DE3604866A1 - Antitumour (1,2-diphenylethylenediamine)platinum (II) complexes - Google Patents

Abstract

Antitumour (1,2-diphenylethylenediamine)platinum (II) complexes of the general formula <IMAGE> in which R7 denotes hydrogen or C1-C6-alkyl and R2 is either a halogen atom and the radicals R1, R3, R4, R5 and R6 are identical or different and denote hydrogen, halogen, trihalomethyl, C1-C6-alkyl, hydroxyl, C1-C6-alkoxy or a C2-C6-alkanoyloxy group which is optionally substituted by halogen or C1-C4-alkanesulphonyloxy or R<2> is a hydroxyl group, a C1-C6-alkoxy group or a C2-C6-alkanoyloxy group which is optionally substituted by halogen or C1-C4-alkanesulphonyloxy in the 4-position and in this case the radicals R1 and R3, which are identical or different, are in the 2- and 6-positions of the phenyl radical and denote halogen, trihalomethyl, C1-C6-alkyl, hydroxyl, C1-C6-alkoxy or a C2-C6-alkanoyloxy group which is optionally substituted by halogen or C1-C4-alkanesulphonyloxy, where R1 can also be hydrogen if R3 is halogen, trihalomethyl or C1-C6-alkyl, and the radicals R4, R5 and R6 are identical or different and denote hydrogen, halogen, trihalomethyl, C1-C6-alkyl, hydroxyl, C1-C6-alkoxy or a C2-C6-alkanoyloxy group which is optionally substituted by halogen or C1-C4-alkanesulphonyloxy, and X stands for the equivalent of a physiologically tolerable anion.

Description

Anti-tumor (1,2-diphenyl-ethylenediamine) platinum (II)

Complexes Antitumor compounds are known from German Offenlegungsschrift 34 05 611. These are (1,2-diphenyl-ethylenediamine) platinum (II) complex compounds of the general formula in which the radicals R1, R2, R3 and R4 are identical or different and denote hydrogen, hydroxyl groups, C1-C6-alkoxy groups, C2-C6-alkanoyloxy groups or C3-C6-alkenoyloxy groups, where at least one of the radicals R1, R2, R3 or R4 is not a hydrogen atom, and X stands for the equivalent of a physiologically acceptable anion.

The invention relates to the subject matter defined by the claims.

The new compounds according to the invention have a pronounced one Antitumor effect with good tolerance.

The effect is particularly evident in the following animal and cell culture models: Mouse leukemia P 388, hormone-independent, human breast cancer cell line MDA-MB 231, hormone-dependent human breast cancer cell line MCF 7, hormone-dependent mouse breast cancer MXT, DMBA-induced hormone-dependent rat breast carcinoma (DMBA = dimethylbenz / / -anthracene), The compounds according to the invention prevent or inhibit both the growth of existing tumor cells and the formation of new ones Tumor cells; they continue to destroy or lead to existing tumor cells to their regression and prevent or weaken the formation of metastases.

In comparison with the known compounds, the compounds according to the invention show Compounds have a better or more advantageous anti-tumor effect.

For example, the compounds of the invention have wherein R2 is a halogen atom (see for example the formula on page 11, where at least one of the radicals R1 to R6 means a halogen atom), a better effect on hormone-independent Tumors such as mouse leukemia P 388 and hormone-independent leukemia human breast cancer cell line MDA-MB 231 than the previously known compounds.

The compounds according to the invention in which R2 is hydroxy, C1-C6-alkoxy or C2-C6-alkanoyloxy (see for example the formula on page 10) a specific effect on estrogen receptor-positive tumors, in particular on the hormone-dependent mouse mammary carcinoma MXT, the DMBA-induced hormone-dependent one Rat breast cancer and the hormone-dependent human breast cancer cell line MCF 7.

This effect on the homon-dependent tumors listed above is considerably stronger than that of the previously known compounds.

In addition, these compounds according to the invention have according to of the formula on page 10 but also an effect on hormone-independent tumors, for Example using the mouse leukemia P 388 and the hormone-independent human breast cancer cell line MDA-MB 231, this effect being compared to that of halogen compounds according to of the formula on page 11 is less pronounced.

The pronounced action of the compounds according to the invention, wherein R2 is hydroxy, C1-C6 alkoxy or C2-C6 alkanoyloxy (see for example the formula on page 10) on estrogen receptor-positive tumors (for example on hormone-dependent Breast carcinomas) is based on the following mechanisms: 1. They compete with endogenous ones (that is, the body's own) estrogens to bind to the tumor cell's estrogen receptors. As a result, they inhibit the tumor growth-stimulating effect of the endogenous estrogens.

2. By binding the complex molecules to estrogen receptors, the Transport into the nucleus of the tumor cell is facilitated. Through this process becomes enables enrichment that contributes to effect specificity. The complex molecules bind to the DNA (deoxyribonucleic acid) via the platinum atom with elimination of X (leaving group).

As a result, the synthesis processes taking place on the DNA (especially the DNA synthesis) and consequently the tumor growth prevented. It deals this involves additional cytostatic properties.

Particularly important compounds according to the invention are described by the following formula: In this formula, possible meanings for the individual radicals R1 to R7 are, for example, the following: R2 = OH, C1-C6-alkoxy, a C2-C6-alkanoyloxy group optionally substituted by halogen or C1-C4-alkanesulfonyloxy; R1, R3 = halogen, trihalomethyl, C1-C6-alkyl, OH, C1-C6-alkoxy, a C2-C6-alkanoyloxy group optionally substituted by halogen or C1-C4-alkanesulfonyloxy, where R1 can also be hydrogen if R3 is halogen, Is trihalomethyl or C1-C6 alkyl; R4, R5, R6 = H, halogen, trihalomethyl, C1-C6-alkyl, OH, C1-C6-alkoxy, a C2-C6-alkanoyloxy group which is optionally substituted by halogen or C1-C4-alkanesulfonyloxy; for example R4 is a halogen atom (F, Cl, Br), preferably in the 4-position, and R5 and R6 are hydrogen or R4 has the same meaning as R2 and is in the 4-position and R1, R3, R5 and R6 are halogen (preferably in each of the 2,6 positions).

R7 = H or C1-C6-alkyl.

For example, the meso form is particularly strong in these compounds effective.

Further important compounds according to the invention are described by the following formula: In this formula, for example, at least one of the radicals R1, R2 and R3 is a halogen atom (for example F, Cl or Br, preferably in the 3- or 4-position), the other radicals R2 and R3, which can be identical or different, are hydrogen or a halogen atom , while the radicals R4, R5 and R6 are identical or different and either all represent hydrogen or also represent hydrogen and halogen (for example F, Cl or bromine), the halogen atoms being preferably in the 3- or 4-position and preferably at least one of the radicals R4, R5 or R6 represents a halogen atom.

In particular, such connections come into question, where the both phenyl rings are symmetrically substituted by the same substituents.

With these compounds, the racemates are generally strongest effective.

The following information relates to preferred embodiments of the invention: The C1-C6-alkyl groups, the occurring alkoxy groups and the C2-C6-alkanoyloxy groups can be straight or branched and preferably consist of 1 to 4 carbon atoms. The acetoxy group is particularly suitable as the alkanoyloxy group. The alkanoyloxy groups can be one or more (for example 1 to 6, in particular 1 to 3) the same or contain different halogen atoms. In particular there are 1, 2 or 3 halogen atoms on a carbon atom, preferably on the o-carbon atom. Furthermore, the halogen atoms and the alkanesulfonyloxy radical, preferably in the is position of the alkanoyloxy radical are located. For example, it is the methane or ethanesulfonyloxy radical.

In particular, fluorine, chlorine and / or are used as halogen substituents Bromine in question. The trihalomethyl group is, in particular, trifluoromethyl.

The substituents R4, R5 and R6 are preferably in 4- and / or 2-position of the phenyl radical. If one of the radicals R4, R5 or R6 is hydrogen, the 2 other substituents can preferably also be in the 2,4-position of the Phenyl radicals are located.

If one or more of the radicals R1, R3, R4, R51, R6 or R7 are Mean alkyl group, it is preferably a methyl group, an ethyl group, an isopropyl group or a butyl group.

The meaning of R7 on the two nitrogen atoms of the platinum-containing Five rings can be the same; but it is also possible that R7 is on one nitrogen atom Is hydrogen and R7 on the other N atom is a C1-C6 alkyl group.

For example, they have a particularly beneficial effect such Compounds of the formula I in which R2 has the meanings given and R1 and R3 are identical or different and are chlorine, fluorine, bromine, iodine, trifluoromethyl, methyl, Mean ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, where also one of the radicals R1 or R3 or both can be hydrogen and the phenyl radical is substituted by the substituents R4, R5 and R6 in the same way (symmetrical Substitution to the phenyl radical with the radicals R1, R2 and R3). Furthermore there are Compounds of importance where R2 has the meanings given and the radicals R1 and R3 have the meanings given above and the right-hand phenyl radical is now asymmetrical to the phenyl radical with the radicals R1, R2 and R3 is substituted within the framework of the for the radicals R4, R5 and R6 given meanings, the latter preferably having the following Have meanings: hydrogen, hydroxy or halogen; here is at least one of the radicals R4, R5 or R6 halogen or hydroxyl group, while the other two Are hydrogen or all of the radicals R4, R5 and R6 are hydrogen.

