DE3605191A1 - Antitumour (1-benzylethylenediamine)platinum(II) complexes - Google Patents

Abstract

Antitumour (1-benzylethylenediamine)platinum(II) complexes of the general formula <IMAGE> in which the radicals R1, R2, R3 and R4 are identical or different and denote hydrogen, a C1-C6-alkyl group, a benzyl group or a phenylethyl group, and B is a thienyl radical, an indolyl radical, an imidazolyl radical or a phenyl radical substituted by the radicals R5, R6 and R7 and the radicals R5, R6 and R7 are identical or different and denote hydrogen, halogen, trihalomethyl, C1-C6-alkyl, hydroxyl, C1-C6-alkoxy, phenoxy, benzyloxy, C1-C6-alkanoyloxy, benzoyloxy, C1-C6-alkanesulphonyloxy, carboxyl, C1-C6-carbalkoxy, cyano, aminocarbonyl, aminocarbonyl which contains 1 or 2 C1-C6-alkyl radicals, C1-C6-alkylcarbonyl, nitro, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, (C1-C6-alkyl)3N<+>, C1-C6-alkanoylamino, C1-C6-alkyl-C1-C6-alkanoylamino, C1-C6-alkanesulphonylamino, C1-C6-alkyl-C1-C6-alkanesulphonylamino, aminosulphonyl, aminosulphonyl which contains 1 or 2 C1-C6-alkyl radicals, C1-C6-alkoxysulphonyl (-SO2-O-C1-C6-alkyl), sulpho (-SO3H) or C1-C6-alkanesulphonyl, and two of these radicals can also be the methylenedioxy group and X stands for the equivalent of a physiologically tolerable anion, and also, if appropriate, their salts with physiologically tolerable cations or anions and their preparation.

Description

Anti-tumor (1-benzyl-ethylenediamine) platinum (II) complexes

It is known that compounds represented by the following formula R1 = H, alkyl R2 = H, alkyl have an anti-tumor effect (Journal of Inorganic Biochemistry 11, 1979, pages 139-149; Biochimie 60, 1978, pages 835-850). Furthermore, antitumor compounds are known from German Offenlegungsschrift 34 05 611. These are (1,2-diphenyl-ethylenediamine) platinum (11) 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, mouse leukemia L 1210, cisplatin-sensitive reticular mouse cell sarcoma M 5076, hormone-independent human breast cancer cell line MDA-MB 231.

The compounds according to the invention reduce or inhibit both the growth of existing tumor cells and the formation of new tumor cells; they also destroy existing tumor cells or lead to their regression and prevent or weaken the formation of metastases.

Compared to the known compounds, those are according to the invention Compounds with a comparable or superior effect are considerably less toxic.

The following information relates to preferred embodiments of the invention: The C1-C6-alkyl groups, the occurring alkoxy groups and the C1-C6-alkanoyloxy groups can be straight or branched and preferably consist of 1 to 4 carbon atoms. The same also applies if C1-C6-alkyl groups are part of other functional groups are (for example in the case of C1-C6-alkanesulfonyloxy or C1-C6-alkylaminocarbonyl etc.) The acetoxy group is particularly suitable as the alkanoyloxy group. As halogen substituents bromine, chlorine and / or fluorine are particularly suitable. For the trihalomethyl group it is preferably trifluoromethyl.

The thiophene radical is preferably the thienyl (2) radical, in the case of the indole radical around the indolyl (3) radical and in the case of the imidazole radical around the imidazolyl (4) radical.

If one or more of the radicals R1, R2, R3 or R4 is an alkyl group mean, it is preferably a methyl group, an ethyl group or an isopropyl group. In the case of the phenylethyl group, it is preferred around the l-phenylethyl group.

The C1-C6-alkyl-C1-C6-alkanoylamino group is a Amino group which contains the C1-C6-alkyl radical and the C1-C6-alkanoyl radical on the nitrogen. The same applies in the case of the C1-C6-alkyl-C1-C6-alkanesulfonylamino group.

