titanium (IV) with x = 1, y = 2 or x = 1, y = 3 or . x = 2, y = 3 or x = 4, y = 5 and / or bis (D-fructosato-O ^x ) bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) titanium (IV ) with x = 1, 2, 3, 4, 5 or 6.

The variables x and y stand for the numbering of the carbon atoms common in sugars and thus define the possible positions of the oxygen atoms over which the respective one Sugar can be bound to the metal central ion.

Hydrohalides are understood to mean hydrochlorides, hydrobromides and hydroiodides, hydrochlorides are preferred.

C ₁ -C ₈ alkyl radicals are to be understood as meaning branched and straight-chain alkyl radicals having one to eight carbon atoms.

In all cases, the pentoses and hexoses are bound to the metal central ion via a or two oxygen atoms.  

Another object of the invention is the use of the compounds of the general Formulas (I), (I ') and (I' ') for combating cancer and for producing Medicines, in particular those against cancer.

The 1,3-diketones are known or can be prepared by methods known per se the. For example, they can be by condensation of the corresponding aryl methyl ketone with ethyl acetate or the corresponding arylacetic acid with sodium amide can be obtained as a condensing agent [J.T. Adams, C.R. Hauser, J. Amer. Chem. Soc. 66, 1220 (1944)]. It is also possible to add the corresponding in ethyl acetate ester dissolved aryl methyl ketone to a suspension of sodium in benzene or toluene to get the 1,3-diketones [D.W. Brown, S.F. Dyke, M. Salisbury, G. Hardy, J. Chem. Soc. (c), 3219 (1971)]. Another possibility is the implementation of arylmethyl ketones with acetic anhydride in the presence of boron trifluoride [H.G. Walker, C.R. Hauser, J. Amer. Chem. Soc. 68, 2742 (1946)]. 1-Benzyl-1,3-diketones are obtained by condensing the corresponding ethyl phenylacetate with the corresponding methyl ketone in counter were made from sodium amide [A. Becker, Helv. Chim. Acta 149, 1114 (1949)].

The invention furthermore relates to a process for preparing the compounds of the general formulas (I) or (I '), preferably (I''), in which M, M' or M '', R1, R1 'or R1'', R2, R2' or R2 '', R3, R3 'or R3'', X⁻ ^{/ 2} ⁻, X'⁻ ^{/ 2} ⁻ or X''⁻ ^{/ 2} ⁻, m, m' or m '' and n have the meanings given above, particularly preferably (I ''), in which X''⁻ ^{/ 2-} single (for n = 0) or double (for n = 1) deprotonated D (-) - ribose , D (-) - arabinose, D (+) - xylose or D (-) - fructose, which is characterized in that a dialkoxybis (β-diketo nato) metal (IV) compound [{R ¹ (CH ₂ ) _m C (O) CR ³ C (O) R ² } ₂ M (OR) ₂ ] or [{R ^{1 '} (CH ₂ ) _m' C (O) CR ^{3 '} C (O) R ^2' } ₂ M (OR) ₂ ] or [{R ^{1 ''} (CH ₂ ) _{m ''} C (O) CR ^{3 ''} C (O) R ^{2 ''} } ₂ ₋ M (OR) ₂ ], where M, M 'or M'', R1, R1' or R1 '', R2, R2 'or R2'', R3, R3' or R3 '' and m, m 'or m''die have the meanings given above and R represents a methyl or ethyl group, with the exclusion of moisture and light ß with the respective dissolved in a suitable solvent (preferably absolute, hot ethanol or methanol) pentoses or hexoses, which by hydrogen, amino, C ₁ -C ₃ alkylamine, thiol, C ₁ -C ₃ alkylthiol, carboxyl, C ₁ -C ₃ alkoxycarbonyl, acetoxy, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy can be mono- or polysubstituted, ie one or more OH groups can be replaced by hydrogen atoms or the groups mentioned above .

The pharmaceuticals according to the invention are primarily intravenous but also intramuscular, in administered traperitoneally, subcutaneously, rectally or orally. An external application is also possible. Administration by intravenous injection or intravenous injection is preferred fusion.

The pharmaceuticals are prepared by methods known per se, the complex ver bonds as such or, if appropriate, in combination with suitable pharmaceutical carriers materials are used. Contain the new pharmaceutical preparations in addition to the Active ingredient pharmaceutical carriers, the active ingredient content of these mixtures is 0.1 to 99.5, preferably 0.5 to 95 percent by weight of the total mixture.

