NO844029L - PROCEDURE FOR THE PREPARATION OF ANTINEOPLASTIC EFFECTIVE PREPARATIONS - Google Patents

Description

Procedure for the production of antineoplastic active preparations.

Technical area

The invention relates to a method for the production of preparations containing antineoplastically effective complex compounds.

State of the art

Recently, a drug containing the complex compound cis-diammine dichloroplatinum(II) was brought to the market as a chemotherapeutic agent against cancer. This compound, which was known under the International Nonproprietary Name (INN) Cisplatin, has proven to be an extremely strong anti-tumor agent, especially in the treatment of testicular tumors, but also e.g. of ovarian tumors and small cell bronchial carcinomas. The unfortunate thing about Cisplatin is its relatively high toxicity. Grave is its nephrotoxicity, as well as its effect that leads to permanent hearing damage. Kidney and hearing damage is established -already, after the administration of a single therapeutic dose with considerable frequency. In addition to the nephro- and hemato-toxic effect, above all the persistent strong feeling of unwellness and the associated nausea are extremely unpleasant for the patients.

More recently, numerous other platinum complexes (DE-OS

24 45 418, DE-OS 28 37 237, DE-OS 26 26 559, DE-OS 25 39 179)

and complex compounds of other transition metals, proposed as cytostatic agents. In DE-OS 28 01 355, a brown amorphous complex, produced by reacting ascorbic acid with a titanium(III) and a copper(II) compound (molar ratio 36:1:6) is attributed curative and prophylactic effects against, among other things . leukemia. Titanocene, zirconocene and hafnocene dichloride were reported to be inhibitory against Ehrlich-Ascites tumor in mice [P. Kopf-Maier, B. Hesse, H. Kopf, J. Cancer Res. Clin. Oncol. 9_6 , 43 (1980)]. EP-OS 49 486 describes dihalogenbis(1,3-diketonato)tin-, -titanium-, -zirconium- and

-hafnium compounds with antineoplastic effect.

y

Description of the invention

Surprisingly, it has now been found that preparations containing complex compounds of the general formula I

[RI(CH2)mC(0)CR3C(0)R2]2M(OR4)2_nXn(I)

in which

M is titanium, zircon or hafnium,

R1 is hydrogen, C1-C8-alkyl or phenyl, which may be singly or multiply substituted with fluorine, chlorine, bromine, nitro, C1-C4-alkyl, C1-C4-alkoxy or trifluoromethyl,

R2 is C1-C8-alkyl or phenyl, which may be singly or multiply substituted with fluorine, chlorine, bromine, nitro, C1-C4-alkyl, C1-C4-alkoxy or trifluoromethyl,

R 3 is hydrogen or phenyl,

R4 is C1-C18-alkyl1, which may be substituted with hydroxy,

Cl-C3 alkylamine or alkali sulfonate groups, or C5-C8 cycloalkyl, which may be substituted with Cl-C5 alkyl groups, hydroxy or alkali sulfonate groups,

X is fluorine, chlorine or bromine,

m means the number 0 or 1, but not 0 when RI has the meaning

hydrogen, and

n is the number 0 or 1,

and provided that the residue R4 contains an amino group, their hydrohalides show an interesting cytostatic activity with a favorable therapeutic range and are suitable for the treatment of cancer diseases.

By hydrogen halides is meant hydrochlorides, hydrobromides

and hydroiodides, with hydrochlorides being preferred.

An alkali sulfonate group is understood to mean an A-SO^ residue, where A means an alkali metal. The sodium sulfonate residue is preferred.

C1-C3-, C1-C4-, C1-C5-, C1-C8, respectively Cl-C18 alkyl1 groups are straight chain or branched alkyl groups with 1 to 3, 1 to 4, 1 to 5, 1 to 8 and 1 respectively to 18 carbon atoms. Alkyl residues with more than 10 carbon atoms are preferably unbranched.

By Cl-C3-alkylamine is meant mono- and di-Cl-C3-alkylamine, whereby diethylamine is preferred.

By C5-C8-cycloalkyl is meant cycloalkyls with 5 to 8 ring carbon atoms, whereby cyclohexyl is preferred.

The object of the invention is therefore a method for the production of antineoplastic active preparations, characterized in that one

a) reacts a tetraalkyloxymetal (IV) compound M(OR4)^, during which

M is titanium, zirconium and hafnium and

R4 means C1-C18-alkyl1, which may be substituted with hydroxy,

C1-C3 alkylamine or alkali sulfonato groups, or C5-C8 cycloalkyl which may be substituted with C1-C5 alkyl groups, hydroxy or alkali sulfonato groups,

under the exclusion of moisture in an inert solvent with a diketone RI (CH2 ) C (0) CHR3C (0) R2 ,' in which RI means hydrogen, Cl-C8 alkyl or phenyl, which may be singly or multiply substituted with fluorine, chlorine , bromine, nitro, C1-C4-alkyl, C1-C4-alkoxy or trifluoromethyl,

R2 means C1-C8 alkyl or phenyl, which may be singly or multiply substituted with fluorine, chlorine, bromine, nitro, C1-C4 alkyl, C1-C4 alkoxy or trifluoromethyl,

R 3 is hydrogen or phenyl, and

m is the number 0 or 1, but not 0 when RI has the meaning

hydrogen,

or

b) reacts a compound of formula

[RI(CH2)mC(0)CR3C(0)R2]2MZ2,

in which

M, R 1 , R 2 , R 3 and m have the above meanings, and

Z means fluorine, chlorine, bromine or 0R4, wherein R4 has the above meanings, with an alcohol H0R4 or its alkali alcoholate, wherein R4 has the above meanings,

and brings an active ingredient thus obtained into a suitable form for pharmaceutical administration.