Such compounds of the formula have a particularly favorable effect I, in which B is a monochlorophenyl radical, for example a 4-chloro-phenyl radical one or more of the radicals R5, R6 and R7 are a carboxy group or a sulfo group contain, the compounds of formula I can also be in the form of the speaking Salts with physiologically compatible cations are present. As such cations come For example in question: cations of the alkali metals (Na, K), the alkaline earth metals (Ca, Mg), cations of aliphatic mono-, di-, tri- or quaternary C1-C6-alkylamines, which can also be substituted by phenyl, NH4 If one or more of the RSg 6 and R7 radicals represent an ammonium group or the group (C1-C6-alkyl) 3N +, the compounds of formula 1 are in the form of the salts with physiologically compatible Anions before. These are, for example, those anions that also for group X come in crage.

The radicals X represent the known and customary physiologically tolerable ones and pharmaceutically acceptable anions of monovalent or polyvalent acids. In particular For example, the anions of the following acids come into question: HBr, HCl, Ho, HF, HNO3, -HSSO4 (SO4); C4 (HPO4--); 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, which optionally are substituted one or two times by methyl groups (toluenesulfonic acid, in particular o- or p-toluenesulfonic acid); aliphatic C1-C4-monocarboxylic acids, which optionally are substituted one, two or three times by halogen atoms (in particular cl, F) (for example am, iron acid, acetic acid, propionic acid, chloroacetic acid, dichloroacetic acid, Trifluoroacetic acid, trichloroacetic acid); aliphatic £ 2-C11 dicarboxylic acids, the optionally a double bond contain (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 up to 6, in particular 2 to 3 carbon atoms, preferably i-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 i-amino acids (for example L-aspartic acid); 1,1-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, Ot -D-glucose- 1-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 (where the phosphoric acid residue on one of the terminal or on the middle Glycerol oxygen atom is bonded) such as i-D, L-glycerol-phosphoric acid, B-glycerol-phosphoric acid; N-phosphono-acetyl-aspartic acid. As acids for the anions X women come into question: Aromatic carboxylic acids that have one or more carboxy groups contain and also c1-c4-alkoxy groups and / or hydroxyl groups if necessary there are several carboxy groups on the aromatic radical <for example benzene ring) are located, at least 2 carboxy groups are preferably adjacent to one another.

For example, if the benzene ring contains 4 or 5 carboxy groups, Complexes can arise which contain 2 moles of platinum per 1 mole of the benzene carboxylic acid anion Component included. 2 adjacent carboxy groups neutralize 1 mole each the platinum component, so that, for example, in the case of benzene pentacarboxylic acid 1- and 2-position and the 4- and 5-position carboxy groups each have 1 mol of the The platinum component saturates (together 2 moles), while the free 3-part Carboxy group free or in the salt form with a physiologically compatible cation (for example alkaline cation, especially sodium cation) is present. This is entirely true in general, if the anions X have additional acid functions that do not are needed for the saturation of the platinum.

The same applies to the case of benzene hexacarboxylic acid, with here optionally 1 mole of this acid can saturate 3 moles of the platinum component Examples for 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: where Rt is hydrogen, a phenyl radical, an indolyl- (3) -methyl radical, imidazolyl- (4) -methyl radical, a C1-C1o-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 radical 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 point of attachment of the alkyl radical with the rest of the molecule) a C2-C6 alkanoylamino group, an imidazolyl (4) methyl radical or an indolyl (3) methyl radical contains. 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 L-form), Isoleucine (preferably D- and L-form), Asparagine (preferably D- and L-form) @ysine (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 amislo groups are protected by a customary acylamino protective group blocked, in particular by the acetyl group or the butyloxycarbonyl group.

Formula 1 also includes the possible enantiomers and diastereomers. If the compounds are racemates, these 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 of the structure of the radicals X, the 1-benzyl-ethylenediamine part already has an asymmetrical one Carbon atom and can therefore be in the pemate form or in left-hand respectively clockwise form. Additional forms can be given by different enantiomers or diastereomeric forms of the radicals X arise.

With regard to the platinum atom, these are those according to the invention Compounds of formula 1 always around the cis compounds.

The starting amine II is used, for example, as a racemate, as a pure legal or levorotatory form or used in some other diastereomeric form.

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 or respectively by adding acids, preferably aqueous hydrochloric acid.