In accordance with the invention, the active ingredients are in any suitable formulation applied under the condition that the training or maintenance of  sufficient drug levels is guaranteed. This can be done, for example, by oral or parenteral administration can be achieved in suitable doses. The pharma is advantageously located Zeutische preparation of the active ingredients in the form of unit doses to the desired Administration are coordinated. For example, a unit dose may be one tablet Dragee, a capsule, a suppository or a measured volume of a powder, a granulate, a solution, an emulsion or a suspension.

"Unit dose" in the sense of the present invention is a physically determined one Unit that contains an individual amount of the active ingredient in combination with a phar contains pharmaceutical carrier understood, the active ingredient content of a fraction or corresponds to a multiple of a single therapeutic dose. A single dose contains preferably the amount of active ingredient which is administered in one application and which is usually corresponds to a whole, a half, a third or a quarter of the daily dose. If for one single therapeutic administration only a fraction like half or a quarter of the one unit dose is needed, the unit dose is advantageously divisible, e.g. B. in the form of a tablet with notch.

The pharmaceutical preparations according to the invention, when in unit doses are available and for the application z. B. intended for humans, about 0.1 to 500 mg, before in some cases contain 10 to 200 mg and in particular 50 to 150 mg of active ingredient.

In general, it has proven advantageous in human medicine to add the active ingredient (s) parenteral administration in a daily dose of about 0.1 to about 5, preferably 1 to 3 mg / kg Body weight, optionally in the form of several, preferably 1 to 3, individual doses of Er to deliver the desired results. A single dose contains the Active ingredients in amounts of about 0.1 to about 5, preferably 1 to 3 mg / kg body weight. Similar doses can be used in oral treatment.

The therapeutic administration of the pharmaceutical preparation can be 1 to 4 times a day Days take place at fixed or varying times, e.g. B. after meals and / or in the evening. However, it may be necessary depending on the type, the body weight and age of the individual to be treated, the type and severity of the er disease, the type of preparation and application of the drug and the period or interval within which the administration takes place from the doses mentioned to deviate. So in some cases it may be sufficient with less than the above amount of active ingredient, while in other cases the above-mentioned active ingredient amount of substance must be exceeded. As usual with internal tumor therapy, can to reduce the risk of side effects, treatment with the medic according to the invention with the administration of other cytostatics with different spectrum of activity be combined. It may also be expedient to treat according to the cyclical principle perform cytostatic therapy. Here, recovery is achieved after each treatment phase. One makes use of the experience that healthy tissue of the most organs regenerate faster than malignant tissue.

The determination of the optimal dosage and type of application of the drug required Substances can easily be made by any specialist based on their specialist knowledge.  

The pharmaceutical preparations usually consist of the complex compounds and non-toxic, pharmaceutically acceptable drug carriers used as an admixture or Diluent in solid, semi-solid or liquid form or as a coating agent for example in the form of a capsule, a tablet cover, a sachet or another Container for the therapeutically active ingredient come into use. A carrier fabric can e.g. B. as a mediator for drug absorption by the body, as a formu lation aids, as sweeteners, as flavor corrections, as colorants or as cones serve as a preservative.

For oral use, e.g. B. tablets, dragees, hard and soft capsules such. B. from Gelatin, dispersible powders, granules, aqueous and oily suspensions, emulsions, Solutions or syrups are coming.

Tablets can contain inert diluents such as e.g. B. calcium carbonate, calcium phosphate, Sodium phosphate or lactose, granulating and distributing agents such. B. corn starch or alginates, binders such as e.g. B. starch, gelatin or acacia and lubricants such as e.g. B. aluminum or magnesium stearate, talc or silicone oil. You can add Lich be provided with a coating that can be such that it delayed Dissolution and absorption of the drug in the gastrointestinal tract causes so that, for. Legs better tolerance, protracting or retardation is achieved. Gelatin Capsules can be mixed with a solid diluent such as e.g. B. Calcium carbonate or kaolin or mixed with an oily diluent such as. B. Contain olive, peanut or paraffin oil.