The radicals X represent the known and customary physiologically tolerable ones and pharmaceutically acceptable anions of mono- or polybasic acids. In particular For example, the anions of the following acids come into question: HBr, Hcl, HJ, HF, HN03, H2S04 (S04), H3P04 (HPO,); H2CO3, (CO3); Camphor sulfonic acid, - aliphatic or aromatic sulfonic acids, for example C1-C6-alkyl sulfonic acids (for example methanesulfonic acid, Ethane, propane or hexanesulphonic acid), benzene or naphthalenesulphonic acid, the are optionally substituted once or twice by methyl groups (toluenesulfonic acid, especially o- or p-toluenesulfonic acid); aliphatic C1-C4 monocarboxylic acids, which are optionally one, two or three times by halogen atoms (in particular cl, F) are substituted (for example formic acid, acetic acid, propionic acid, chloroacetic acid, Dichloroacetic acid, trifluoroacetic acid, trichloroacetic acid); aliphatic C2-C11 dicarboxylic acids, which may contain a double bond (for example oxalic acid, malonic acid, 2-Amino-malonic acid, malonic acid, which is in the 2-position by a benzyl group or one or two C1-C4-alkyl groups is substituted, maleic acid, fumaric acid, succinic acid); aliphatic monohydroxy and dihydroxy monocarboxylic acids with 2 to 6, in particular 2 to 3 carbon atoms, preferably «-monohydroxycarboxylic acids acts like lactic acid, glyceric acid or glycolic acid; aliphatic monohydroxy and dihydroxy, di and tricarboxylic acids having 3 to 8 carbon atoms, in particular 3 to 6 carbon atoms such as malic acid, tartaric acid, malonic acid attached to the middle C atom substituted by a hydroxyl group and optionally a C1-C4 alkyl group can be isocitric acid or citric acid; Phthalic acid, if necessary through a carboxy group (especially in the 4-position) is substituted; Gluconic acid; Glucuronic acid; the natural "amino acids (to the game L-aspartic acid); 1, l-cyclobutanedicarboxylic acid; Organophosphoric acids such as aldose and ketose phosphoric acids (for example the corresponding mono- and diphosphoric acids) for example aldose-6-phosphoric acids such as D- or L-glucose-6-phosphoric acid, q -D-glucose-l-phosphoric acid, D-fructose-6-phosphoric acid, D-galactose-6-phosphoric acid, D-ribose-5-phosphoric acid, D-fructose-1,6-diphosphoric acids; Glycerol phosphoric acids (with the phosphoric acid residue on one of the terminal or is bound to the central glycerol oxygen atom) such as t-D, L-glycerol phosphoric acid, ß-glycerol phosphoric acid; N-phosphonoacetyl aspartic acid.

The following acids are also suitable for the anions X: Aromatic Carboxylic acids that contain one or more carboxy groups and also C1-C4 alkoxy groups and / or hydroxyl groups. If there are several carboxy groups the aromatic radical (for example benzene ring) are at least 2 carboxy groups preferably in adjacent positions.

For example, if the benzene ring contains 4 or 5 carboxy groups, Complexes can arise which contain 2 moles of the platinum component per 1 mole of the benzene carboxylic acid anion contain. 2 adjacent carboxy groups each neutralize 1 mole of the platinum component, so that, for example, in the case of benzene pentacarboxylic acid, the 1- and 2-position as well as the 4- and 5-position carboxy groups each saturate 1 mol of the platinum component (together 2 moles), while the free 3-position carboxy group is free or in the Salt form with a physiologically compatible cation (e.g. alkaline cation, especially sodium cation) is present. This is generally true when the anions X still have additional acid functions that are not necessary for saturating the platinum to be needed.

The same applies to the case of benzene hexacarboxylic acid, whereby here optionally 1 mole of this acid can saturate 3 moles of the platinum component.

Examples of such acids are: benzene monocarboxylic acid, benzene dicarboxylic acids, Benzene tricarboxylic acids (for example trimellitic acid), benzene tetracarboxylic acids, benzene pentacarboxylic acid, Benzene hexacarboxylic acid; Syringic acid, orotic acid.

Also suitable as acids which form the anions X are amino acids or amino acid derivatives whose basic amino group is neutralized by an acid group. These are, for example, amino acids with the following structure: wherein R 'is hydrogen, a phenyl radical, an indolyl- (3) -methyl radical, imidazolyl- (4) -methyl radical, a C1-C10-alkyl group or a C1-C10-alkyl group, which is replaced by a hydroxy group, a carboxy group, a C1- C6-alkoxy group, a mercapto group, a C1-C6-alkylthio group, a phenyl group, a hydroxyphenyl group, a C2-C6-alkanoylamino group or a C1-C6-alkoxycarbonyl group is substituted.

The basic amino group in the 2-position is here by a customary one Amino acid protecting group neutralized (acylated), for example by a C2-C6-alkanoyl rest or the butyloxycarbonyl radical.

If R 'in the above formula is an alkyl group, it is preferably a C1-C6-alkyl group, for example in 2-, 3-, 4-, 5- or 6-position (counting starts at the junction of the alkyl restes with the remaining molecule) a C2-C6-alkanoylamino group, an imidazolyl- (4) -methyl radical or contains an indolyl (3) methyl radical. Individual examples of such amino acids are: leucine (preferably D- and L-form), valine (preferably D- and L-form), phenylalanine (preferably D- and L-form), phenylglycine (preferably D- and L-form), alanine (preferably D- and form), isoleucine (preferably D- and L-form), asparagine (preferably D- and L-form, lysine (preferably D- and L-form), tryptophan (preferably D- and L-form), tyrosine (preferably D- and L-form), ornithine (preferably D- and L-form).

Here, the basic amino groups are protected by a customary acylamino protective group blocked, in particular by the acetyl group or the butyloxycarbonyl group.

The formula I also includes the possible enantiomers and diastereomers. If the compounds are racemates, they can be used in a manner known per se Example split into the optically active isomers by means of an optically active acid will. But it is also possible from the outset to be enantiomeric or optionally also use diastereomeric starting materials, with a corresponding end product then pure optically active or diastereomeric compound is obtained. Independent The 1,2-diphenyl-ethylenediamine part already possesses the structure of the X radicals 2 asymmetric carbon atoms and can therefore be in the racemate form or in left- or clockwise form or in the meso form. Additional Shapes can be through various enantiomeric or diastereomeric forms the residues X arise. They have particularly beneficial effects at both centers of asymmetry of the 1,2-diphenyl-ethylenediamine part with the same configuration.

With regard to the geometry at the platinum atom, these are those according to the invention Compounds of the formula I always around the cis compounds.

The starting amine II is, for example, as a racemate, as a meso compound, as a pure clockwise or counterclockwise form or in another diastereomeric form Form used. This configuration remains in the manufacture of the platinum complex obtain.

The process for the preparation of the compounds I according to the invention is in a solvent at temperatures between 0 and 900 C, preferably 10 to 600 C, in particular 20 to 500 C carried out.

Examples of suitable solvents are: water, C1-C6 alkanols (Methanol, ethanol, tert-butanol), tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide, Ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and mixtures of these solvents, especially mixtures with water.

The two reaction components (platinum compound and compound II) are preferably used in equimolar amounts. The pH of the reaction solution should be between 5 and 7, preferably at pH 6. Adjusting the pH value takes place in particular by adding alkali, preferably aqueous sodium hydroxide solution or potassium hydroxide solution or, for example, also by means of sodium carbonate.

As tetrahalogen platinum (II) compounds (acid and complex salts) the corresponding tetrachloro, tetrabromo and tetraiodo compounds come in Question.

If platinum (II) halides are used as the starting component, the same halogen atoms come into question.

Possible monovalent cations are: alkali ions, in particular Sodium and potassium; but lithium, rubidium, cesium or thallium salts can also be used can be used, as well as NH4 +, NR4 +, PR4 or AsR4 +, in which R is a C1-C6-alkyl radical or is a phenyl radical. Divalent cations can be: alkaline earth ions, in particular Mg2 + and Ca, but also Zn. As platinum (II) halides, for example, PtCl2, PtBr2 and PtJ2 in question.

The compound II is either in the form of the diamine or in the form of a Acid addition salt used: for example as monohydrochloride or dihydrochloride, Mono- or dihydrobromide, mono- or dihydroiodide or as a salt with another usual acid. In particular, the acids are also suitable, the anions of which the Form residues X. Furthermore, the diamine can be in the form of the acetate or diacetate are used, optionally before mixing the reaction components Potassium chloride (e.g. 2 moles per 1 mole of compound II) is added. as well the diamine II can be used in the form of the carbonate.

In compounds of the formula I, free phenolic hydroxyl groups can be present acylated by C1-C6 alkanoyl groups. These alkanoyl groups can contain halogen atoms (for example cl, Br) or C1-C4-alkanesulfonyloxy groups. This acylation can for example by means of C1-C6-alkanoyl halides or the anhydrides of C1-C6-carboxylic acids at temperatures between 10 and 800 C, in particular 20-300 C in the presence of more common acid-binding substances. The alkanoyl halides or anhydrides can optionally contain at least 1 halogen atom or at least one C1-C4-alkanesulfonyloxy group contain. Into the- special aliphatic substances come as acid-binding substances tertiary amines such as, for example, diisopropylethylamine. As an inert solution or suspending agents for the acylation are, for example: lower aliphatic halogenated hydrocarbons (chloroform), aprotic solvents such as amides, C1-C4-alkylamides and C1-C4-dialkylamides of aliphatic C1-C4-carboxylic acids (Dimethylformamide, dimethylacetamide), N-methyl-pyrrolidone, dimethyl sulfoxide or Mixtures of these agents.

