FI75171C - FOERFARANDE FOER FRAMSTAELLNING AV VID BEHANDLING AV KANCERSJUKDOMAR ANVAENDBARA SAMUTFAELLNINGAR. - Google Patents

Description

751 71

A method for preparing co-precipitates for the treatment of cancer

The invention relates to a process for the preparation of antineoplastic active co-precipitates from complex compounds and hydrophilic polymers.

Recently, a cancer-containing drug containing a complex of cis-diamine chloroplatin (II) as a chemotherapeutic agent has been marketed. This compound, known as cispla-10 in the International Nonproprietary Name (INN), has been shown to be a very potent antitumor agent, especially in the treatment of testicular tumors, but also in ovarian tumors and small cell lung carcinomas.

15 On the other hand, cisplatin has a relatively high toxicity. Particularly harmful is its renal toxicity and its effect on permanent hearing damage. Renal and hearing damage are often seen after a single therapeutic dose. In addition to the effect on the kidneys and blood-20 organs, the patient is, above all, very disgusted with long-term severe malaise and associated vomiting.

Recently, several other platinum complexes have been proposed (DE-A-2 445 418, 2 837 237, 25 2 626 559 and 2 539 179), and other transition metal complexes for use as cytotoxic agents. DE-A-2 801 355 discloses that the brown amorphous complex obtained by the reaction of ascorbic acid with a titanium (III) and copper (II) compound (molar ratio 36: 1: 6) has a curative and prophylactic effect, e.g. leukemia. According to the literature, titanocene, zirconocene and hafnosene chlorides have an inhibitory effect on mouse Ehrlich ascites tumors (e.g. Köpf-Maier, B. Hesse and H. Köpf, 35 J. Cancer Res. Clin. Oncol, 96 (1980), p. 43}.

EP 49,486 describes dihalobis (1,3-diketonate) tin, titanium, zirconium 75171 and hafnium compounds having antitumor activity.

Surprisingly, it has been found that co-precipitates prepared from hydrophilic polymers and complexes of the formula

/ R1 (CH-) C (O) CR3C (O) R1 / oM (OR4) 0 X I

^ z m · * z z-n n where 10 M is titanium, zirconium or hafnium,

R x is hydrogen, C 1-6 alkyl or phenyl which may have 1 or more fluoro, chloro, bromo, nitro, C 1-6 alkyl, C 1-4 alkoxy or trifluoromethyl substituents, 2 R is C 1-6 alkyl or phenyl which may have 1 or more fluoro, chloro, bromo, nitro, C 1-6 alkyl, C 1-6 alkoxy or trifluoromethyl substituents, R 3 is hydrogen or phenyl, R is C 1-6 alkylx, which may be substituted by hydroxy, C 1-6 alkylamine or alkali sulfonate groups, or C 5-8 cycloalkyl, which may be substituted by C 1-5 alkyl groups, hydroxy or alkali sulfonate groups, X is fluorine, chlorine or bromine, 25 m is the number 0 or 1, but not 0 when R 1 is hydrogen, and n is the number 0 or 1, 4 or when the residue R contains an amino group, of the hydrohalides of these compounds is of interest. -30 thermostatic effect and at the same time a favorable therapeutic scope, and that they are thus suitable for the treatment of cancer.

Hydrohalides refer to hydrochlorides, hydrobromides and hydroiodides, especially hydrochlorides-35 and.

By alkali sulfonate group is meant an A-SO 2 residue in which A is an alkali metal. The sodium sulfonate residue is preferred.

3 75171 ^ 1_3- '4 ~' ^ ΐ-5 ~ '^ 1-8-C1-6-alkyl groups are straight-chain or branched alkyl groups having 1-3, 1-4, 1-5, 1-8 or 1-18 carbon atoms. Alkyl groups having more than 10 carbon-5 liatomers are preferably unbranched.

By C 1-6 alkylamine is meant mono- and di-C 1-6 alkylamines, of which diethylamine is preferred.

C8-8 cycloalkyl means cycloalkyls containing 5 to 8 ring carbon atoms, of which cyclohexyl is preferred.