Aqueous suspensions can include suspending agents such as e.g. B. sodium carboxymethyl cellulose, Methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth rubber or acacia, dispersing and wetting agents such. B. polyoxyethylene stearate, Heptadecaethyleneoxycetanol, polyoxyethylene sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monooleate) or lecithin, preservatives such. B. methyl or propyl hydroxy benzoates, flavoring agents and / or sweeteners such as. B. sucrose, lactose, sodium cyclamate, dextrose or invert sugar syrup.

Oily suspensions can e.g. B. peanut, olive, sesame, coconut or paraffin oil and Thickeners such as B. beeswax, hard paraffin or cetyl alcohol, further Sweeteners, flavors and antioxidants.

Water-dispersible powders and granules can mix the complex compounds with dispersing, wetting and suspending agents such. B. the above, as well Contain sweeteners, flavors and colors.

Emulsions can e.g. B. olive, peanut or paraffin oil in addition to emulsifiers such. B. Acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleat and sweetener and flavoring included.

Sterile injectable aqueous suspensions are used for the parenteral use of the drugs. isotonic salt solutions or other solutions, the dispersing or wetting agents and / or pharmacologically acceptable diluents such as. B. propylene or butylene  glycol and / or solubilizers (e.g. tweene, chremophore or polyvinylpyrrolidone) contain.

It is particularly advantageous to administer solutions of the complex compounds in aqueous solutions of those pentoses or hexoses whose deprotonated or also twice deprotonated form X⁻ / X ^{2- is} already bound as a ligand in the complex. X⁻ / X ^2- have the meanings given above.

The active ingredient can optionally with one or more of the specified carrier or Additives can also be formulated in microencapsulated form.

Manufacturing examples 1. (D-arabinosato-O ^x , O ^y ) bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) titanium (IV)

x = 1, y = 2; x = 3, y = 4

Batch: 0.921 g = 2 mmol [Ti (bzac) ₂ (OEt) ₂ ] * (C ₂₄ H ₂₈ O ₆ Ti 460.38 g / mol)
0.300 g = 2 mmol D (-) - arabinose (C ₅ H ₁₀ O ₅ 150.13 g / mol)
* [Ti (bzac) ₂ (OEt) ₂ ] = cis-diethoxybis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) titanium (IV), budotitanium (INN)
0.3 g D (-) - arabinose are dissolved in 50 ml hot, absolute ethanol at an oil bath temperature of 90 ° C. A solution of 0.921 g of [Ti (bzac) ₂ (OEt) ₂ ] in 30 ml of absolute toluene is added dropwise within one hour. The deep yellow reaction mixture is heated for a further 5 hours at an oil bath temperature of 90 ° C. After cooling, the solution is stirred at room temperature overnight, concentrated to 40 ml and filtered through a G4 frit. The filtrate is evaporated to dryness, leaving a yellow, foamy solid which is dried, crushed and placed in another flask. The yellow powder thus obtained is washed with absolute n-hexane and dried in vacuo at 40-60 ° C.
Appearance: yellow solid, powder
Yield: 0.890 g = 1.72 mmol = 86%
Elemental analysis: calculated for C ₂₅ H ₂₆ O ₉ Ti 518.37 g / mol
calculated: C 57.93; H 5.06; O 27.78; Ti 9.24
found: C 57.89; H 5.19; O -; Ti 9.37.

2. bis (D-arabinosato-O ^x ) bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) titanium (IV)

x = 1, 2, 3, 4 or 5

Batch: 0.921 g = 2 mmol [Ti (bzac) ₂ (OEt) ₂ ] (C ₂₄ H ₂₈ O ₆ Ti 460.38 g / mol)
0.601 g = 4 mmol D (-) arabinose (C ₅ H ₁₀ O ₅ 150.13 g / mol).

The reaction is carried out and worked up analogously to 1.

The arabinose is dissolved in 100 ml of absolute, hot ethanol. The solution of [Ti (bzac) ₂ (OEt) ₂ ] in 30 ml of absolute toluene is added dropwise over a period of 2 hours.
Appearance: yellow solid, powder
Yield: 0.911 g = 1.36 mmol = 68%
Elemental analysis: calculated for C ₃₀ H ₃₆ O ₁₄ Ti 668.50 g / mol
calculated: C 53.90; H 5.43; O 33.51; Ti 7.17
found: C 54.26; H 5.59; O -; Ti 6.96.

3. bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) (D-xylosato-O ^x , O ^y ) titanium (IV)

x = 1, y = 2; x = 3, y = 5

Batch: 0.921 g = 2 mmol [Ti (bzac) ₂ (OEt) ₂ ] (C ₂₄ H ₂₈ O ₆ Ti 460.38 g / mol)
0.300 g = 2 mmol D (+) - xylose (C ₅ H ₁₀ O ₅ 150.13 g / mol).

The reaction is carried out and worked up analogously to 1.

The xylose is dissolved in 30 ml of absolute, hot ethanol.
Appearance: yellow solid, powder
Yield: 0.456 g = 0.88 mmol = 44%
Elemental analysis: calculated for C ₂₅ H ₂₆ O ₉ Ti 518.37 g / mol
calculated: C 57.93; H 5.06; O 27.78; Ti 9.24
found: C, 58.02; H 5.09; O -; Ti 9.24.

4. bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) bis (D-xylosato-O ^x ) titanium (IV)

x = 1, 2, 3, 4 or 5

Batch: 0.921 g = 2 mmol [Ti (bzac) ₂ (OEt) ₂ ] (C ₂₄ H ₂₈ O ₆ Ti 460.38 g / mol)
0.601 g = 4 mmol D (+) - xylose (C ₅ H ₁₀ O ₅ 150.13 g / mol).

The reaction is carried out and worked up analogously to 1.

The xylose is dissolved in 50 ml of absolute, hot ethanol. The solution of [Ti (bzac) ₂ (OEt) ₂ ] in 30 ml of absolute toluene is added dropwise over a period of 2 hours.
Appearance: yellow solid, powder
Yield: 1.182 g = 1.77 mmol = 88%
Elemental analysis: calculated for C ₃₀ H ₃₆ O ₁₄ Ti 668.50 g / mol
calculated: C 53.90; H 5.43; O 33.51; Ti 7.17
found: C 54.08; H 5.72; O -; Ti 7.00.

5. bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) (D-ribosato-O ^x , O ^y ) titanium (IV)

x = 1, y = 2; x = 2, y = 3; x = 3, y = 4

Batch: 0.921 g = 2 mmol [Ti (bzac) ₂ (OEt) ₂ ] (C ₂₄ H ₂₈ O ₆ Ti 460.38 g / mol)
0.300 g = 2 mmol D (-) - ribose (C ₅ H ₁₀ O ₅ 150.13 g / mol).

The reaction is carried out and worked up analogously to 1.

The ribose is dissolved in 30 ml of absolute, hot ethanol.
Appearance: yellow solid, powder
Yield: 0.480 g = 0.93 mmol = 46%
Elemental analysis: calculated for C ₂₅ H ₂₆ O ₉ Ti 518.37 g / mol
calculated: C 57.93; H 5.06; O 27.78; Ti 9.24
found: C 57.70; H 5.35; O -; Ti 9.19.

6. bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) bis (D-ribosato-O ^x ) titanium (IV)

x = 1, 2, 3, 4 or 5

Batch: 0.921 g = 2 mmol [Ti (bzac) ₂ (OEt) ₂ ] (C ₂₄ H ₂₈ O ₆ Ti 460.38 g / mol)
0.601 g = 4 mmol D (-) - ribose (C ₅ H ₁₀ O ₅ 150.13 g / mol).

The reaction is carried out and worked up analogously to 1.

The ribose is dissolved in 60 ml of absolute, hot ethanol. The solution of [Ti (bzac) ₂ (OEt) ₂ ] in 30 ml of absolute toluene is added dropwise over a period of 2 hours.
Appearance: yellow solid, powder
Yield: 1.010 g = 1.51 mmol = 75%
Elemental analysis: calculated for C ₃₀ H ₃₆ O ₁₄ Ti 668.50 g / mol
calculated: C 53.90; H 5.43; O 33.51; Ti 7.17
found: C 53.95; H 5.62; O -; Ti 6.98.

7. (D-Fructosato-O ^x , O ^y ) bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) titanium (IV)

x = 1, y = 2; x = 1, y = 3; x = 2, y = 3; x = 4, y = 5

Batch: 0.921 g = 2 mmol [Ti (bzac) ₂ (OEt) ₂ ] (C ₂₄ H ₂₈ O ₆ Ti 460.38 g / mol)
0.360 g = 2 mmol D (-) - fructose (C ₆ H ₁₂ O ₆ 180.16 g / mol).