Preferred is the preparation according to the invention of pharmaceutical preparations which contain

diethoxybis(1-phenyl-1,3-butanedionato)titanium(IV), di(iso-propoxy)bis-(1-phenyl-1,3-butanedionato)titanium(IV), bis (2-hydroxypropoxy)bis(1 -phenyl-1,3-butanedionato)titanium(IV), diethoxybis(3-phenyl-2,4-pentanedionato)titanium(IV), chloro(2,3-dimethyl-2,3-butanediolato)bis(1-phenyl -1,3-butanedionato)titanium-(IV), chloro(2-hydroxypropanolato)bis(1-phenyl-1,3-butanedionato)titanium (IV) , bis (tridec.anolato) bis (1-phenyl-l, 3-butanedionato) titanium (IV) and/or diethoxybis(3-phenyl-2,4-pentanedionato) titanium (IV), especially diethoxybis(1-phenyl-1,3-butanedionato); titanium (IV).

The preparations are produced by processes known per se, during which the complex compounds can be used as such or possibly in combination with suitable pharmaceutical carriers. If the new pharmaceutical preparations contain pharmaceutical carriers next to the active substance, the active substance content in these mixtures is 0.1-99.5, preferably 0.5-95% by weight of the total mixture.

The pharmaceutical preparations according to the invention can, when they are intended for use e.g. on humans, contain 0.1-500 mg, preferably 10-200 mg and especially 50-150 mg of active ingredient.

In general, it has proven advantageous in human medicine to give the active substance or substances parenterally in a daily dose of approx. 0.1 to approx. 5, preferably 1-3 mg/kg body weight, possibly in the form of several, preferably 1-3 single doses to achieve the desired results. A single dosage contains active substances or the active substances in amounts of approx. 0.1-5, preferably 1-3 mg/kg body weight. For an oral treatment, similar dosages can be used. Thus, in some cases it may be sufficient to use less than the above-mentioned amount of active substance, while in other cases the above-mentioned amount of active substance must be exceeded. As is normal in internist tumor therapy, the treatment with the drugs 'according to the invention' can be combined with the administration of other cytostatics with different spectrums of action to reduce the risk of side effects. It may also be appropriate to ■ carry out the treatment according to the principle of cyclic cytostatic therapy. Below is a break to recover after each treatment. This is based on the experience that healthy tissue in most organs regenerates faster than cancerous tissue.

The determination of the relevant, necessary, optimal dosage and type of application of the active substances is easy to carry out for a professional with his knowledge.

The preparations produced according to the invention are above all given intravenously, but also intramuscularly, intraperitoneally, subcutaneously, rectally or orally. An external application is also possible. Administration by intravenous injection or intravenous infusion is preferred.

The pharmaceutical preparations usually consist of complex the compounds and the non-toxic, pharmaceutically tolerable drug carriers known to the person skilled in the art, which can be used as an additive or diluent1 in solid, semi-solid or liquid form, or as a coating agent, e.g. in the form of a capsule, a tablet coating, a bag or another container, for the therapeutically active ingredient.

Sterile injectable aqueous suspensions, isotonic saline solutions or other solutions containing dispersing or wetting agents and/or pharmacologically tolerable diluents, e.g. propylene or buty leng.lykol, and/or solution mediators, e.g. "Tweene", "Cremophore" or

. polyyinylpyrrolidone.

It is particularly advantageous to mix solutions of the complex compounds in an anhydrous organic solvent with solutions of hydrophilic polymers, such as e.g. polyvinyl pyrrolidones (PVP) or polyoxyethylene sorbitan fatty acid esters ("Tweene") or especially glycerol polyethylene glycol, ricinoleate ("Cremophor"EL) and after evaporation, of the solvent or solvents give the remaining residues as aqueous solutions. As organic solvents, e.g. chloroform or methylene chloride in particular, which must be made anhydrous in the usual way before use. It has proven advantageous to use the hydrophilic polymers in a 5- to 50-, preferably 10- to 35-fold excess on a weight basis in relation to the complex compound. It is also possible to introduce the polymers as such in solutions of the complex compounds. The residue that remains after evaporation of. the solvent or solvents are preferably freed from solvent residues as much as possible in a high vacuum. Depending on the nature and quantity of the hydrophilic polymer used, solid crystalline glassy or also liquid or sticky residues are obtained. The latter can usually be transferred into solid, mostly waxy products on cooling.

In the present invention, these new residues shall be termed coprecipitates. It has a beneficial effect on the solution properties of the coprecipitates when, during the preparation of these, additional dispersing or wetting agents such as propylene or butylene glycol, preferably propylene glycol, are added to the mixture of the solutions of the complex compounds and the hydrophilic polymer.