The invention thus relates to a process for the preparation of co-precipitates for the treatment of cancer, which process is characterized in that the complex compound of the formula I as defined above or, when the group R contains an amino group, its hydrohalogen dissolved in an inert organic solvent together with a hydrophilic solvent with the polymer is evaporated to dryness.

Preferably, co-precipitates are prepared according to the invention in that the complex compound of the formula I is diethoxybis (1-phenyl-1,3-butanedioate) titanium (IV), di (isopropoxy) bis (1-phenyl-1,3-butanedione) ) titanium 25 (IV), bis (2-hydroxypropoxy) bis (1-phenyl-1,3-butanedione) titanium (IV), diethoxybis (3-phenyl-2,4-pentanedione) titanium (IV), chloro (2,3-dimethyl-2,3-butanediolate) bis (1-phenyl-1,3-butanedioate) titanium (IV), chloro (2-hydroxypropanolate) bis (1-phenyl-1,3-butanedioate) titanium (IV), bis (tridecanolate) bis (1-phenyl-1,3-butanedione) titanium (IV) and / or diethoxybis (3-phenyl-2,4-pentanedione) titanium (IV), especially diethoxybis (1 -phenyl-1,3-butanedioate) titanium (IV).

75171

Metal complexes are prepared either by reacting the corresponding metal tetraalcoholate with the corresponding diketone in a molar ratio of 1: 2. Yamamoto and S. Kambara, J. Am. Chem. Soc. 79 (1957), p. 43447 or by reacting the corresponding dihalobobis (diketonate) metal (IV) with the corresponding alcohol or also its alcoholate, preferably an alkali alcoholate, in a molar ratio of 1: 1 when a monohalometallic (IV) complex has to be prepared. (n has the meaning 1 in formula I) or in a molar ratio of 1: 2; when a dialcoholate bis-diketonate metal (IV) complex (n is in formula 0) / D is to be prepared. M. Puri and R. C. Mehrotra, J. Ind. Chem. Soc. 39 (1962), p. 4997. When carrying out the reaction of a dihalobis (diketonate) metal (IV) complex with an alcohol, it is expedient to carry out the reaction in the presence of a base. Ammonia, which is passed through the reaction mixture, is preferably used as the base. The resulting ammonium halide is sparingly soluble in the solvents used and can be removed by filtration and / or centrifugation. Ammonium halide residues can be removed from the final product by sublimation under high vacuum. The alcoholate groups of the alcohol-diketonate metal (IV) complexes can be exchanged for other alcoholate groups (p. B. Sa-Xena et al., J. Chem. Soc. A. (1970), p. 904; and D. M.

25 Puri and R. C. Mehrotra, J. Ind. Chem. Soc. 39 (1962), p. 4997. The alcohol-diketonate metal (IV) complex whose alcoholate group is 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 the exchange of a lower alcoholate anion for a higher alcohol alcoholate anion. In many cases, the exchange can be promoted by distilling off the azeotropically released alcohol. The reactions are conveniently carried out in a dry protected atmosphere, preferably under a nitrogen atmosphere, and using anhydrous starting materials and optionally carefully dried solvents.

11 75171

The reactions are performed either without a solvent or in an inert solvent such as benzene, n-hexane, diethyl ether, methylene chloride or chloroform. It is possible to work without a solvent, especially when at least one of the parties to the reaction is a liquid. When one of the reaction parties is insoluble in the solvent used, it is formed into a suspension in this solvent, and the soluble reaction party is added to the suspension as a solution.

10 Depending on the intensity of the reaction, work is carried out at room temperature, cooling or heating, for example at reflux temperature. To complete the reaction, it may be necessary to heat the reaction mixture to reflux for 1-3 days.

In reactions in which hydrogen halide is liberated, it may be advantageous to remove it by passing dry nitrogen through the reaction mixture. The reaction products are precipitated from the reaction solution either by concentration and / or cooling and / or by the addition of a precipitating solvent, in particular hexane-20 and petroleum ether.