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: AllSali ions, in particular Sodium and potassium; however, lithium, rubidium and cesium can also be used are also NH4 + NR4 +, PR4 + or AsR4 +, in which R is a C 1-C6-alkyl radical or is a phenyl radical. Divalent cations can be: alkaline earth ions, in particular Mg² + and Ca 2+ but also Zn2 +. 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, hydroxyl groups and / or can be present Amino groups or C1-C6-alkylamino groups of the radical B through C1-C6-alkanoyl groups or acylated by C1-C6 alkanesulfonyl groups. In hydroxyl groups of the remainder B, the benzoyl group can also be introduced in the same way. This acylation can for example by means of phosgene, C1-C6-alkanoyl halides, benzoyl halides, C1-C6 alkanesulfonyl halides or the anhydrides of the saturated aliphatic C1-C6 monocarboxylic acids at temperatures between -10 and 800 C, in particular 20 - 300 C in the presence of the usual acid-binding substances. In particular, come as acid-binding substances, aliphatic tertiary amines such as diisopropylethylamine into consideration. As an inert solvent or suspension medium for acylation for example: lower aliphatic halogenated hydrocarbons (chloroform), aprotic solvents such as amides, C1-C4-alkylamides and C1-C4-dialkylamides more 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, with the help of a Anion exchanger obtained acylated platinum (II) complex is deposited insoluble and the mixture of acid chloride and tertiary amine (diisopropylethylamine) itself is in the chloroform phase. The corresponding acid halides are preferably used Chlorides, bromides and optionally iodides are possible. As anhydrides come in Question: Benzoic anhydride and the anhydrides of C1-C6 carboxylic acids, for example symmetrical acid anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride.

The exchange of the ligands X for other ligands can take place, for example, by means of silver halide precipitation. For this purpose, for example, a dihalogeno- (1-benzyl-ethylenediamine) platinum (II) compound of the formula I, in which X is halogen (chlorine, bromine or iodine), is used in a solvent or suspension medium at temperatures between 0 and 90 ° C, preferably 10 to 500 C, in particular 30 to 40 ° C, preferably 400 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 C1-, Br- in the form of NaCl, KCl, NaBr, KBr, malonate²-chloroacetate (), oxalate2, 1,1-octylbutanedicarboxylic acid anion2 as well as the Displace the other specified acid residues X, used in the form of the acids or their salts, in particular their alkali metal 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 4 2-respectively Oxaate anion) is in the case of sulfato- or oxalato- (1-benzyl-ethylenediamine) -platinum (II) compounds also by reaction with alkaline earth salts, which give the desired Contain X ligands (for example glyceric acid), if the resulting Complex is water-soluble and thus the separation of the poorly water-soluble alkaline earth metal sulfate or oxalate allowed.

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

The solvents or suspending agents 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.

Preparation of starting substances of the formula II, in which B is an optionally substituted phenyl radical or a heterocyclic radical suitable for B is.

The preparation of these compounds (optically active compounds and Racemates) can, for example, analogously to the known preparation of benzylethylenediamine (D- and L-form, racemate) take place according to the following stereospecific synthesis: esterification of the phenylalanine or des appropriately substituted in the phenyl nucleus substituted in the B-position by a thiophene radical, indole radical or imidazole radical Alanine (D- or L-form or racemate) by refluxing with thionyl chloride in Methanol.

The methyl esters are obtained as hydrochloride (Helv.

Chim. Acta 39, 1421 (1956)). Repeated saturation of the methanolic Solution with ammonia at -5 ° C to 0 ° C leads to the corresponding amides (J. Amer. Chem. Soc. 53: 3183 (1931); j. Biol Chem.

199: 801 (1952); Inorg. Chem. 18, 206 (1979)), the hydrogen chloride the ester hydrochloride remains partially bound to the amide. Under the reaction conditions Part of it also precipitates as ammonium chloride, which is produced by fractional crystallization can be separated. In the third reaction step, the ol-amino acid amides reduced to the diamines.

This is done by adding the solid amide to a suspension of Lithium aluminum hydride in tetrahydrofuran, reflux and final hydrolysis (Helv. Chim. Acta 38, 203G, 1955e Tnorg.