The preparation of the aqueous solutions of the copper precipitates takes place by treating the copper precipitates with water. PVP copper precipitates usually go into solution already at room temperature. Co-precipitates with polyoxyethylene sorbitan fatty acid esters or glycerol-polyethylene glycol ricinoleate are advantageously brought into solution when the co-precipitate and water are heated before mixing to 2.5-60°C, preferably 30-40°C.

It is particularly advantageous to dissolve the copper precipitates in physiological saline solution instead of in water.

A preferred embodiment of the method according to the invention is characterized by evaporating the obtained complex compounds of formula I

[R1(CH0)C(0)CR3C(0)R2]oM(0R4)0 X (I),

2 m. 2 2 -n n

in which M, R1, R2, R3, R4, X, m and n have the meanings given above, and if the residue R4 contains an amino group, their hydrohalides, dissolved in an inert organic solvent together with an optionally dissolved hydrophilic polymer until dryness and prepares the coprecipitate obtained as an aqueous solution.'

The procedure for producing the new copper precipitates, characterized by evaporating a complex compound of formula I v

[RI(C<H>2)mC(0)CR3C(0)R2]2M(OR4)2_nXn(I),

wherein M, R1, R2, R3, R4, X, m and n have the above meanings, and if a residue R4 contains an amino group, their hydrohalides, dissolved in an inert organic solvent together with a similarly dissolved hydrophilic polymer to dryness, is a further object of the invention.

The production of the metal complexes takes place either by reacting the corresponding metal tetraalcoholate with the corresponding diketone in a molar ratio of 1:2 [A. Yamamoto, S. Kambara, J. Am. Chem. Soc. 7J3, 4344 (1957)] or by reaction of the corresponding dihalogenobis(diketonato)-metal (IV) with the corresponding alcohol or also its alcoholate, preferably alkali alcoholate, in a molar ratio of 1:1, when a monohalogen metal (IV) complex (n i the general formula I has the meaning 1) is to be prepared, or in a molar ratio of 1:2, when a dialcohol bis-diketonatometal (IV) complex (n in the general formula I has the meaning. 0) is to be prepared [D.M. Puri, R.C. Mehrotra, J. Ind. Chem. Soc. 39, 499 (1962)]. In the reaction of a dihalgenobis-(diketonato)-metal(IV) complex with an alcohol, it is appropriate to work in the presence of a base. As a base, ammonia is advantageously used, which can be passed through the reaction mixture. The ammonium halide formed is only slightly soluble in the solvents used and can be separated by filtration and/or centrifugation. Remains of the ammonium halide can be removed from the final product by sublimation in a high vacuum. The alcoholato group of the alcoholato-diketonato metal(IV) complexes can be replaced by other alcoholato groups [U.B. Saxena et al., J.Chem.Soc. A 19 70, 904; D.M. Puri, R.C. Mehrotra, J. Indian Chem. Soc. 39_, 499

(1962)]. The alcoholato-diketonatometal(IV) complex, whose alcoholato groups are to be replaced, is heated as such or in a suitable solvent together with an alcohol, which is preferably used in excess. This method is particularly suitable for replacing a lower alcohol anion. against the alcohol anions of a higher alcohol. In many cases, the replacement can be favored as the liberated alcohol is distilled off as an azeotrope. The reaction is suitably carried out in a dry protective gas atmosphere, preferably a nitrogen atmosphere, and using anhydrous starting materials and possibly carefully dried solvents. ■ ••

The reactions are carried out either without solvents or in inert solvents, such as e.g. benzene, n-hexane, diethyl ether, methylene chloride. or chloroform. Without a solvent, one can above all work when at least one of the reaction parts is present as a liquid. If one of the reaction partners is insoluble in the solvent used, it is used as a suspension in this solvent and the soluble reaction partner is added dropwise dissolved.

Depending on the intensity of turnover, one works at room temperature during cooling or heating, e.g. by back race. To make the reaction complete, it may be necessary to heat the reaction mixture for 1-3 days at reflux. In reactions in which halogen hydride is released, it is advantageous to expel this by passing dry nitrogen through the reaction mixture. The reaction products are precipitated from the reaction solution either by evaporation and/or cooling, and/or by the addition of precipitating solvents, especially

.hexane and petroleum ether.

The 1,3-diketones are known or can be prepared according to methods known per se. E.g. they can be prepared by ester condensation of the corresponding aryl acetic acid ethyl ester with acetic acid ethyl ester or the corresponding aryl acetic acid ethyl ester with sodium amide as condensation agent (J.T. Adams, CR. Hauser, J. Amer. Chem. Soc. 6_6, 1220 [ 1944 ]). Furthermore, it is possible, by adding the corresponding arylmethyl ketone dissolved in acetic acid ethyl ester, to a suspension of sodium in benzene or toluene to arrive at the 1,3-dike tone t (D.W. Brown., S.F. Dyke, M. Sainsbury, G. Hardy, • J. Chem. Soc. Oe) 1971, 3219). A further possibility consists in the reaction of aryl methyl ketones with acetic anhydride in the presence of boron trifluoride [H.G. Walker, CR. Hauser, J. Amer. Chem. Soc. 6 8 ,

2742 (1946)]. 1-Benzy1-1,3-diketones are produced by condensation of the corresponding phenylacetic acid ethyl ester with

■the corresponding methyl ketone in the presence of sodium amide [A. Becker, Heiv. Chim. Acta 149 , 1114 (1949)].-

Examples

'1• Diethoxybis-(1-phenyl-1,3-butanedionato)-titanium(IV)

To 11.4 g (0.05 mol) of titanium tetrachloride, while excluding moisture, 15.8 g (0.097 mol) of benzpylacetone in 200 ml of dry n-hexane are rapidly added dropwise. The reaction mixture is heated for 2 hours at reflux in a dry nitrogen atmosphere. The precipitated colorless product is filtered off, suspended in boiling hexane, filtered again and freed from solvent residues in a high vacuum. Melting point: 110°C.