1,3-Diketones are known and can be prepared by methods known per se. They can be obtained, for example, by ester condensation of the corresponding aryl methyl ketone with ethyl acetate or by ester condensation of the corresponding aryl acetic acid ethyl ester using sodium amide as a condensing agent (J. Adams, and CR Hauser, J. Amer. Chem. Soc. 66 (1944), p. 1220). possible to obtain 1,3-ketones by adding a solution of the corresponding arylmethyl ketone in ethyl acetate or toluene to a suspension of sodium (DW Brown, SF Dyke, M. Sainsbury and G. Hardy, J. Chem. Soc. (c) (1971), p. 32197). Another possibility is to react the aryl methyl ketone with acetic anhydride in the presence of boron trifluoride.

35 Walker and C. R. Hauser, J. Amer. Chem. Soc. 68 (1946), pp. 2742. 1-Benzyl-1,3-diketones are prepared by condensing the corresponding phenylacetic acid ethyl ester with the corresponding methyl ketone in the presence of sodium amide (A. Becker, Helv. Chim. Acta 149 (1949), p. 1114).

Co-precipitates are prepared by mixing a solution of the complexes in an anhydrous organic solvent with a hydrophilic polymer such as polyvinylpyrrolidone (PVP) or polyoxyethylene sorbitan fatty ester (Tween ®) or especially (S) glycerol-polyethylene glycol 10 the solvent is evaporated. Suitable organic solvents are, for example, chloroform or methylene chloride, which are rendered anhydrous in the usual manner before use. It has proven expedient to use hydrophilic polymers in 5 to 50-, preferably 10- to 35-fold weight excesses over the complex compound. It is also possible to add the polymers as such to solutions of complex compounds. After removal of the solvent or solvents, the residual solvent is expediently removed as accurately as possible under high vacuum.

Depending on the type and amount of hydrophilic polymer used, solid, crystalline or glassy masses, or also liquid or sticky residues, are obtained. The latter can generally be converted by cooling into solid, usually pasty products.

In the present invention, these new residues are termed co-precipitates. The dissolution behavior of the co-precipitates is preferably influenced when a dispersing or wetting agent, such as propylene or butylene glycol, preferably propylene glycol, is added to the mixture of the complex compounds and the hydrophilic polymer solution.

Aqueous solutions of co-precipitates are prepared by treating the co-precipitates with water. PVP co-alloy-35 nuclei are usually soluble already at room temperature. Combined with polyoxyethylene sorbitan fatty acid esters or glycerol polyethylene glycol ricinoleate

II

75171 7 The precipitate is preferably dissolved by heating the co-precipitate and water to 25-60 ° C, preferably 30-40 ° C, before mixing.

Particularly preferably, the co-precipitate is dissolved in physiological saline instead of water.

The co-precipitates prepared according to the invention are preferably administered by intravenous injection or intravenous infusion.

Preparation Example 10 Dietoxybis (1-phenyl-1,3-butanedione) titanium (IV) To 11.4 g (0.05 mol) of titanium tetraethoxide are rapidly added dropwise under moisture-protected conditions 15.8 g (0.097 mol) of benzoylacetone in 200 ml of: dry 15 n-hexane. The reaction mixture is heated at reflux for 2 hours under cooling under a dry nitrogen atmosphere. The precipitated colorless product is filtered off with suction, slurried in boiling hexane, filtered off with suction again and the residual solvent is removed from the precipitate under high vacuum. Sp. 110 ° C.

20 The second method of production has been proposed by Mr O. M.

Puri and R. C. Mehrotra, J. Ind. Chem. Soc. 39 (8) (1962), p. 499.

2. Dietoxibis (1-phenyl-1,3-butanedione) - titanium (IV) / Cremopho] ®EL co-precipitation 1:10 25 In a dry nitrogen atmosphere, prepare solutions of 1 g of dietoxibis (1-phenyl-1, 3-butanedioate) titanium (IV) and 10 g of dried Cremophor®EL (BASF AG). The solutions are combined and the solutions are evaporated under reduced pressure. The remaining 30 yellowish co-precipitates are then kept under high vacuum for 24 hours. The co-precipitate is dissolved in water or physiological saline.

The co-precipitate solution in physiological saline solution is particularly preferably prepared by spray-3¾ rack in a syringe to a co-precipitate preheated to 40 ° C while stirring a physiological saline solution (0.9% aqueous sodium chloride solution) preheated to 40 ° C.