This acylation can, for example, also be carried out in a two-phase system for example water / chloroform carry out, in which case the acylated platinum (II) complex generally in the water phase and the mixture of acid chloride and tertiary Amine (diisopropylethylamine) is in the chloroform phase. The acylated platinum (II) complex can be converted into a less water-soluble, Convert the desired complex and can be isolated by filtering off.

This applies in particular if the acylated dihydroxoplatinum (II) complex is in the water phase is present. In general, it is useful in the acylation in a two-phase system the anion X of the platinum complex of the formula I before the acylation by means of an anion exchanger to be exchanged for OH, since the corresponding dihydroxoplatinum (II) complex is readily water-soluble is. The corresponding chlorides and bromides are preferably used as acid halides and optionally iodides.

The symmetrical anhydrides of C1-C6 carboxylic acids are particularly suitable Acid anhydrides in question.

The ligands X can be exchanged for other ligands, for example, by means of silver halide precipitation. For this purpose, for example, a dihalo (1,2-diphenyl-ethylenediamine) platinum (II) compound of the formula I, in which X is halogen (chlorine, bromine or iodine), is used in a solution or suspension medium at temperatures between 0 and 900 ° C. preferably 10 to 500 C, in particular 15 to 250 C with the silver salts of another acid, which corresponds to the meaning X, reacted. Here, however, silver nitrate (for example aqueous silver nitrate solution) can also be used as the silver salt and an ionic diaquo complex of the formula is obtained From this complex, the weakly bound ligand water can easily be replaced by more affine anions (for example Cl-, Br- in the form of NaCl, KCl, NaBr, KBr, malonate²-chloroacetate (-), oxalate²-, 1,1-cyclobutanedicarboxylic acid anion2 and displace the other specified acid radicals X, used in the form of the acids or their salts, in particular their alkali salts.

The same compounds can also be converted into equimolar amounts Amounts of HX and nitrate-free Platinum complex (the latter under Use of anion exchangers in the hydroxide form, for example Dowex 1 - 8X) to win.

An exchange of the leaving group (for example S04 or Oxalate anion2 ') is in the case of sulfato or oxalato (1,2-diphenyl-ethylenediamine) platinum (II) compounds also by reaction with alkaline earth salts, which form the desired X ligands (for example Glyceric acid), if the resulting complex is water-soluble is and thus the separation of the poorly water-soluble alkaline earth sulfate or oxalate permitted.

X ligands suitable for this process are preferably the anions of hydroxycarboxylic acids, sulfonic acids, haloacetic acids, nitric acid.

The solution or suspending agent required for the manufacturing process of the compounds I specified are also suitable for the exchange reaction (In particular, water and dimethylformamide as well as methanol, ethanol, tert-butanol). The exchange reaction is, for example, in a pH range between 3 and 7 carried out.

Production of unknown starting amines of the formula II: Production of 1,2-diaryl-ethylenediamines with symmetrically substituted phenyl radicals of the formula II, insofar as these are not described.

In this regard, reference is also made to the following literature: Journal of Medicinal Chemistry, 1982, Volume 25, pages 1374-1377; Chemical reports 1976, Volume 109, page 1.

A. General rule of the ether cleavage with BBr3 for illustration of hydroxy-substituted meso- and d, t-1,2-diarylethylenediamines of the formula II 5.5 mmol of the methoxy-substituted meso- or d, -1, 2-diarylethylenediamine in question are dissolved in 150 ml of anhydrous CH2Cl2 and cooled to -50 ° C. Under a nitrogen atmosphere 22 mmol of boron tribromide are added and the mixture is stirred at this temperature for 30 minutes. After stirring for a further 18 hours at room temperature, the excess BBr3 is under Ice cooling carefully hydrolyzed with methanol and the solvent mixture spun off. The residue is taken up in 50 ml of water and the pH value with saturated NaHCO3 solution adjusted to pH 7. The precipitate is filtered off with suction and washed with water and ethanol and CH2Cl2 and dry over P205. As a rule, analytically pure products are obtained. For example, the starting amines for Examples 2, 4, 10, 12, 14, 16, 20, 21 and 24 obtained this way.

The ether cleavage can also be carried out with hydrobromic acid, for example be carried out according to the following rule: 0.01 mol of the methoxy-substituted in question meso-1,2-Diarylethylendiamins are in 60 ml of 47% HBr 24 - Heated under reflux for 48 hours. After cooling, the precipitate is suctioned off, washed with very little ice water and dissolved in water. This is added as much 20% NaOH solution until the precipitated ethylenediamine as phenolate is back in Solution works. After filtering, the pH is adjusted to 7 with 2N Hcl and the precipitate sucked off. It is washed with water and ethanol and dried, which is mostly analytically pure Product about P2O5.

In this way, for example, became the starting amines for the examples 6, 8 and 18 received.

B. General procedure for the preparation of the mesoconfigured 1,2-diarylethylenediamines of formula II via the meso # meso-Diaza-Cope rearrangement 0.5 mol of N, N'-disalicylidene-meso-1,2-diarylethylenediamine are suspended in 200 ml of 2 N H2SO4 or half-concentrated H2SO4. The salicylaldehyde released during the hydrolysis is removed by steam distillation removed from the reaction mixture. If no more aldehyde can be detected in the distillate, the reaction solution is filtered hot and, after cooling, carefully with 20% NaOH solution adjusted to pH 11-12. The precipitate is extracted with CH2Cl2, the combined extracts are washed with water and dried over MgSO4. The solvent is concentrated until the product begins to precipitate.

About 100 ml of ether are added and the mixture is allowed to crystallize in the refrigerator. The ethylenediamine is filtered off with suction, washed with ether and recrystallized from ethanol.

The corresponding N, N'-disalicylidene meso-l, 2-diarylethylenediamines (Diaza-Cope rearrangement) can be carried out, for example, by the following method: meso-1,2-bis (2-hydroxyphenyl) ethylenediamine is mixed with 2 molar equivalents of the corresponding benzaldehyde of the formula heated under reflux in acetonitrile. The suspension is constantly stirred and heated to the boil until uniform, yellow cubes form (approx. 4 - 5 hours). After half of the solution has been distilled off by means of and cooling to room temperature, the precipitate is filtered off with suction, washed with a little acetonitrile and dried over P205 in a vacuum desiccator.

For Examples 15 and 16, the corresponding mixture in toluene Heated under reflux on a water separator for 24 hours. It can only be a mixture N, N'-disalicylidene-meso-1,2-bis (2,6-dimethyl-4-methoxyphenyl) ethylenediamine and the unrearranged diimine N, N'-bis (2,6-dimethyl-4-methoxybenzylidene) -meso-1,2-bis (2-hydroxyphenyl) ethylenediamine are isolated, which is implemented further without further separation.

C. General instructions for the synthesis of d, e-configured 1,2-diarylethylenediamines of the formula II via the degenerate Diaza-Cope rearrangement 0.1 mol of the relevant N, N'-dibenzylidene-meso-1,2-diarylethylenediamines are placed in a 1 liter three-necked flask kept stirring in the oil bath at its melting temperature until the crystal mass is completely melted. After cooling to approx. 800 C, 250 ml of 2 N H2S04 are added added and the suspension is subjected to steam distillation until no more aldehyde passes over. The clear solution is filtered hot and left Stands overnight at room temperature to crystallize. The crystalline dihydrosulfate the racemic 1,2-diarylethylenediamine is filtered off and with a little ice cold Washed 2 N H2 SO4. Then it is in a separating funnel with 2 N NaOH solution covered and extracted with CH2Cl2. After drying over MgSO4, it is rotated The solvent is removed and the oily residue is recrystallized from ethanol.

In the case of products that are difficult to crystallize, the dihydrochloride can be used precipitate with ethereal Hcl. The filtrate contains the dihydrosulfate of the meso-configured 1,2-diarylethylenediamine, which can be re-isolated analogously to method B.

In this way, for example, becomes the starting amine for the complexes of Examples 3 and 4 obtained.

The N, N'-dibenzylidene-meso-1,2-diarylethylenediamines used here can be obtained, for example, as follows: The respective meso-1,2-diarylethylenediamine is dissolved in acetonitrile and after adding 2 molar equivalents of corresponding benzaldehyde as indicated under B, heated under reflux for 3 hours. It is allowed to cool, suctioned off on a Buchner funnel and washed with a little acetonitrile and acetone. Drying in the desiccator via P205.

D. General instructions for the preparation of d,? - configured 1,2-diarylethylenediamines via the d, 4 d, e -diaza-Cope rearrangement, 25 mmol of d, l-1,2-bis (4-methoxyphenyl) ethylenediamine are dissolved in 250 ml of methanol and added to 50 mmol of the corresponding, as under B specified, benzaldehyde, dissolved in methanol, given The solution is 24 hours heated under reflux and then the solvent is spun off. The oily residue can be separated by column chromatography over silica gel 60. The applied Diimine mixture is usually already hydrolyzed on the column and you can use suitable Choice and sequence of solvent mixtures Isolate isomer-free d, l product. After adding ethereal HCl to the ethanolic solution, d, l-1,2-diarylethylenediamine can be added can be obtained in crystalline form as dihydrochloride.

For example, this method became the starting amine for the compound obtained according to Example 19.