A further manufacturing method is to be found in O.M. Puri, R.C. Mehrotra, J. Ind. Chem. Soc. 39(8), 499 (1962).

2. Diethoxybis-(1-phen y1- 2, 4- pentanedionato)- titanium( IV)

In a dry nitrogen atmosphere, 3.7 g (0.021 mol) of 1-phenyl-2,4-pentanedione are added with vigorous stirring to 2.2 ml (0.0105 mol) of titanium tetraethoxide. From the yellow reaction mixture, the volatile components are evaporated first with a water jet vacuum and then with an oil pump vacuum. This leaves 5.1 g of a red oil.

Yield: quantitative.

Analysis: Calculated: 63.93% C; 6.60% H; 9.81% Ti;

Found: 63.44% C; 6.71%. H; 10.14% Ti;

The production of 1-phenyl-2,4-pentanedione is carried out according to

R. Levine et al., J. Am. Chem. Soc. 6_7, 1510 (1945).

3. Diethoxybis-(4,4-dimethyl-1-phenyl-1,3- pentanedionato)-titanium(IV)

5.28 g (0.0097 mol) of the title compound is obtained as a reddish-yellow oil in quantitative yield by proceeding analogously to example 2 starting from 3.95 g (0.0194 mol) 4,4-dimethyl1-1-phenyl1- 1,3-pentanedione and 2.21 g (0.0097 mol) titanate traethoxide.

Analysis: Calculated: 66.17% C; 7.40% H; 8.80 Ten;

Found: 66.44% C; 7.57% H; 8.34 Ten.

The preparation of 4,4-dimethyl-1-phenyl-1,3-pentanedione is described in R. Levine et al., J. Am. Chem. Soc. 73.' 5614 (1951)

4. Diethoxybis-(1-phenyl-1,3-hexanedionato)-titanium(IV)

5 g (0.0097 mol) of the title compound is obtained as a yellow oil

in quantitative yield by proceeding analogously to example 2 starting from 3.69 g (0.0194 mol) 1-phenyl-1,3-hexanedione and 2.21 g (0.0097 mol) titanium tetraethoxide.

Analysis: Calculated: 65.12. %C; 7.02% H; 9.27% Ti;

Found: 65.38% C; 7.30% H; 9.30% Ten.

5. Diethoxybis-(1-phenyl-1,3-pentandionato)-titanium(IV)

4.73 g (0.0097 mol) of the title compound is obtained as a yellow oil in quantitative yield by proceeding analogously to example 2 starting from 3.42 g (0.00194 mol) 1-phenyl1-1,3-pentane -dione and 2.21 g (0.0097 mol) titanium tetraethoxide.

Analysis: Calculated: 63.94% C; 6.60% H; 9.80% Ti;

Found: 63.92% C; 6.61% H; 9.67% Ten.

6. Di-(n-propoxy)-bis-(1-phenyl-1,3-butanedionato)-titanium(IV)

To a benzene solution of 7.1 g (0.025 mol) of titanium tetra-n-propoxide is added 8.11 g (0.05 mol) of benzoylacetone in benzene in a dry nitrogen atmosphere. After 3 hours of boiling at reflux, the benzene is distilled off, the remainder is taken up with it. diethyl ether, and the title compound is precipitated by the addition of n-hexane and dried under high vacuum.

Yield: 11.5 g (94% d.Th.); melting point: 133°C. Analysis: Calculated: 63.9% C; 6.6% H; 9.8% Ti;

Found: 6 3.5% C; 6.5% H; 10.3% Ten.

7. Bis-(sodium-2-sulfonatoethanolato)-bis-(1-phenyl-1,3-butanedionato)-titanium( IV)

2.96 g (0.022 mol) of the sodium salt of 2-hydroxyethanesulfonic acid are stirred in a dry nitrogen atmosphere with 4.41 g (0.01 mol) of dichloro-bis-(1-phenyl-1,3-butanedionato)-titanium(IV) in 250 ml of benzene under reflux for 3 days. After completion of hydrogen chloride development, a yellow product is precipitated from the yellow solution with petroleum ether (boiling point 60-70°C) and dried under high vacuum.

Yield: 6.4 g (96% d.Th); melting point: 184°C.

Analysis: Calculated: 43.4%.C; 3.9% H;

Found: 43.4% C; 4.0% H.

8. Di-(2-propanolato)-bis-(1-phenyl-1,3-butanedionato)- titanium-(IV)-

In a dry nitrogen atmosphere, 3.55 g (0.0125 mol) of titanium tetraisopropoxide in benzene and 4.05 g (0.025 mol) of benzoylacetone in benzene are added. The reaction mixture is heated for 2-3 hours at reflux and, after partial distillation of the benzene, is mixed with hot n-hexane. It is stirred while cooling and the separated yellow product is then filtered and dried under high vacuum.