0.36 g D (-) - fructose are dissolved in 20 ml absolute, hot ethanol at an oil bath temperature of 70 ° C. A solution of 0.921 g of [Ti (bzac) ₂ (OEt) ₂ ] in 20 ml of absolute toluene is added dropwise over the course of 30 minutes. The orange reaction mixture is heated for a further 5.5 hours at an oil bath temperature of 70 ° C. The suspension obtained after cooling is stirred overnight at room temperature and then filtered through a G4 frit. The filtrate is evaporated to dryness, leaving an orange, foamy solid which is dried, crushed and placed in another flask. The orange-brown powder thus obtained is washed with absolute n-hexane and dried in vacuo at 40-60 ° C.
Appearance: orange-brown solid, powder
Yield: 0.783 g = 1.43 mmol = 71%
Elemental analysis: calculated for C ₂₆ H ₂₈ O ₁₀ Ti 548.40 g / mol
calculated: C 56.94; H 5.15; O 29.17; Ti 8.73
found: C 57.09; H 5.23; O -; Ti 8.68.

8. bis (D-fructosato-O ^x ) bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) titanium (IV)

x = 1, 2, 3, 4, 5 or 6

Batch: 0.921 g = 2 mmol [Ti (bzac) ₂ (OEt) ₂ ] (C ₂₄ H ₂₈ O ₆ Ti 460.38 g / mol)
0.721 g = 4 mmol D (-) - fructose (C ₆ H ₁₂ O ₆ 180.16 g / mol).

The reaction is carried out and worked up analogously to 7.

The fructose is dissolved in 80 ml of absolute, hot ethanol at an oil bath temperature of 80 ° C. A solution of [Ti (bzac) ₂ (OEt) ₂ ] in 40 ml of absolute toluene is added dropwise over a period of 2 hours.
Appearance: ocher-colored solid, powder
Yield: 0.284 g = 0.39 mmol = 19%
Elemental analysis: calculated for C ₃₂ H ₄₀ O ₁₆ Ti 728.56 g / mol
calculated: C 52.76; H 5.53; O 35.14; Ti 6.57
found: C 52.94; H 5.63; O -; Ti 6.83.

Notes on the manufacturing examples:
All syntheses were carried out under an argon inert gas atmosphere and light protection in anhydrous, organic solvents. The complexes were worked up and stored under inert gas and light protection.

Claims (19)