Chem. 18, 206, 1979; Gazz. Chim. Ital. 85, 1354, 1955; Bull. Chem. Soc. Yep 49, 101, 1976) or for AllBH4) 3 in dioxane (prepared in situ from NaBH4 and AlCl3; see J. Am. Chem. Soc. 78, 2582, 1956). The hydrolysis products of lithium aluminum hydride are filtered off and the diamines are removed by stripping off the by means of isolated as viscous oils. They can be removed by distillation under reduced pressure clean or by reaction with concentrated hydrochloric acid or with ethereal Convert hydrochloric acid into the hydrochloride.

This procedure can for example be analogous to that in the dissertation by Manfred Schmidt, 1984, University of Regensburg, pages 119-22 described manner take place.

The substituted phenylalanines used for this synthesis route can be obtained, for example, in the following way: In the first step, one "Azlactone synthesis according to E. Erlenmeyer jun.", The radicals R5, R6 and R7 substituted benzaldehydes with N-acetyl or N-benzoylglycine in the Heat under the action of sodium acetate in acetic anhydride to the unsaturated Azlactones (oxazolones) condensed (Org. React. 3, 198 (1946)).

The second stage, the conversion of the azlactones into the corresponding o6 / N-acylamino-cinnamic acids, takes place in two steps, namely via saponification with dilute sodium hydroxide solution and subsequent precipitation with dilute hydrochloric acid. It is important to use both strongly acidic (J. Amer. Chem. Soc. 64, 885 (1942)) or basic conditions (J. Biol. Chem. 82, 438 (1929)) and long-term heating (J. Biol. Chem.

82, 438 (1929)), since otherwise the primarily arising ot / N-acylamino-cinnamic acids are hydrolyzed to ol-keto acids. Because of the high The stability of the unsaturated azlactones, especially the 2-phenylazlactones, leave However, these conditions cannot be avoided entirely, which may arise reflected in lower yields.

In the third reaction stage, the cinnamic acids are converted to the benzoyl or AcetylAminosa: acids reduced. To do this, the cinnamic acids are in water suspended and mixed with solid sodium amalgam at room temperature (Ber. Dtsch. Chem. Ges. 3633 99)).

The acetyl or benzoyl amino acids can then, according to Decant the resulting solution from the mercury, precipitated with hydrochloric acid will.

The hydrolysis of the N-benzoyl group or the N-acetyl group In the last reaction step, the acids are boiled in 20% hydrochloric acid for several hours achieved. The substituted amino acids then fall after adding ammonia to to a weakly acidic pH range. You can by dissolving in acid and precipitating be recrystallized with ammonia or sodium acetate.

This procedure can for example be analogous to that in the dissertation by Manfred Schmidt, 1984, University of Regensburg, page 111-114 described manner take place.

Another way is the following: In this one reduced to two levels The benzaldehydes substituted by the radicals R5, R6 and R7 are synthesized with Hydantoin (molar ratio 1: 1) and molten, anhydrous sodium acetate 1600 C within 15 hours almost quantitatively to the corresponding benzalhydantoins implemented. These stable, mostly yellowish solids are produced by reduction and simultaneous ring splitting with ammonium sulfide at 1000 C in a stirred autoclave converted directly into the i-amino acids within 60 hours.

This procedure can for example be analogous to that in the dissertation by Manfred Schmidt, 1984, University of Regensburg, page 116-119 described way take place.

The starting aldehydes used here can, for example, from the benzene derivatives substituted by the radicals R5, R6 and R7 by the following, known implementation can be obtained: By treating with paraformaldehyde in concentrated Hydrochloric acid is introduced a chloromethyl group, then the chloromethyl group hydrolyzed to the hydroxymethyl group by means of sodium hydroxide solution (if mixtures from isomeric hydroxymethyl compounds, these can be chromatographed be separated, for example with CH2Cl2 / ether 1: 1), then the Hydroxymethyl group by means of freshly precipitated active manganese dioxide to the aldehyde group oxidized.

This procedure can for example be analogous to that in the dissertation by Manfred Schmidt, 1984, University of Regensburg, page 115-116-described manner take place.