Yield: 5.6 g (93% d.Th); melting point: 89°C.

Analysis: Calculated: 6 3.9% C; 6.6% II; 9 .8% Ti;

Found: 6 3.9% C? 6.6. %. H; 9.6%.Ti.

9. Chloro-(2-hydroxyethanolato)-bis-(1-phenyl-1,3-butanedionato)-titanium (IV)

4.41 g (0.01 mol) of dichlorobis-(1-phenyl-1,3-butanedionato)-titanium(IV) in 80 ml of benzene are added dropwise in a dry nitrogen atmosphere while heating 0.62 g (0.01 mol) of ethylene glycol dissolved in 40-ml benzene. After completion of hydrogen chloride evolution (approx.

3 hours) is evaporated to dryness and the remainder taken up with it

methylene chloride. When n-hexane is added, the yellow product precipitates and is dried in high vacuum.

Yield: 4.25 g (91% d.Th.); melting point: 73°C.

Analysis:. Calculated: 56.6% C; 5.0% H; 10.2% Ti;'

Found: 57.1% C; 5.3% H; 10.8% Ten.

10. Chloro-(2-hydroxypropanolato)-bis-(1-phenyl-1,3-butanedionato)-titanium(IV)

4.41 g (0.01 mol) dichlorobis-(1-phenyl-1,3-butanedionato)-titanium (IV), in 80 ml of benzene is added dropwise in a dry nitrogen atmosphere - while heating 0.76 g (0.01 mol ) 1,2-propanediol in 40 ml of benzene. After completion of hydrogen chloride evolution, the yellow product is precipitated by the addition of n-hexane. After reprecipitation once from methylene chloride using n-hexane, the yellow powder is dried in high vacuum.

Yield: 4.6 g. (96% d.Th..); melting point: 78°C.

Analysis: Calculated: 5 7.5% C; 5.2% H; 10.0% Ti;

Found: 5 7.5% C; .5.6% H; 10.6% Ten.

11. Tert.-butanolatochlorobis-(1-phenyl-1,3-butanedionato)-titanium(IV)

In a dry nitrogen atmosphere, 4.41 g (0.01 mol) of di-chloro-bis-(phenyl1-1,3-butanedionato)-titanium(IV), suspended in 70 ml of methylene chloride, is added dropwise to 0.74 g (0.01 mol ) tert.-butanol, dissolved in 20 ml of methylene chloride. You boil for so long at reflux that hydrogen chloride no longer escapes. Mix carefully with petroleum ether (boiling point 60-70°C) until a brown oil falls out. After depositing the oil, the yellow supernatant solution is decanted and evaporated until a yellow product precipitates. This is filtered off and washed with a lot of petroleum ether.

Yield: 1.9 g (40% d.Th.); melting point: 70-75°C. Analysis: Calculated: 60.2% C; 5.7% H; 10.0% Ti;

Found: 6 0.3% C; 5.9% H; 10.0% Ten.

12. Chloro-(2,3-dimethyl-2,3-butanediolato)-bis-(1-phenyl-1,3-butanedioriato)-titanium( IV)

In a dry nitrogen atmosphere, a slurry of 4.41 g (0.01 mol) of dichlorobis-(1-phenyl-1,3-butanedionato)-titanium(IV) is added dropwise to 100 ml of dry methylene chloride 1.18 g (0.01 mol) 2,3-dimethyl-2,3-butanediol, dissolved in 30 ml of methylene chloride. You boil for so long at reflux that hydrogen chloride is no longer developed. The solution is mixed until it becomes cloudy with petroleum ether

(boiling point 60-70°C). After standing for several hours at -18°C from raf, the yellow precipitate is filtered out and washed with petroleum ether.

Yield: 2.1 g (40% d.Th.); melting point: 80-90°C. Analysis: Calculated: 59.7% C; 6.0% H; 9.2%. Ten;

Found: 5 8.9% C; 6.3% H; 9.2% Ten.

13. Chloro- mentholato- bis-(1- phenyl- 1, 3- butanedionato)- titanium( IV)

In a dry nitrogen atmosphere, a slurry of 4.41 g (0.01 mol) of dichlorobis-(1-phenyl-1,3-butanedionato)-titanium (IV) in 70 ml of methylene chloride is added dropwise to 1.56 g (0.01 mol) of menthol ,' dissolve t in 30 ml of methylene chloride rapidly. Boil at reflux until hydrogen chloride evolution is complete. After cooling the mixture to room temperature, the clear yellow product is precipitated by the careful addition of petroleum ether (boiling point 60-, 70°C). This fraction is filtered and washed with petroleum ether (boiling point 60-70°C).

Yield: 2.24 g (40% d.Th.); melting point: 95°C.

Analysis: Calculated: . 64.2% C; 6.7% H; 8.5% Ti;

Found: 6 4.2% C; 6.8% H; 8.6% Ten.