E. General instructions for the preparation of N, N'-dialkylated 1,2-diarylethylenediamines by reductive dimerization of the corresponding benzaldehyde alkyl imines with tetraphenyl ethanediol A mixture of 0.04 mol of benzaldehyde alkyl imine of the formula and 0.04 mol of 1,1,2,2-tetraphenylethanediol in 200 ml of 2-propanol is refluxed for 24 hours.

After cooling, the precipitate (meso isomer) is filtered off with suction, in CH2C12 dissolved and extracted with 2N HCl.

The aqueous phase is made alkaline with 2 N NaOH and extracted with CH2Cl2. The organic phase is washed with water and dried over MgSO4. After rotation of the solvent, the meso product is obtained in crystalline form, that in ethanol is recrystallized. The filtrate of the reaction mixture is evaporated and the remaining brown bl column chromatographed over silica gel 60. The isomer-free dr d,? - product is obtained by successive elution with CH2Cl2, ether and methanol and can be recrystallized from acetonitrile.

The benzaldehyde alkaline imines are prepared from them accordingly substituted benzaldehydes and the Alkylamine NH2R7 in the usual Way, for example in chloroform, first at room temperature (2 hours stirring) followed by refluxing (30 minutes).

The following are the manufacturing instructions for various Benzaldehydes that have not yet been described are given that are used in the methods given above are used as starting aldehydes for the production of the amines II. Others don't known benzaldehydes can be obtained in an analogous manner.

2-iodo-4-methoxy-benzaldehyde 0.1 mole of 4-methoxybenzaldehyde dimethyl acetal is placed in a flame-dried flask under an N2 atmosphere with 500 ml of anhydrous Added ether and cooled to -600 C in a dry ice-acetone cold bath. With help a long, flexible steel needle is 0.11 moles of a solution of tertiary butyllithium expelled in hexane through a serum cap from the storage bottle under nitrogen pressure. The color suddenly changes to yellow. The temperature is left at -250.degree rise and stir for another 3 hours, until a yellow, voluminous precipitate forms has formed. The thus obtained 2-lithium-4-methoxybenzaldehyde dimethylacetal becomes immediately dropwise with 0.11 mol of I2 dissolved in 200 ml of anhydrous ether at -250 C offset. The remaining iodine color indicates the end of the reaction. The solution will be stirred for a further 30 minutes at room temperature and then mixed with water. Extract with ether, wash successively with aqueous Na2SO3 solution, 2N HCl solution, saturated NaHCO3 solution and water and dry over MgSO4.

The solvent is spun off and the residue in Methanol recrystallized.

colorless needles, F. 109-1110 C 2-Bromo-4-methoxybenzaldehyde, 2-lithium-4-methoxybenzaldehyde dimethyl acetal 0.11 mol of bromine is quickly added at -60 ° C. This is followed by 1 hour at Room temperature stirred.

It is mixed with water, extracted with ether and washed successively with aqueous NaSO3 solution, 2 N HCl solution, saturated NaHCO3 solution and water. After drying over MgSO4 and spinning off the ether, a red-brown blue remains, which is subjected to steam distillation. The distillate is extracted with CH2Cl2, dry over MgSO4 and concentrate. The residue is over silica gel 60 (Merck, Darmstadt) column chromatographed with ether / petroleum ether 40-60 1: 2 (Rfs 0.5-0.6).

colorless, long needles, F. 73-740 C.

2-fluoro-4-methoxy-benzaldehyde By reacting 3-fluoroanisole with Bromine in the presence of iron powder in cHcl3 at -600 C in a dry ice-acetone cold bath analogous to that of Quelet, R .; Paty M. in Proces Verbaux soc. sci. phys. et nat. Bordeaux, 1944-45, 19 is obtained after fractional distillation in a water jet vacuum an isomer mixture of 4-bromo-3-fluoroanisole and 2-bromo-5-fluoroanisole, without Separation is processed further.

colorless liquid, boiling point 93-950 C / 14 torr 0.1 mol n-butyllithium-hexane solution 150 ml of anhydrous ether are added in a nitrogen atmosphere and the temperature is increased to -700 C cooled. 0.1 mole of that previously described Mixture of isomers is taken up in 50 ml of anhydrous ether and added dropwise at such a rate that that the reaction temperature does not exceed -55 ° C.

The mixture is stirred at this temperature for 15 minutes and then N-formylpiperidine, dissolved in 25 ml of anhydrous ether, too, the temperature again being below -55 ° C is held. If the subsequent test for organometallic compounds fails Michler's ketone turns out negative, is brought to room temperature, acidified with 2 N Hcl and the organic phase separated. The ether phase is washed with saturated NaHCO3 solution and water, dry over MgSO4 and remove the solvent. The oily residue is chromatographed on silica gel 60 with CH2Cl2 / petroleum ether 40-60 1: 1 (Rf'v 0.45-0.5).

colorless needles, F. 42.5-440 C The 4 -Me thoxy- 2 - tr ifluoromethylbenzaldehyde (m.p. 38-390 C, after purification by column chromatography over silica gel with ether / petroleum ether) over a mixture of 4-bromo-3-trifluoromethyl anisole / 2-bromo-5-trifluoromethyl anisole (Boiling point 46-470 C / 0.6 Torr).

Carrying out the bromination: 18 hours at room temperature.

2,6-dichloro-4-methoxybenzaldehyde 1 mol of precipitated, active manganese dioxide and 800 ml of benzene are heated to boiling on a water separator for 2 hours. Afterward 0.2 mol of 2,6-dichloro-4-methoxybenzyl alcohol are added and again overnight heated under reflux on a water separator.

After cooling to room temperature, the brownstone is poured over a glass filter crucible sucked off and washed with benzene. After the solvent has been spun off man mostly a very pure product, which as required, but with a greater loss of yield, can be recrystallized from methanol.

colorless needles, mp 108-111 ° C. The 2,6-dichloro-4-methoxybenzyl alcohol used is obtained as follows: 0.56 mol of 3,5-dichloroanisole are mixed with 30.3 g of paraformaldehyde in 1.5 liters of concentrator Hcl and 15 ml of concentrated H2 SO4 for 7 hours at 600 C reaction temperature stirred. After cooling, the phases are separated, the aqueous Phase extracted with CH2Cl2 and the combined organic phases washed with water. After drying over MgSO4 and spinning off the solvent, a colorless one remains oil back.

530 ml of 2N NaOH solution, 530 ml of water and 530 ml are added to this oil ml of dioxane are added and the mixture is heated to boiling for 3 hours. The organic Phase is separated after cooling, the aqueous phase is extracted with CH2Cl2 and then the combined organic phases are washed with water and dried over MgSO4. After the solution has been spun off, the oily residue becomes 100 ml of Hcl3 are added and the precipitate which forms is filtered off.

The chloroform is rotated off and the oily residue is separated off by column chromatography on silica gel 60 with a 1: 1 mixture of petroleum ether 40-60 / ether.

colorless needles, F. 78-790 C 2-chloro-4-methoxybenzaldehyde 0.1 mol 2-Lithium-4-methoxybenzaldehyde dimethyl acetal is at -600 C with 0.11 mol of benzenesulfonic acid chloride, dissolved in 50 ml of anhydrous ether, added via syringe. You can then 1 hour at room temperature stir. By adding ice water the white precipitate that has formed dissolves again. Extract with ether, washed with 2 N HCl solution, saturated NaHCO3 solution and water, dried over MgSO4 and draws off the solvent. The residue is over silica gel 60 (Merck, Darmstadt) separated by column chromatography with ether / petroleum ether 40-60 1: 2.

Rf 0.75-0.8 colorless needles, F. 60-610 C.

The compounds of the invention show on human MDA-MB 231 - Breast cancer cell line (Dissertation Jennerwein, University of Regensburg, 1985, Page 151) in leukemia P 388 (mouse) (see dissertation Johann F.X. Karl, Universität Regensburg, 1985, pages 88-89; 93, 94; 99-102), on DMBA-induced breast tumors in the rat and in the human MCF 7 breast cancer cell line exhibited good antitumor activity.

For example, in the mammary carcinoma of the rat, which is caused by 7,12-dimethylbenz / a -j-anthracene (DMBA) was induced, with the compound according to Example 18 at a Dose of 3 x 6.5 mg / kg body weight / week in 88% of the tumors a complete decrease established.

When testing the hormone-independent human mammary tumor cell line MDA-MB 231 show the compounds according to the invention in vitro, for example in Concentrations between 10 5 and 10 7 mol / liter show a 50% growth inhibition this cell line.

The inhibition of ~ H7-thymidine incorporation is of the same order of magnitude. The compounds according to the invention act on lymphocytic leukemia P 388 (mouse) for example in doses between 10 and 50 mg / kg mouse (intraperitoneal application).

The direction of action of the compounds according to the invention is the same comparable to the well-known drug cisplatin.

The lowest dose leading to 65% complete remissions in the animal experiment given above is 3 x 3.25 mg / kg subcutaneously, respectively also intravenously.

As a general dose range for the effect (animal experiment as above) for example: 5-20 mg / kg orally, especially 10 mg, 1-10 mg / kg intravenously, especially 6.5 mg.

Indications for which the compounds according to the invention are suitable can occur: tumor diseases, especially breast, endometrial, cervical, ovarian and Prostate carcinoma, also leukemia, testicular enteroma and bladder carcinoma.

The pharmaceutical preparations generally contain between 100 to 200, preferably 150 mg of the active component according to the invention.