1. Medicament containing one or more metal complexes of the general formula (I),
[{R ¹ (CH ₂ ) _m C (O) CR ³ C (O) R ² } ₂ M (X) _2-n ] (I),
wherein
M titanium, zircon or hafnium,
R ¹ is hydrogen, C ₁ -C ₈ alkyl or phenyl substituted by fluorine, chlorine, bromine, nitro, C ₁ -C ₄ - may be substituted alkyl, C ₁ -C ₄ alkoxy or trifluoromethyl mono- or polysubstituted,
R ² C ₁ -C ₈ alkyl, C ₁ -C ₄ alkoxy or phenyl, which is replaced by fluorine, chlorine, bromine, nitro, C ₁ - C ₄ alkyl, C ₁ -C ₄ alkoxy or trifluoromethyl one or more times can be substituted
R ^{3 is} hydrogen, C ₁ -C ₄ alkoxycarbonyl or phenyl,
X⁻ ^{/ 2-} single (for n = 0) or double (for n = 1) deprotonated pentoses or hexoses caused by hydrogen, amino, C ₁ -C ₃ alkylamine, thiol, C ₁ -C ₃ alkylthiol, carboxyl , C ₁ - C ₃ alkoxycarbonyl, acetoxy, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy can be mono- or polysubstituted, ie one or more OH groups can be hydrogen atoms or the groups mentioned above be replaced
m is the number 0 or 1, but not 0 if R ^{1 is} hydrogen, and
n is the number 0 or 1
mean and, insofar as a ligand X⁻ / X ^2- contains an amino group, its hydrohalides. 2. Medicament containing one or more metal complexes of the general formula (I '),
[{R ^{1 '} (CH ₂ ) _m' C (O) CR ^{3 '} C (O) R ^2' } ₂ M '(X') _2-n ] (I '),
wherein
M 'titanium, zircon or hafnium,
R ^{1 'is} hydrogen, C ₁ -C ₆ alkyl or phenyl, which can be mono- or polysubstituted by fluorine, chlorine, bromine, nitro, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy or trifluoromethyl,
R ^{2 '} C ₁ -C ₆ alkyl, C ₁ -C ₂ alkoxy or phenyl, which can be substituted by C ₁ -C ₂ alkoxy,
R ^{3 'is} hydrogen, C ₁ -C ₂ alkoxycarbonyl or phenyl,
X'⁻ ^{/ 2-} single (for n = 0) or double (for n = 1) deprotonated pentoses or hexoses, which are replaced by hydrogen, amino, thiol, carboxyl, C ₁ -C ₂ alkoxycarbonyl, acetoxy, methyl or C ₁ -C ₂ alkoxy can be mono- or polysubstituted, ie one or more OH groups can be replaced by hydrogen atoms or the groups mentioned above,
m 'is the number 0 or 1, but not 0 if R ^{1' is} hydrogen, and
n is the number 0 or 1
mean and, insofar as a ligand X'⁻ / X ' ^2- contains an amino group, its hydrohalides. 3. Medicament containing one or more metal complexes of the general formula (I "),
[{R ^{1 ''} (CH ₂ ) _{m ''} C (O) CR ^{3 ''} C (O) R ^{2 ''} } ₂ M '' (X '') _2-n ] (I ''),
wherein
M '' titanium, zircon or hafnium,
R ^{1 ″ is} hydrogen, C ₁ -C ₄ -alkyl or phenyl, which may be substituted by C ₁ -C ₂ -alkoxy,
R ^{2 ''} C ₁ -C ₄ alkyl or phenyl,
R ^{3 '' is} hydrogen or phenyl,
X''⁻ ^{/ 2} ⁻ single (for n = 0) or double (for n = 1) deprotonated pentoses or hexoses,
m "is the number 1 if R ^{1" is} hydrogen and the number 0 if R ^{1 "is} phenyl,
n is the number 0 or 1
mean. 4. Compounds of the general formulas (I), (I '), (I'') given in claims 1 to 3, wherein M, M', M '', R1, R1 ', R1'', R2, R2 ', R2'', R3, R3', R3 '', X⁻ ^{/ 2} ⁻, X'⁻ ^{/ 2} ⁻, X''⁻ ^{/ 2} ⁻, m, m ', m''and n the in the claims Have 1 to 3 meanings given. 5. (D-arabinosato-O ^x , O ^y ) bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) titanium (IV) x = 1, y = 2; x = 3, y = 4. 6. bis (D-arabinosato-O ^x ) bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) titanium (IV) x = 1, 2, 3, 4 or 5. 7. bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) (D-xylosato-O ^x , O ^y ) titanium (IV) x = 1, y = 2; x = 3, y = 5. 8. bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) bis (D-xylosato-O ^x ) titanium (IV) x = 1, 2, 3, 4 or 5. 9. bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) (D-ribosato-O ^x , O ^y ) titanium (IV) x = 1, y = 2; x = 2, y = 3; x = 3, y = 4. 10. bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) bis (D-ribosato-O ^x ) titanium (IV) x = 1, 2, 3, 4 or 5. 11. (D-Fructosato-O ^x , O ^y ) bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) titanium (IV) x = 1, y = 2; x = 1, y = 3; x = 2, y = 3; x = 4, y = 5. 