8 75171

Pharmacology A. Tumor model 1. Sarcoma-180 tumor model (subcutaneous)

Female NaRI mice weighing 18 to 20 g at about 6 weeks of age are implanted subcutaneously (i.p.) in each of approximately 20 x 10 ° sarcoma-180 tumor cells in 0.2 ml of physiological saline. The tumor is allowed to pass through in the same mouse population. Tumor cells are taken from newly killed animals immediately before transplantation. Animals are randomly selected for cell transplantation. 6 mice are used per dose. The number of control groups (untreated animals) is chosen to correspond approximately to the square of the integer number of the groups.

15 When the median tumor weight is 0.5 g, which is achieved under the given conditions in about 8 days, therapy is started. Co-precipitates are administered as solutions in physiological saline twice a week into the tail vein.

20 Tumor weight is assessed during the experiment in the usual manner by manual palpation and comparison with standardized buffer balls.

2. Ehrlich ascites tumor model

On day 25, NMRI mice as defined in point 1 are transfected with 10 .mu.l of Ehrlich ascites tumor cells in 0.2 ml of physiological saline. On day 1, mice are given intraperitoneal co-precipitates as solutions in physiological saline. On day 10, the animals are sacrificed and Ehrlich ascites tumor cells count to 30 anyone. 3 animals are used per group.

B. Test results

The following Table I shows the results in A.l. described from the sarcoma-180 tumor model. A clear decrease in tumor weight can be observed compared to the tumor weight of control-35 animals.

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10,751 71

The following table shows the results in section A.2. described Ehrlich ascites tumor model. Significantly lower numbers of Ehrlich ascites tumor cells are observed in treated animals than in untreated control animals.

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Claims (5)

12 Claims „_ _„ _ 751 71 A process for the preparation of co-precipitates for the treatment of cancers from complex compounds of the formula / R 1 (CH 2) C (O) CR 3 C (O) R 7 70 M (O R 4) _ XI vzm ^ λ 2-nn wherein 10. is titanium, zirconium or hafnium, R 1 * · is hydrogen, C 1-6 alkyl or phenyl, which may have 1 or more fluoro, chloro, bromo, nitro, C 1-4 alkyl, C 1-4 alkoxy or a trifluoromethyl substituent, 2 15. is C 1-8 alkyl or phenyl which may have 1 or more fluoro, chloro, bromo, nitro, C 1-6 alkyl, C 1-6 alkoxy or trifluoromethyl substituents , 3 R is hydrogen or phenyl, 4 R is C 1-6 alkyl which may be substituted by hydroxy, C 1-8 alkylamine or alkali sulfonate groups, or C 1-6 cycloalkyl which may be substituted by C 1-6 cycloalkyl alkyl groups, hydroxy or alkali sulfonate groups, X is fluorine, chlorine or bromine, 25. is a number 0 or 1, but not 0 when R 1 is hydrogen, and n is a number 0 or 1, 4 3a when residue R contains an amino group, example hydrohalides and hydrophilic polymers of n compounds, characterized in that a complex compound of the formula I in which M, R, R, R, 4 R, X, m and n have the same meaning as above and when 4 R contains an amino group, its hydrohalide dissolved in an inert organic solvent together with the same dissolved hydrophilic polymer is evaporated to dryness. Il 13 751 71 Process according to Claim 1, characterized in that the hydrophilic polymer is polyvinylpyrrolidone, polyoxyethylene sorbitan monofatty acid ester or glycerol polyethylene glycol cross-oleate. Process according to Claim 1 or 2, characterized in that the hydrophilic polymer is glycerol polyethylene glycol castor oleate. Process for the preparation of a co-precipitate of diethoxybis (1-phenyl-1,3-butadionate) titanium (IV) and glycerol polyethylene glycol ricinoleate according to Claim 3, characterized in that diethoxybis (1-phenyl-1,3- butanedioate) a solution of titanium (IV) and dried glycerol polyethylene glycol ricinoleate in anhydrous ethanol is evaporated to dryness. Process according to Claim 4, characterized in that propylene glycol is added to the ethanol solution before evaporation. 751 71 14