Administration can, for example, in the form of tablets, capsules, Pills, coated tablets, suppositories, ointments, jellies, creams, powders, dusting powders, aerosols or in liquid form. For example, there are liquid forms of application in question: oily or alcoholic or aqueous solutions and suspensions and emulsions. Preferred application forms are tablets between 100 and 200 mg or solutions containing between 0.02 to 0.04% of the active substance.

The single dose of the active components according to the invention can, for example a) for oral dosage forms between 100 and 200 mg, preferably 150 mg, b) in the case of parenteral dosage forms (for example intravenous, intramuscular) between 100 and 200 mg / m2, preferably 150 mg / m2 body surface, c) in drug forms for rectal or vaginal application between 1 and 5%, preferably 2.5%, d) for dosage forms for local application to the skin and mucous membranes (for example in the form of solutions, lotions, emulsions, ointments and so on) between 1 and 5%, preferably 2.5%.

- (The doses are in each case based on the free base) - For example 1 to 4 tablets containing 100 to 200 mg 3 times a day can be more effective Substance or, for example, in the case of intravenous injection 1000 ml with an active ingredient content Accordingly, 100 to 200 mg / m2 body surface area are recommended. When administered orally for example, the minimum daily dose is 300 and the maximum daily dose oral administration should not exceed 800 mg.

The acute toxicity of the compounds according to the invention in the mouse (expressed by the LD 50 / kg; Miller and Tainter method: Proc. Soc. Exper. Biol. A. Med.

57 (1944) 261) is above, for example, in the case of oral administration 100 mg / kg intraperitoneally, often above 1000 mg / kg.

The drugs can be used in human medicine, veterinary medicine can be used alone or in admixture with other pharmacologically active substances. Examples Examples 1-24 are listed in Table 1.

The physical characteristics of the platinum (II) complexes are given in the table 2 specified.

Examples 1-24 relate to the preparation of platinum (II) complexes according to the invention of the following formula: All complexes according to Examples 1-24 are pale yellow to yellow powders.

General instructions for the representation of the platinum complexes in water Medium: 1 mmol of 1,2-diarylethylenediamine is suspended in 20 ml of distilled H2O and dissolved by adding 2 ml of 2 N HCl.

The filtered solution is mixed with 20 ml of tertiary butanol and heated to 40 ° C. With stirring, so much 0.5 N NaOH is slowly added dropwise until the free base begins to precipitate (note pH). The solution will then 415 mg (1 mmol) of K2PtCl4, dissolved in 10 ml of H2O, are added dropwise. One omits Stir in the exclusion of light at 40 ° C and adjust the pH at intervals of 4 - 5 hours to the noted value. This is shown by a constant pH value over a long period of time End of reaction. After cooling to room temperature, the yellow one is mostly analytically pure The precipitate is suction filtered through a frit (G-4), successively with 2 N Hcl and water washed and dried in the drying gun at 1000 C over P205. If required, the complexes are dissolved in a little dimethylformamide for cleaning and with 5% NaCl solution pleases.

According to this method, the complexes according to Examples 1-15, 17 - 21 and 23 - 24 manufactured.

General rule for the representation of the platinum complexes in the organic Medium: 1 mmol of the 1,2-diarylethylenediamine in question is dissolved in 20 ml of dimethylformamide dissolved or suspended and with 1 mmol K2PtCl4, dissolved in 5 ml H2O / dimethylformamide (1: 1 mixture) added. The mixture is stirred in the dark at room temperature, until there is a color change from red to yellow.

If no color change is noticeable after 3 days, then 1 ml of dimethyl sulfoxide is added and the solution is stirred for a further 3-4 hours.

The yellow solution is then concentrated to dryness in a high vacuum. 50 ml of 5% NaCl solution are added to the yellow, oily residue and the mixture is added Stirred for 6 hours. The yellow, finely crystalline precipitate is filtered off, with 2 Washed with N Hcl and water and dried over P205 in a drying gun at 1000 C.

According to this method, the complexes according to Examples 16 and 22 manufactured.