14. Diethoxybis-(1-phenyl-1,3-butanedionato)- hafnium (IV)

To a slurry of 10 g of hafnium tetrachloride in 400 ml of dry ether, 30.4 g of benzoylacetone dissolved in 200 ml of dry ether are added dropwise under a stream of nitrogen and while boiling at reflux. After boiling at reflux for 24 hours, the formed precipitate is filtered off and washed twice with 100 ml of ether each time and dissolved in approx. 600 ml of chloroform. After evaporation until a clear solution is obtained, it is filtered and the solution is allowed to stand at -5°C. The colorless precipitate is recrystallized from chloroform. 6 g (33.7% d.Th.) of dichlorobis-(1-phenyl-1,3-butanedionato)-hafnium(IV) with a melting point of 231-232°C are obtained

.(red sme 1te) .

In a dry nitrogen atmosphere, 5.71 g (0.01 mol) dichloro-bis-(1-phenyl-1,3-butanionato)-hafnium (IV) and 1.2 g (0.026 mol) absolute eta.no] are stirred . in 100 ml of benzene while introducing dry ammonia. After the exothermic reaction is finished, it is heated for 4 hours at reflux. Then dry ammonia is introduced for 3 days at room temperature. After fractional centrifugation of the ammonium chloride formed, the solution is evaporated to dryness. The residue is dried in high vacuum, whereby white crystals sublimate away at a bath temperature of 90° C. The title compound remains.

Yield: 4.41 g (74.7% d.Th.) ;

Melting point: 98°C (sintering at 87-97°C).

Analysis: Calculated: 48.78% C; 4.77% H•,

Found: 50.09% C; 4.33% H.

15. Bis-(2-diethylaminoethoxy)-bis-(1-phenyl-1,3-butanedionato)-hafnium(IV) hydrochloride

Under a dry nitrogen atmosphere, 5.71 g (0.01 mol) of di-chloro-bis-(1-phenyl-1,3-butanedionato)-hafnium(IV) and 2.34 g (0.02 mol) of freshly distilled diethylaminoethanol are stirred i- 70 ml of dry methylene chloride in a tightly closed flask for 2 days. The reaction mixture is evaporated on a rotary evaporator and the residue is dried under high vacuum.

Yield: 5.08 g (76% d.Th.);

Melting point: 135°C (sintering at 125°C).

16 . Diethoxybis-(1-phenyl-1,■3-butanedionato)-zirconium (IV)

..Under a dry nitrogen atmosphere, .3.87 g (0.008 mol) of dichlorobis-(1-phenyl-1,3-butanedionato)-zirconium(IV) are suspended in 50 ml of dry methylene chloride and mixed with a solution of 1.71 g (0.025 mol) of sodium ethanolate in 50 ml of absolute ethanol. After 1 day of boiling at reflux, dry ammonia is introduced for 3 Jagers. After filtering off the precipitate, the filtrate is freed from residues of the precipitate by centrifugation. The clear solution is evaporated to dryness on a rotas ion evaporator and the residue is dried in a high vacuum, during which white crystals sublimate away at 90°C bath temperature. The title connection will return.

■ Yield: 5.8 g (72% d.Th); melting point: 122-124°C.

17. Bis-(1-phenyl-1,3-butanedionato)-di-(n-propanolato)-zirconium(IV)

10.38 g (0.05 mol) of tetra-n-propoxyzirconium(IV) and 16.2 g (0.01 mol) of benzoylacetone are dissolved in 100 ml of freshly distilled chlorobenzene. The chlorobenzene/propanol azeotrope is distilled off until the boiling temperature of 132°C is reached. It is then evaporated to dryness on a rotary evaporator. The residue is dried for 4 hours at 80°C in a high vacuum and then overnight at room temperature.

Yield: 23.4 g (88% d.Th); melting point: -6°C.

Analysis: Calculated: 58.7%C; 6.1% H;

Found: 60.8% C; 5.5% H.

18. Di-(n- butanoiato)- bis-(l- phenyl- 1, 3- butanedionato)- zirconium-(IV)

Analogously, with example 17, 28.62 g (0.625 mol) of tetra-(n-butoxy)-zirconium(IV)-butanol are reacted with 20.65 g (0.125 mol) of benzoylacetone in 100 ml of chlorobenzene. The residue is then dried in high vacuum for 5 hours at 70°C and then 10 hours at room temperature. trip.

Yield: 28.7 g (82% d.Th); melting point: -2°C.

Analysis: Calculated: 60.1% C; 6.5% II;

Found: 58.3% G; 6.3% H.

19. Bis-(tridecanolato)-bis-(1-phenyl-1,3-butanedionato)-titanium(IV)

Under a dry nitrogen atmosphere, a solution of 4.6 g (0.01 mol) diethoxybis-(1-phenyl-1,3-butanedionato)-titanium(IV) 1 100 ml methylene chloride is added dropwise to a solution of 4.0 g ( 0.02 mol) 1-tridecanol (tridecyl alcohol, CH^ (CH2)12OH) in 50 ml of methylene chloride rapidly. Stir for 2 hours at room temperature and then evaporate on a rotas ion evaporator. The resulting red oil is freed of volatile substances in high vacuum. It decomposes above 250°C.

Yield: 7.68 g (100% d.Th.); boiling point (26.6' Pa): 140°C. Analysis: Calculated: 70.2% C; 9.5% H; 6.1% Ti;

Found: 6 9.5% C; 9.4% H; 6.0% Ti.