12. Bis (D-fructosato-O ^x ) bis (1-phenylbutane-1,3-dionato-O ¹ , O ³ ) titanium (IV) x = 1, 2, 3, 4, 5 or 6. In claims 5 to 12, the variables x and y represent the usual number for sugars tion of the carbon atoms and thus define the possible positions of the acid atoms of matter via which the respective sugar can be bound to the metal central ion. 13. A process for the preparation of the compounds according to claim 4, which is characterized in that a dialkoxybis (β-diketonato) metal (IV) compound [{R ¹ (CH ₂ ) _m C (O) CR ³ C (O) R ² } ₂ M (OR) ₂ ] or [{R ^{1 '} (CH ₂ ) _m' C (O) CR ^{3 '} C (O) R ² } ₂ M (OR) ₂ ] or [{R ^{1 ''} (CH ₂ ) _{m ''} C (O) CR ^{3 ''} C (O) R ^{2 ''} } ₂ M (OR) ₂ ], where M, M 'or M'', R1, R1' or R1 ", R2, R2 'or R2", R3, R3' or R3 "and m, m 'or m" have the meanings given above and R represents a methyl or ethyl group, below Exclusion of moisture and light with the respective pentoses or hexoses dissolved in a suitable solvent (preferably absolute, hot ethanol or methanol) by hydrogen, amino, C ₁ -C ₃ -alkylamine, thiol, C ₁ -C ₃ -alkylthiol, carboxyl , C ₁ -C ₃ alkoxycarbonyl, acetoxy, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy can be mono- or polysubstituted, ie one or more OH groups can be substituted by hydrogen atoms or the abovementioned Groups replaced, implemented. 14. Medicament containing one or more complex compounds according to one or several of claims 5 to 12. 15. Aqueous solutions obtained from the metal complexes of the general formula (I)
Ie [{R ¹ (CH ₂ ) _m C (O) CR ³ C (O) R ² } ₂ M (X) _2-n ] (I),
wherein
M titanium, zircon or hafnium,
R ¹ is hydrogen, C ₁ -C ₈ alkyl or phenyl substituted by fluorine, chlorine, bromine, nitro, C ₁ -C ₄ - may be substituted alkyl, C ₁ -C ₄ alkoxy or trifluoromethyl mono- or polysubstituted,
R ² C ₁ -C ₈ alkyl, C ₁ -C ₄ alkoxy or phenyl, which is replaced by fluorine, chlorine, bromine, nitro, C ₁ - C ₄ alkyl, C ₁ -C ₄ alkoxy or trifluoromethyl one or more times can be substituted
R ^{3 is} hydrogen, C ₁ -C ₄ alkoxycarbonyl or phenyl,
X⁻ ^{/ 2} ⁻ single (for n = 0) or double (for n = 1) deprotonated pentoses or hexoses caused by hydrogen, amino, C ₁ -C ₃ alkylamine, thiol, C ₁ -C ₃ alkylthiol, carboxyl , C ₁ - C ₃ alkoxycarbonyl, acetoxy, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy can be mono- or polysubstituted, ie one or more OH groups can be hydrogen atoms or the groups mentioned above be replaced
m is the number 0 or 1, but not 0 if R ^{1 is} hydrogen, and
n is the number 0 or 1
mean and, insofar as a ligand X⁻ / X ^2- contains an amino group, its hydrohalides and aqueous solutions of sugars / sugar derivatives of the general formula HX or H ₂ X, or also X⁻ or X ^2- / HX⁻ (or their salts), where X⁻ / X ^{2- have} the meanings given above. 16. A process for the preparation of aqueous solutions according to claim 15, which is characterized in that a metal complex of the general formula (I),
[{R ¹ (CH ₂ ) _m C (O) CR ³ C (O) R ² } ₂ M (X) _2-n ] (I),
wherein
M titanium, zircon or hafnium,
R ¹ is hydrogen, C ₁ -C ₈ alkyl or phenyl substituted by fluorine, chlorine, bromine, nitro, C ₁ -C ₄ - may be substituted alkyl, C ₁ -C ₄ alkoxy or trifluoromethyl mono- or polysubstituted,
R ² C ₁ -C ₈ alkyl, C ₁ -C ₄ alkoxy or phenyl, which is replaced by fluorine, chlorine, bromine, nitro, C ₁ - C ₄ alkyl, C ₁ -C ₄ alkoxy or trifluoromethyl one or more times can be substituted
R ^{3 is} hydrogen, C ₁ -C ₄ alkoxycarbonyl or phenyl,
X⁻ ^{/ 2} ⁻ single (for n = 0) or double (for n = 1) deprotonated pentoses or hexoses caused by hydrogen, amino, C ₁ -C ₃ alkylamine, thiol, C ₁ -C ₃ alkylthiol, carboxyl , C ₁ - C ₃ alkoxycarbonyl, acetoxy, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy can be mono- or polysubstituted, ie one or more OH groups can be hydrogen atoms or the groups mentioned above be replaced
m is the number 0 or 1, but not 0 if R ^{1 is} hydrogen, and
n is the number 0 or 1
mean and, insofar as a ligand X⁻ / X ^2- contains an amino group, the hydrohalides thereof to an aqueous solution of H ₂ X or HX or also X ^2- / HX⁻ or X⁻ (or their salts), where X ⁻ / X ^{2- have} the meanings given above, and stirs between one and five days, preferably two to three days. 17. Use of the metal complexes specified in claims 1 to 12 Cancer treatment.