Table 1 Example R1, R4 R2, R5 R3, R6 R7 x configuration color no. (both) 1 CH3 OCH3 H H Cl meso pale yellow powder 2 CH3 OH H H Cl meso pale yellow Powder 3 CH3 OCH3 H H Cl d, 1 pale yellow powder 4 CH3 OH H H Cl d, 1 pale yellow powder 5 J OCH3 H H Cl meso yellow powder 6 J OH H H Cl meso light yellow powder 7 Br OCH3 H H Cl meso light yellow powder 8 Br OH H H Cl meso light yellow powder 9 Cl OCH3 H H Cl meso light yellow powder 10 Cl OH H H Cl meso light yellow powder 11 F OCH3 H H Cl meso light yellow powder 12 F OH H H Cl meso light yellow powder 13 CF3 OCH3 H H Cl meso yellow powder 14 CF3 OH H H Cl meso yellow powder 15 CH3 OCh3 CH3 H Cl meso yellow powder 16 CH3 OH CH3 H Cl meso pale yellow powder 17 Cl OCH3 Cl H Cl meso pale yellow powder Continuation of table 1 example- R1, R4 r2, R5 R3, R6 R7 x configuration color no. (Both) 18 Cl OH Cl H Cl meso pale yellow powder 19 Cl OCH3 Cl H Cl d, l pale yellow powder 20 Cl OH Cl H Cl d, l pale yellow powder 21 Cl OCH3 / OH * Cl H Cl meso yellow powder 22 Cl OCH3 Cl CH3 Cl meso pale yellow powder 23 Cl OCH3 Cl CH3 Cl d, l pale yellow powder 24 Cl OH Cl CH3 Cl d, l pale yellow powder Tabel 2 Physical properties of the compounds from Table 1: IR = IR spectrum in KBr (br = broad, m = medium strength, s = strong, sh = shoulder, vs = very strong, w = weak) 1 H-NMR = nuclear magnetic resonance spectrum, shift of protons in ppm uptake in deuterated dimethylformamide (d7 - DMF) / tetramethylsilane 250 megahertz br = broad, s = singlet, d = doublet, t = triplet, q = multiplet: J = coupling constant J1,2 = e.g. coupling constant for neighboring protons C-atoms, JHF = for example coupling constant resulting from an H..F coupling Compound IR 1 H-NMR according to Example 1 3280 m, 3180 m, 3120 m (# -NH); 2960w, br (CH); 2840 w 1.93 (s, 2 CH3); 3.77 (s, 2 OCH3); (OCH3); 1615 s, 1580 s (# -NH); 340 m, 330 m (Pt-Cl) 4.55 (br, 2 NH); 5.34 (m, br, 2NH); 6.06 (d, br, 2 CH); 6.64-6.73 (m, 4 Ar-H); 8.21 (d, br, 2 Ar-H) 2 3420 s, br (# -OH); 3280 s, 3240 m, 3210 m, 3210 m, 3180 m, 1.87 (s, 2 CH3); 4.47 (br, 2NH); 5.17 3110 m (# -NH); 2980 w (CH); 1620 s, 1590 s (# -NH); (m, br, 2 NH); 6.01 (d, br, 2CH); 6.53-340 m, 330 m (Pt-Cl) 6.62 (m, 4 Ar-H); 8.05 (br, 2Ar-H; 9.51 s, 2OH) 3 3240 s, 3210 m, 3130 m, (# -NH), 2960 w, 2930 w (CH); 2.27 (s, 2CH3); 370 (s, 2OCH3); 4.60 2830 w (OCH3); 1610s, 1580 s (# -NH); 335 m, 330 m (m, br, 2 NH); 5.15 (m, br, 2NH); 6.30 (Pt-Cl) (d, br, 2 CH); 6.56 (d, J1.3 = 2 Hz, 2Ar, H); 6.78 (q, J1,2 = 8 Hz, J1,3 = 2 Hz, 2 Ar-H); 7.91 (d, J1,2 = 8 Hz, 2 Ar-H) Continuation of Table 2 Compound IR 1 H-NMR according to Example 4 3350 sh, 3240 s, br, 3130 m (# -OH, # -NH); 2.20 (s, 2 CH3); 4.62 (m, br 2 NH); 5.12 2970 w (CH), 1630 s, 1580 s (# -NH); 340 m, (m, br, 2NH); 6.21 (d, br, 2 CH); 6.43 br (Pt-Cl) (d, J1.3 = 2 Hz, 2 Ar-H); 6.66 (q, J1,2 = 8 Hz, 2 Ar-H); 7.82 (d, J1,2 = 8 Hz, 2 Ar-H); 9.44 (s, br, 2 OH) 5, 3250 m, 3180 m, 3090 m (# -NH); 2960 , w 2940 w, 3.81 (s, 2 OCH3); 4.54 (br, 2NH); 5.58 (CH); 2830 w (OCH3); 1600 s (# -NH); (m, br, 2 NH); 6.50 (d, br, 2 CH); 6.96 350 m, br (Pt-Cl) (q, J1,2 = 9 Hz, J1,3 = 3 Hz, 2 Ar-H); 7.33 (d, J1,3 = 3 Hz, 2 Ar-H); 8.25 (d, br, 2 Ar-H) 6 3380 s, br (# -OH); 3270 m, 3220 m, 3180 w, 4.48 (br, 2 NH); 5.46 (m, br, 2NH); 6.45 3110 m (# -NH); 1595 s, 1525 s, (# -Nh); 330 m, (d, br, 2 CH); 6.82 (q, J1,2 = 9 Hz, J1-3 = 3 Hz, 320 m (Pt-Cl) 2 Ar-H); 7.25 (d, J1,3 = 3 Hz, 2 Ar-H); 8.14 (br, 2 Ar-H); 10.05 (br, 2 OH) 7 3250 m, 3180 m, 3090 m (# -Nh); 2960 w, 2940 w (CH); 3.82 (s, 2OCH3); 4.72 (br, 2 NH); 5.61 (m, br 2830 w (OCH3); 1605 s, 1565 s (# -NH); 330 m, br (Pt-Cl) 2 NH); 6.44 (d, br, 2 CH); 6.95 (q, J1,3 = 3 Hz, 2 Ar-E); 8.38 (d, br, J1.2 = 7 Hz, 2 Ar-H) 8 3450-3390 br (# -OH); 3260 w, 3200 s, 3100 m (# -NH) 4.67 (br, 2 NH); 5.52 (m, br, 2 NH); 6.38 (d, 1605 s, 1580 m (# -NH); 325 w (Pt-Cl) br, 2 CH); 6.80 (q, J1,2 = 8 Hz, J1,3 = 2 Hz, 2 Ar-H); 6.96 (d, J1,3 = 2 Hz, 2 Ar-H); 8.26 (d, br, J1,2 = 7 Hz, 2 Ar-H); 10.17 (br, 2 OH) Continuation of Table 2 Connection IR 1 H-NMR according to Example 9 3200 m, 3180 m, 3100 m (# -NH); 2960 w (CH); 2830 w 3.82 (s, 2 OCH3); 4.77 (br, 2NH); 5.64 (OCH3); 1605 s, 1570 s (# -NH); 335 m, 325 m (Pt-Cl) (m, br, 2 NH); 6.40 (d, br, 2 CH); 6.90 -6.92 (m, 4 Ar-H); 8.41 (d, br, 2 Ar-H) 10 3560 m; 3385 m (# -OH); 3265m, 3230m, 3200m, 4.71 (br, 2NH); 5.54 (m, br, 2 NH); 6.34 3095 m (# -NH); 1605 s, 1575 s (# -NH); 320 w (Pt-Cl) (d, br, 2 CH); 6.74 - 6.78 (m, 4 Ar-H); 8.32 (d, br, 2 Ar-H); 10.20 (br, 2 OH) 11 3250 m, 3170 m, 3100 m (# -NH); 2960 w, 2940 w (CH); 3.80 (s, 2 OCH3); 4.60 (br, 2 NH); 5.61 2835 w (OCH3); 1625 s, 1580 s (# -NH); 330 m (Pt-Cl) (m, br, 2 NH); 6.30 (d, br, 2 CH); 6.67 (q, J1,3 = 3 Hz, JHF1,2 = 12 Hz, 2 Ar-H9; 6.77 (q, J1,2 = 9 Hz, J1,2 = Hz, 2 Ar-H); 8.36 (t, J1,2 = 9 Hz, JHF1,3 = 9 Hz, 2 Ar-H) 12,3,400 s, br (# -NH); 3260 s, 3210 s, 3105 m (# -NH); 4.54 (br, 2NH); 5.50 (m, br, 2NH); 6.23 1625 s, 1595 s (# -NH); 325 w (Pt-Cl) (d, br, 2 CH); 6.44 (q, J1,3 = 2 Hz, JHF1,2 = 12 Hz, 2 Ar-H); 6.63 (q, J1,2 = 9 Hz, J1,3 = 2 Hz, 2 Ar-H); 8.23 (t, J1,2 = 9 Hz, JHF1,3 = 9 Hz, 2 Ar-H), 10.17 (br, 2 OH) 13,3,200 m, 3100m (# -NH); 3010 w, 2950 w (CH); 3.88 (s, 2 OCH3); 4.59 (br, 2NH); 5.88 2840 w (OCH3); 1620 s, 1585 s (# -NH); 330 m, br (Pt-Cl) (m, br, 2NH); 6.73 (d, br, 2nd CH); 7.14 (d, J1,3 = 3 Hz, 2 Ar-H); 7.20 (d, br, J1,2 = 9 Hz, 2 Ar-H); 8.64 (br, 2 Ar-H) Continuation of Table 2 Compound IR 1 H-NMR according to the example 14 3340 br, sh (# -NH); 3140 s (# -NH); 3010 w, 4.54 (br, 2 NH); 5.77 (m, br, 2NH); 6.67 2890 w (CH); 1620 m, 1580 w (# -NH); 323 w (Pt-Cl) (d, br, 2 CH); 7.02-7.06 (m, 4 Ar-H); 8.46 (br, 2 Ar-H); 10.45 (s, br, 2 OH) 15 3540 w, br (# -NH); 3150 w, br (# -NH); 2960 w (CH); 2.03 (s, 2 CH3); 2.74 (s, 2 CH3); 3.74 2840 w (OCH3); 1605 s, 1580 m (# -NH); 325 w (Pt-Cl) (s, 2 OCH3); 4.90 (m, 2NH2); 6.41 (d, br, 2 CH); 6.53 (s, 4 Ar-H) 163430 s, br (# -NH); 3330 w, 3160 w (CH); 1.97 (s, br, 2 CH3); 2.67 (s, br, 2 CH3); 1610 s, 1590 s, (# -NH); 330 m (Pt-Cl) 4.75 - 4.9 (m, br, 2nd NH2); 6.35 (d, br, 2 CH); 6.41 (s, 4 Ar-H); 9.43 (s, 2 OH) 17 3310 m, 3270 w, 3250 w, 3180 w, br, 3105 m (# -NH); 3.86 (s, 2OCH3); 5.35 (m, 2NH2); 6.75 3008 w, 2975 w, 2940 w (CH); 2835 w (OCH3); 1602 s, (d, br, 2 CH); 7.01 (s, 2 Ar-H); 7.04 (s, 2 Ar-H) 1555 s (# -NH), 317 w (Pt-Cl) 18 3370 s, br (# -NH); 3295 m, 3245 m, 3160 m, br, 5.30 (m, 2NH2); 6.73 (d, br, 2 CH); 6.82 (s, 3085 w, 3060 w (# -NH); 1607 s, 1560 s (# -NH); 2 Ar-H); 6.85 (s, 2 Ar-H); 10.86 (s, 2 OH) 327 sh, 317 w (Pt-Cl) 19 3290s, 3190s, 3100, br (# -NH); 2955 w, 3.86 (s, 2 OCH3); 4.99 (m, 2NH); 5.58 (m, 2930 w (CH); 2830 (OCH3); 1600 s, 1552 s (# -NH); 2 NH); 6.90 (d, br 2 CH); 6.96 (d, J = 2 Hz 335 m, 322 m (Pt-Cl) 2 Ar-H); 7.19 (d, J = 2 Hz, 2 Ar-H) continuation Table 2 Compound IR 1 H-NMR according to Example 20 3240 s, br (# -NH); 3300 s (# -NH); 2880 w (CH); 4.92 (m, 2NH); 5.50 (m, 2 NH); 6.88 1610 s, 1572 s (# -NH); 335 sh, 328 w (Pt-Cl) (d, br, 2 CH); 6.78 (d, J = 2 Hz, 2 Ar-H); 6.98 (d, J = 2 Hz, 2 Ar-H); 10.57 (s, 2 OH) 21 3270 s, 3230 w, 3190 w (# -NH); 2960 w, 2940 w 3.86 (s, 1 OCH 3); 5.25-5.45 (m, br, 2NH2); (CH); 2840 w (OCH3); 1615 s, 1585 m, 6.75 (br, 2 CH); 6.82 (s, 1 Ar-H); 6.85 (# -NH); 325 w (Pt-Cl) (s, 1 Ar-H); 7.01 (s, 1 Ar-H); 7.04 (s, 1 Ar-H), 10.89 (s, 1 OH) 22 3290 m, 3160 m, 3090 w (# -NH); 2960 w (CH); 2.92 (s, 2 CH3); 3.88 (s, 2 OCH3); 5.04 1600 s, 1555 s (# -NH); 345 m, br (Pt-Cl) (t, J = 2 Hz, 1 NH); 5.06 (t, J = 2 Hz, 1 NH); 6.05 (m, br, 2 CH); 7.06 (d, J1,3 = 3 Hz, 2 Ar-H); 7.13 (d, J1.3 = 3 Hz, 2 Ar-H) 23 3280 m, 3200 m, 3080 w (# -NH); 2990 w, 2940 m 2.74 (s, 2 CH3); 5.43 (t, J = 3 Hz, 1 NH); (CH); 1600 s, 1560 s (# -NH); 340 m, 335 sh (Pt-Cl) 5.45 (t, J = 3 Hz, 1 NH); 5.94 (m, br 2 CH); 7.04 (d, J1,3 = 3 Hz, 2 Ar-H); 7.23 (d, J1.3 = 3 Hz, 2 Ar-H) 24,330 s, br (# -NH); 3230 m, 3190 m (# -NH); 2.75 (s, 2 CH3); 5.36 (t, J = 3 Hz, 1 NH); 2940 w (CH); 1610 s, 1570 s (# -NH); 340 m, 5.39 (t, J = 3 Hz, 1 NH); 5.87 (d, br, 2 CH); 330 m (Pt-Cl) 6.82 (d, J1.3 = 3 Hz, 2Art-H); 7.00 (d, J1.3 = 3 Hz, 2 Ar-H); 10.85 (br, 2 OH) example 25 meso-dichloro / 1,2-bis (2,6-dichloro-phenyl) -ethylenediamine / -platinum (II) production takes place in accordance with the general instructions given in an aqueous medium. The substance is a light yellow powder.