2 0. Diethoxybis-[ 1-( 3, 4- dimethoxyphenyl)- 1, 3- butanedionato] titanium( IV)

In a dry nitrogen atmosphere, 2.28 g (0.01 mol) of titanium tetraethoxide, dissolved in 50 ml of methyl chloride, are added dropwise to 4.44 g (0.02 mol). 1-(3,4-dimethoxyphenyl)-1,3-butanedione, dissolved in 20 ml of methylene chloride quickly. The clear yellow solution is stirred for 1.5 hours at room temperature, and then evaporated to dryness. The yellow residue is dried under high vacuum.

Melting point: 98-105°C.

Yield: quantitative.

Analysis: Calculated: 5 7.9% C; 6.3% H;

Found: 58.2% C; 6.3% H.

.21. Diethoxybis-(3-pheny1-2,4- pentanedionato)-titanium(IV)

2.3 g (0.01 mol) of traethoxy titanium (IV) and 3.5 g (0.02 mol) of 3-phenyl-2,4-pentanedione [preparation according to J.T. Adams, C.R.

Hauser, J. Am. Chem. Soc. 6_7 , 284 (1945)] in 100 ml of benzene is heated at reflux in a dry nitrogen atmosphere.. Ethanol/ben-. the zen azeotrope is distilled off until the mixture has reached a boiling temperature of 80°C. The reddish-brown clear solution is evaporated to dryness. The reddish-yellow mass is recrystallized from benzene and dried under high vacuum.

Yield: 3.2 g (65% d.Th.); melting point: 103-112°C (decomposition).

Analysis: Calculated: 63.93% C; 6.60% H; 9.91 Ten;

Found: 6 3.78% C; 6.77% H; 9.72 Ten.

22. Coprecipitate diethoxy-bis-(1-phenyl-1,3-butanedionato)-titanium(IV)/"Cremop hor" EL 1:10

In a dry nitrogen atmosphere, solutions of 1 g of diethoxy-bis-(1-phenyl-1,3-butanedionato)-titanium(IV) and 10 g of dry "Cremophor"EL (Company BASF) are prepared in dry, pure ethanol. After combining both solutions, the solvent is distilled off under reduced pressure. The remaining yellowish coprecipitate is then kept. 2 4 hours under high vacuum'. The coprecipitate is dissolved in water or physiological saline solution.

A solution of the coprecipitate in physiological sodium chloride solution is particularly advantageously prepared, by injecting the coprecipitate that has been preheated to 40°C in a syringe into a physiological saline solution (0.9%-lg aqueous sodium chloride solution) also preheated to 40°C.

F pharmacology

•A. Tumor models

1. Sarcoma 180 tumor model (intraperitorial)

About. 6-week-old female NMRI mice weighing 18-20 g are each fed approx. 10^ sarcoma. 180 tumor cells in 0.2 ml physiological saline solution intraperitoneally (i.p.). The tumor is kept in passage on the same mouse strain. The tumor cells are taken from recently killed animals, immediately before the transplant. In the case of over-grafting, the animals are used statistically. 6 mice are used per dosage. The number of control groups (untreated animals) is chosen so that they correspond approximately to the square of the total number of the group. The substances are injected intraperitoneally as suspensions in common solvents, such as e.g. "tween"

(polyoxyethylene derivatives of sorbitan esters), always 2 4 hours . after, the transplant.

2. Sarcoma 180 tumor model (subcutaneous)

NMRI mice that under 1. are transferred every approx. 20*10^ sarcoma 180 tumor cells in 0.2 ml physiological saline solution subcutaneously (s.c). At a median tumor weight of 0.5 g, which is achieved after approx. 8 days under the present experimental conditions, one begins with the therapy. The metal complexes are given as solutions of copper precipitates in physiological saline solution twice a week in the tail vein.

The tumor weight is estimated during the experiment in the usual way by palpation and comparison with standardized knuckles.

3. Ehrlich Ascites tumor model

NMRI mice under 1. are transferred on day 0 every 10 6 Ehrlich Ascites tumor cells in 0.2 ml physiological saline solution intraperitoneally. On day 1, the metal complexes are given as solutions of copper precipitates in physiological saline solution intraperitoneally. On day 10, the animals and Ehrlich are killed

The ascites tumor cells are counted. 3 animals are used per group.

,B. Test results

In the following table I are the results from the one under point Al. described sarcoma 180 tumor model summarized. The indicated dose was applied once at the beginning of the trial as indicated. The factor T/C stated as a percentage means the percentage extension of the median survival time of the treated animals compared to the median survival time of untreated control animals.

The experiment is stopped as soon as the median survival time T/C of the treated animals has reached 300% of the median survival time of the untreated animals. To calculate the median survival time, the animals that are still alive at the end of the experiment are considered to have died at the end of the experiment. The comparison compound cisplatin works in a dosage range from approx. 8-10 mg/kg therapeutic and the animals are largely cured. The median survival time of the animals treated with cisplatin is already at a dose of approx. 20 mg/kg less than for the untreated control animals.s.

In the following Table II are the results of the sarcoma 180 tumor model described under A2. indicated. One sees a clear decrease in the tumor weight in comparison with. the control animals.

on day 20 there are 30 animals, then before that 18 control animals with one errors were not taken into account; 1) Ti(bzac)2(OEt)2= diethoxy-bis-(1-phenyl-1,3-butanedionato)-titanium(IV);

T60 = "Tween" 60; PVP 30 BT = polyvinylpyrrolidone with an average molecular weight of 30,000.

In the following table III are the results of the one under point A3. described Ehrlich Ascites tuaror model indicated. By

.the treated animals observe a significantly lower number of Ehrlich Ascites tumor models than in the untreated control animals.

Claims (11)

1. Process for the production of antineoplastically effective preparations, characterized in that mana.) reacts a tetra-alkoxymetal (IV) compound M(OR4)^ , where M means titanium, zirconium and hafnium and R4 means C1-C18-alkyl1, which may be substituted with hydroxy, Cl-C3 alkylamine or alkali sulfonate groups, or C5-C8 cycloalkyl, which may be substituted with Cl-C5 alkyl groups, hydroxy or alkali sulfonate groups, under the exclusion of moisture in an inert solvent with a diketone R1(CH2 0)mC(0)CHR3C(0)R2, in which R 1 means hydrogen, C 1 -C 8 alkyl or phenyl, which may be singly or multiply substituted by fluorine, chlorine, bromine, nitro, Cl-.C4-alk <y> 1, Cl-C4- alkoxy or trifluoromethyl, R2 means Cl-C8-alkyl or phenyl, which may be single- or multiply substituted with fluorine, chlorine, bromine, nitro, C1-C4- alkyl, C1-C4-alkoxy or trifluoromethyl, R 3 means hydrogen or phenyl, and m means the number 0 or 1, but not 0, when R 1 has the meaning hydrogen, or b) reacts a compound of formula in which M, R1, R2, R3 and m are as defined above, and Z is fluorine, chlorine, bromine or 0R4, wherein R4 is as defined above, with an alcohol H0R4 or its alkali alcoholate, wherein R4 is as defined above meanings, and brings an active ingredient thus obtained into a suitable form for a pharmaceutical administration. 2. Procedure according to claim 1, characterized in that one a) reacts tetraethoxytitanium(IV) with benzoylacetone in the molar ratio 1:2, or b) dichlorobis(1-phenyl-1,3-butanedionato)titanium(IV) with ethanol or sodium ethanolate in a molar ratio of 1:2 and brings the thus obtained diethoxybis(1-phenyl-1,3-butanedionato) titanium (IV) into a suitable form for pharmaceutical administration. 3. Method according to one of claims 1 or 2, characterized by evaporating an obtained complex compound in an inert organic solvent together with a possibly dissolved hydrophilic polymer to dryness, and bringing the obtained copper precipitate into aqueous solution. 4. Method according to claim 3, characterized in that the copper precipitate obtained is brought into solution in physiological saline solution. 5. Method according to claim 3, characterized in that the hydrophilic polymer is polyvinylpyrrolidone, polyoxyethylene sorbitan monofatty acid esters ("Tween") or glycerol polyethylene glycol ricinoleate ("Cremo-phor"EL). 6. Method according to claim 3, characterized by adding a dispersing or wetting agent to the solution of the complex compound and the hydrophilic polymer. 7. Method according to claim 6, characterized in that the dispersant or wetting agent is propylene glycol or butylene glycol. 8. Procedure for the preparation of coprecipitates of complex compound Iser with the general formula I, • in which- M means titanium, zircon or hafnium, R 1 means hydrogen, C 1 -C 8 alkyl or phenyl, which may be singly or multiply substituted with fluorine, chlorine, bromine, nitro, Cl-C4-alkyl .1, Cl-C4-alkoxy or trifluoromethyl, R 2 means C 1 -C 8 alkyl or phenyl, which may be single or multiply substituted with fluorine, chlorine, bromine, nitro, C1-C4-alkyl, C1-C4-alkoxy or trifluoromethyl, R3 means hydrogen or phenyl, R4 means C1-C18-alkyl1, which may be substituted with hydroxy, Cl-C3-alkylamine or alkali sulfonato groups, or C5-C8-cycloalkyl, which may be substituted with Cl-C5-alkyl groups, hydroxy or alkali sulfonato groups, X means fluorine, chlorine or bromine, m means the number 0 or 1, but not 0, when RI has the meaning hydrogen, and n means the number 0 or 1, and, if the residue R4 contains an amino group, their hydrohalides and hydrophilic polymers, characterized in that a complex compound is evaporated with. the general formula I, in which M, R1, R2, R3, R4, X, m and »n have the .previously stated meanings, and if the residue R4 contains an amino group, their hydrohalide, dissolved in an inert organic solvent together with an optionally dissolved hydrophilic polymer, until dryness. 9. Method according to claim 8, characterized in that the hydrophilic polymer is glycerol polyethylene glycol ricinoleate ("Cremophor" EL). 10. Method for producing a coprecipitate of diethoxybis(1-phenyl-1,3-butanedionato)titanium(IV) and glycerol polyethylene glycol ricinoleate ("Cremophor"EL) according to claim 8, characterized by evaporating a solution of diethoxybis(1 -phenyl-1,3-butanedionato)titanium(IV) and dried glycerol-polyethylene glycol ricinoleate in anhydrous ethanol to dryness. 11. Method according to claim 10, characterized in that before the evaporation, the ethanolic .solution propylene glycol.