IR spectrum in KBr: 3375 w, 3315 m, 3280 w, 3225 m, 3200 w, 3060 w (# Nh); 2960 w (CH); 1580 m, 1562 m (# NH); 325 sh, 317 w (Pt-Cl) 1 H NMR: & = 5.50 (m. 2 NH2); 6.86 (d, br, 2 CH); 7.30-7.52 (m, 6 Ar-H) example 26 d, l-Dichloro- [1,2-bis- (2,6-dichloro-phenyl) -ethylenediamine] -platinum- (II) The production takes place in accordance with the general instructions given in an aqueous medium.

The substance is a yellow powder.

IR spectrum in KBr: 3300 s, 3195 m, br, 3100 w, 3060 w (# NH); 3000 w (CH); 1580 s, 1562 s (&NH); 330 sh, 322 m (Pt-Cl) 1 H-NMR: = 5.15 (m; 2 NH); 5.72 (m, br, 2NH); 7.00 (d, br, 2 CH); 7.31-7.60 (m, 6 Ar-H) synthesis of Pt complexes according to Examples 27-32: To dissolve 2 mmol of the corresponding 1,2-Diphenylethylenediamine dihydrochloride in approx. 10 ml H2O becomes 830 mg (2 mmol) K2PtCl4, dissolved in 8 ml H2O, was added dropwise.

The solution is brought to pH 5.5-6.5 with NaOH.

The mixture is stirred and neutralized at room temperature with the exclusion of light the solution every 1 - 2 hours. The constancy of the pH value shows this End of reaction. The product is filtered off with suction and washed free of chloride with H2O and dried.

Example 27 (+) - Dichloro- / 1,2-bis (4-fluorophenyl) -ethylenediamine-7-platinum (II) ((+) 4-F) Yellow powder, F. approx. 3800 C (decomposition) IR spectrum in KBr: 3270 s, 3190 s (NH2), 1610 s, 1515 s, 1240 s, 1170 m, 840 m, 320 w 1H-NMR: & = 5.05 (broad, 2H, NH); 5.90 (br, 2H, NH); 6.50 (d, 2H, CH); 7.06 (t, HH = 8.8 Hz, JHF = 8.9 Hz 4H, meta H); 7.74 (q, JHF = 8.8 Hz, HF = 5.4 Hz, 4 H, ortho H).

The starting amine is prepared, for example, as follows: 19.9 mmol 1-Azido-2-amino-1,2-bis (4-fluoro-phenyl) -ethane are dissolved in about 60 ml of absolute ether solved and under Ice cooling to 1.52 g (40 mmol) LiAlH4 in 60 ml added dropwise to absolute ether. After refluxing for 4.5 hours, it is allowed to cool and hydrolyzed at 0-5 "C with moist ether and a little water. From aluminum hydroxide is suctioned off and this extracted several times with methylene chloride.

After removing the solvent, the D, L-1,2-bis (4-fluorophenyl) ethylenediamine remains as oil back.

IR (film / base): 3380 m, 3300 m (NH), 1600 s, 1510 s, 1220 s, 830 s.

The 1-azido-2-amino-1,2-bis (4-fluoro-phenyl) -ethane is made from 4,4'-difluoro-stilbene via the aziridine analogously to the specification given in DE-OS 34 05 611 (pages 17-19) obtain. The carbamate obtained as an intermediate product was used without any further Cleaning processed.

The 2,3-bis (4-fluoro-phenyl) -aziridine was obtained by chromatography Silica gel 60 purified with benzene / methylene chloride as the eluant. Next to the Little trans-aziridine was obtained for cis-aziridine.

IR (film): 3330 m (NH), 1610 s, 1510 s, 1220 s.

Example 28 (+) - Dichloro- / 1,2-bis (4-chloro-phenyl) -ethylenediamine 7-platinum (II) ((+) 4-Cl) yellow powder, F. approx. 3700 C (decomposition) IR spectrum in KBr .: 3210 s, 3190 s, 3100 m (NH2), 1600 m, 1560 m, 1495 s, 1415 m, 1090 s, 1015 s, 825 s, 600 s, 520 m, 320 m (Pt-Cl) 1 H-NMR: S = 5.55 (br, 2 H, NH); 6.28 (br, 2H, NH); 6.72 (d, 2H, CH); 7.34 (d, J = 8.5 Hz, 4H, meta H); 7.86 (d, J = 8.5 Hz, 4H; ortho H).

The starting amine is obtained according to method C.

Example 29 meso-dichloro- / 1,2-bis (4-chloro-phenyl) ethylenediamine / platinum (II) (meso 4-Cl) yellow powder, m.p. approx. 3150 C (decomposition) IR spectrum in KBr .: 3240 s, 3180 s, 3100 m, 3020 m (NH2); 1550 m, 1170 s, 1040 s, 812 s, 770 s, 315 m (Pt-Cl) 1 H NMR: 6 = 4.65 (br, 2 H, NH); 5.79 (br, 2H, NH); 6.25 (d, 2H, CH); 7.34 (d, J = 8 Hz, 4 H, meta H); 7.64, 7.68 (d, J = 8 Hz, 4 H, ortho H).

The starting amine is obtained according to method B.

Example 30 (#) - Dichloro- [1,2-bis (3-chloro-phenyl) -ethylenediamine] -platinum (II) ((+) 3-Cl) Yellow powder IR spectrum in KBr .: 3260 s, 3200 s (NH2), 1600 m, 1575 s, 1480 m, 1440 m, 790 s, 720 m, 690 s, 440 w, 320 m (Pt-Cl) 1H-NMR: = 5.39 (broad, 2 H, NH); 6.14 (broad, 2H, NH); 6.62 (d, 2H, CH); 7.29 - 7.88 (m, 8H, aromat H).

The starting amine can, starting from 3,3'-dichlorostilbene, via the corresponding cis-1,2-bis (3-chlorophenyl) aziridine and threo-1-azido-2-amino-1,2-bis (3-chlorophenyl) ethane can be obtained analogously to the procedure described in DE-OS 34 05 611, pages 17-19 is specified.

Example 31 meso-dichloro- / 1,2-bis (3-chloro-phenyl) -ethylenediamine / -platinum (II) (meso 3-Cl) reaction time 3 days yellow powder IR spectrum in KBr .: 3240 s, 3180 s, 3100 m, 3020 m (NH2), 1550 m, 1170 s, 1040 s, 812 s, 770 s, 315 m (Pt-CI) 1H-NMR: = 4.64 (broad, 2H, NH); 5.91 (broad, 2H, NH); 6.26 (d, 2H, CH); 7.27 - 7.78 (m, 8H, aromatic H).

The starting amine is known.

Example 32 meso-dichloro- / 1,2-bis (3-fluoro-phenyl) -ethylenediamine / -platinum (II) (meso 3-F) synthesis with the addition of tertiary butanol.

Yellow powder IR spectrum in KBr .: 3200 s, 3120 s (NH2), 1630 m, 1600 s, 1500 m, 1460 m, 780 s, 700 s, 520 w, 320 m (Pt-Cl) 1 H-NMR: # = 4.73 (broad, 2nd H, NH); 5.87 (broad, 2H, NH); 6.30 (d, 2H, CH); 7.08-7.16 (m, 2H, aromatics H); 7.28 - 7.39 (m, 4H, aromatic H); 7.58-7.62 (d, 2H, aromatic H).

The starting amine is obtained according to method B.

Example 33 meso-dichloro- [1,2-bis (4-fluoro-phenyl) -ethylenediamine] -platinum (II) (meso 4-F) 248 mg (1 mmol) of meso-1,2-bis (4-fluoro-phenyl) -ethylenediamine are in 40 ml of 50% tertiary butanol dissolved with heating. 415 is added dropwise to the solution mg K2PtCl4, dissolved in 10 ml H2O. At 50-60 ° C is 5 hours with exclusion of light stirred, then the product filtered off with suction, washed with tertiary butanol and H2O and dried.

Yellow powder, m.p. approx. 3050 C (decomposition) IR spectrum in KBr .: 3250 s, 3190 s, 3120 s (NH2), 1610 s, 1560 s, 1515 s, 1230 s, 805 s, 325 m.

H-NMR: 6 = 4.53 (br, 2H, NH); 5.69 (br, 2H, NH); 6.20 (d, 2H, CH); 7.10 (t, JHH = 8.8 Hz, JHF = 8.9, 4H, meta H); 7.64 (q, JHH = 8.8 Hz, HF = 5.4 Hz, 4 H, ortho H).

The starting diamine is known.

Examples 34-40 Replacement of the anion X with other anions Example 34 Diaquo-meso-1,2-bis (2,6-dichloro-4-hydroxyphenyl) ethylenediamine platinum (II) sulfate 194 mg (0.3 mmol) of meso-1,2-bis (2,6-dichloro-4-hydroxyphenyl) -ethylenediamine-dichloro-platinum (II) complex are suspended with 93 mg (0.3 mmol) of silver sulfate in 60 ml of water in an ultrasonic bath and stirred for 3 days at 50 ° C with exclusion of light. The AgCl formed and not converted meso-1,2-bis (2,6-dichloro-4-hydroxyphenyl) ethylenediamine-dichloro-platinum (II) complex are sucked off through a membrane filter. After suction, an aqueous one remains Solution that is concentrated to dryness at the oil pump. The residue is with absolute Methanol digests, whereby the complex goes into solution so we don't react Ag2 SO4 can be separated. The methanolic solution is concentrated as much as possible and the complex precipitated with diisopropyl ether. The precipitate is sucked off, washed with a lot of diisopropyl ether and dried over P 205 at room temperature.

White powder, soluble in water; Yield: 80 mg (38% of theory).

Example 35 Diaquo-meso-1,2-bis (4-fluorophenyl) ethylenediamine platinum (II) sulfate 514 mg (1 mmol) of the corresponding dichloro complex are mixed with 310 mg (1 mmol) Silver sulfate suspended in 60 ml of water in an ultrasonic bath and kept at 500 ° C. for 3 days stirred with exclusion of light. The formed AgCl and unreacted dichloro complex are sucked off through a membrane filter. A yellow solution remains that the oil pump is concentrated to dryness.

The residue is digested with absolute methanol, whereby the complex goes into solution and so the unreacted Ag2 SO4 can be filtered off. the methanolic solution is concentrated and the complex is precipitated with diisopropyl ether. The precipitate is filtered off with suction, washed with a lot of diisopropyl ether and dried over P 205 dried at room temperature.

White dust; Yield: 307 mg (52% of theory).

The following sulfates were analogous to the Diaquo-meso- 1,2-bis- (4-fluorophenyl) -ethylenediamine-platinum (II) -sulfate produced: Example 36 Diaquo-d, t -1,2-bis (4-fluorophenyl) ethylenediamine platinum (II) sulfate Approach: 514 mg (1 mmol) of the corresponding dichloro complex, 310 mg (1 mmol) Ag2SO4 white Powder; Yield: 160 mg (26% of theory).

Example 37 Diaquo-meso-1,2-bis (3-hydroxyphenyl) ethylenediamine platinum (II) sulfate Approach: 693 mg (1 mmol) of the corresponding Dijodo complex, 310 mg (1 mmol) Ag2SO4 White dust; Yield: 437 mg (77% of theory).

The diiodo starting complex meso-1,2-bis (3-hydroxyphenyl) -ethylenediamine-diiodo-platinum (II) is made, for example, as follows: 4 g of KI and 420 mg (1 mmol) of K2PtCl4 are made dissolved in 10 ml of water and stirred for 20 minutes. This solution becomes a suspension of 244 mg (1 mmol) of meso-1,2-bis (3-hydroxyphenyl) ethylenediamine in a 50% tert. Butanol / water mixture was added dropwise and 18 hours at 500 C, with exclusion of light, touched. The complex is filtered off with suction, washed with 0.1 N HCl and warm water and dried over P205.

Yellow powder; Yield: 634.5 mg (92% of theory).

Example 38 Diaquo-d, 4g-1,2-bis (3-hydroxyphenyl) ethylenediamine platinum (II) sulfate Approach: 693 (1 mmol) of the corresponding Dijodo complex, 310 (1 mmol) Ag2SO4 light yellow Powder; Yield: 513 mg (90% of theory).

The Dijodo starting complex is obtained analogously to Example 37.

Example 39 Diaquo-meso-1,2-bis (2-fluoro-4-hydroxyphenyl) ethylenediamine platinum (II) sulfate Approach: 526 mg (1 mmol) of the corresponding dichloro complex 310 mg (1 mmol) Ag2SO4 White dust; Yield: 600 mg (98% of theory).

Example 40 Diaquo-meso-1,2-bis (2,6-dichloro-4-hydroxyphenyl) ethylenediamine platinum (II) sulfate Approach: 194 mg (0.3 mmol) of the corresponding dichloro complex 93 mg (0.3 mmol) Ag2SO4 white powder; Yield: 80 mg (38% of theory).

Examples of pharmaceutical preparations Example (lyophilisate): 10 g of D-mannitol and 3 g of Diaquo-meso / 1,2-bis (2,6-dichloro-4-hydroxyphenyl) ethylenediamine / platinum (II) sulfate dissolved and the volume made up to 1 liter with water for injections.

This solution is passed through a membrane filter under aseptic conditions Sterile-filtered from 0.22 µm pore size and 10 ml in 15 ml injection bottles of hydrolytic class I. The bottles come with a freeze-drying stopper provided and lyophilized in a suitable facility. Fumigated after drying one with sterile, dried nitrogen and closes the bottles in the plant. The stoppers are secured with a crimp cap.

For intravenous use, the lyophilizate becomes more physiological in 10 ml Saline solution reconstituted.

1 ml of solution contains 3 mg of active ingredient.

Example (tablets): 200 g d, -dichloro- / T, 2-bis- (2,6-dichloro-4-hydroxyphenyl) -ethylenediamine / -platinum (II) (according to Example 20), 500 g of lactose, 360 g of microcrystalline cellulose, 130 g corn starch and 10 g magnesium stearate are passed through a sieve with a mesh size of 0.8 mm given and homogenized. This mass becomes tablets in a known manner of 120 mg pressed.

1 tablet contains 20 mg of active ingredient.

Example (coated tablets) For the production of film-coated tablets are tablets according to the previous example in a known manner Provide a gastric or small intestinal-soluble coating with the help of a spray device, that from a suitable polymeric film former such as, for example, esters of acrylates or methacrylates and suitable auxiliaries such as wetting agents, plasticizers, dyes, Lubricants etc. may exist. The tablets can also be taken in the usual way Dragees are processed.

Claims (1)

Tumor-inhibiting (1,2-diphenyl-ethylenediamine) -platinum (II) complexes Patent claims: 1. (1,2-Diphenyl-ethylenediamine) -platinum (II) complexes of the general formula where R7 is hydrogen or C1-C6-alkyl and R2 is either a halogen atom and the radicals R1, R3, R4, R5 and R6 are identical or different and are hydrogen, halogen, trihalomethyl, C1-C6-alkyl, hydroxy, C1-C6 -Alkoxy or a C2-C6-alkanoyloxy group optionally substituted by halogen or C1-C4-alkanesulfonyloxy or in which R2 is a hydroxy group, a C1-C6-alkoxy group or a C2-C6-alkanoyloxy group optionally substituted by halogen or C1-C4-alkanesulfonyloxy is in the 4-position and in this case the radicals R1 and R3, which are identical or different, are in the 2- and 6-position of the phenyl radical and optionally halogen, trihalomethyl, C1-C6-alkyl, hydroxy, C1-C6-alkoxy or one C2-C6-alkanoyloxy group substituted by halogen or C1-C4-alkanesulfonyloxy, where R1 can also be hydrogen if R3 is halogen, trihalomethyl or C1-C6-alkyl, and the radicals R4, R5 and R6 are identical or different and are hydrogen , Halogen, T rihalomethyl, C1-C6-alkyl, hydroxy, C1-C6-alkoxy or a C2-C6-alkanoyloxy group optionally substituted by halogen or C1-C4-alkanesulfonyloxy, and X stands for the equivalent of a physiologically acceptable anion. Process for the preparation of (1,2-diphenyl-ethylenediamine) platinum (II) complexes of the general formula where R7 is hydrogen or C1-C6-alkyl and R2 is either a halogen atom and the radicals R1, R3, R4, R5 and R6 are identical or different and are hydrogen, halogen, trihalomethyl, C1-C6-alkyl, hydroxy, C1- C6-alkoxy or a C2-C6-alkanoyloxy group optionally substituted by halogen or C1-C4-alkanesulfonyloxy, or in which R2 is a hydroxy group, a C1-C6-alkoxy group or a C2-C6-alkanoyloxy group optionally substituted by halogen or C1-C4-alkanesulfonyloxy is in the 4-position and in this case the radicals R1 and R3, which are identical or different, are in the 2- and 6-position of the phenyl radical and optionally halogen, trihalomethyl, C1-C6-alkyl, hydroxy, C1-C6-alkoxy or one C2-C6-alkanoyloxy group substituted by halogen or C1-C4-alkanesulfonyloxy, where R1 can also be hydrogen if R3 is halogen, trihalomethyl or C1-C6-alkyl, and the radicals R4, R5 and R6 are identical or different and are hydrogen , Halogen, T rihalomethyl, C1-C6-alkyl, hydroxy, C1-C6-alkoxy or a C2-C6-alkanoyloxy group optionally substituted by halogen or C1-C4-alkanesulfonyloxy, and X stands for the equivalent of a physiologically acceptable anion, characterized in that one a tetrahalo-platinum (II) acid, a tetrahalo-platinum (II) complex salt with two monovalent or one divalent cations or a platinum (II) halide with a compound of the formula or an acid addition salt of the compound II, where the radicals R1, R2, R3, R4, Rg, R6 and R7 have the meanings given, converts a C2-C6- which is optionally substituted by halogen or C1-C4-alkanesulfonyloxy into free phenolic hydroxyl groups present. Introduces alkanoyl group, and optionally exchanging the radical X or the radicals X in a compound of the formula I obtained for other physiologically acceptable anions. 3. Medicaments containing a compound of the general formula I in addition to customary carriers and / or diluents or auxiliaries. 4. A method for the production of a medicament, characterized in that that a compound of general formula I with common pharmaceutical Carriers or diluents or other auxiliaries processed pharmaceutical preparations or in a therapeutic applicable form is brought. 5. Use of compounds of the general formula I for the preparation of medicines.