Benzylethylenediamines, which contain free hydroxyl groups in the phenyl nucleus, are expedient from the corresponding Benzylethylendiaminen, in which one or more of the radicals R5, R6 and R7 are methoxy groups (those on the previously indicated Way can be prepared) by ether cleavage with boron tribromide, for example obtained in methylene chloride suspension at -60 ° C (E. von Angerer, habilitation thesis, University of Regensburg 1983). The dihydrobromides thus obtained are expedient of the hydroxy compounds after the amines have been released in methanol or ethanol with ethereal hydrochloric acid or in ether with hydrogen chloride gas into the corresponding Dihydrochloride of the diamines II converted, in which B the radicals R5, R6 and R7 is substituted phenyl and in this case at least one of the radicals R5, R6, R7 represents a hydroxyl group.

The diamines II, in which R1 or R1 and R2 are C1-C6-alkyl groups, benzyl groups or phenylethyl groups are formed from the corresponding CC amino acid amides obtained, when they are prepared, instead of ammonia, a C1-C6-alkylamine, a C1-C 6-dialkylamine, benzylamine or phenylethylamine is used. Here it is where appropriate advantageous, the 05-amino group of the α-amino acid used with a customary Protecting group (for example the benzyloxycarbonyl radical) to protect.

The reaction of the protected i-amino acid thus obtained with the amine HNR1R2 is expediently carried out in a known manner in the presence of N-hydroxysuccinimide and dicyclohexylcarbodiimide.

The d-amino protective group is then cleaved off acidolytically in a known manner (for example with saturated hydrogen bromide solution in glacial acetic acid) before the reduction with LiAlH4. If, on the other hand, the benzyloxycarbonyl radical (as a protective group for the α-amino group) is not split off beforehand, but the protected amide is reduced directly with LiAlH4, corresponding amines of the formula II are obtained, in which the radical R3 is a methyl group (R4 = H, R1 , R2 = H, C1-C6-alkyl, benzyl or phenylethyl). Amines of the formula II in which R3 and / or R4 are C1-C6-alkyl groups (R1 and R2 have the meanings given for them) can also be prepared, for example, in a known manner by mono- and dialkylation of the corresponding acid amides of the formula and subsequent reduction with LiAlH4. To prepare diamines II, in which R3 or R3 and R4 or R1 and R3 are methyl groups, the corresponding amino acid amides or the corresponding diamines are, for example, with methyl chloroformate (Bull. Chem. Soc. Jpn.

53, 2275 (1980)) or by reductive alkylation with formaldehyde in the presence of formic acid (Org. Synth.

Coll. Vol. III, 723) mono- or dimethylated, their reduction with lithium aluminum hydride in the usual way (for example after the dissertation by Manfred Schmidt, University of Regensburg, 1984, page 121) the N-substituted Diamine II yields. During this reaction, the methyl formate residue is also formed converted into a methyl group. To introduce four methyl groups in the places R1, R2, R3 and R4 become the diamines II with R1, R2, R3, R4 = H with formaldehyde / Formic acid reductively alkylated (Org. Synth. Coll. Vol. III, 723).

Diamines II in which R1 and R3 are isopropyl groups are for example synthesized by transferring them to the ship's bases in a known manner with acetone and reduced this with lithium aluminum hydride.

An isopropyl group at the position R3 can also be introduced, by condensing the amino group of the ol-amino acids with acetone and these derivatives in the manner described with sodium borohydride into the diamines II (see dissertation by Manfred Schmidt, 1984, University of Regensburg, page 119-122).

The imine group is reduced to the N-isopropyl group.

Similarly, there are benzyl or phenylethyl groups at the point R3 introduced by changing the amino groups of the O (-amino acid derivatives with benzaldehyde or acetophenone condensed and then reduced with LiAlH4.

The preparation of diamines of the formula II in which B is one of the specified represents heterocyclic radicals, can, for example, from the corresponding heterocyclic aldehydes (for example thienyl (2) aldehyde) or the corresponding heterocyclic amino acids (i.e. derivatives of alanine, the alanine is substituted in the ß-position by the corresponding heterocyclic radical) according to the methods given above Acylation can in OH groups or amino groups that are located on the phenyl radical of the diamines II, C1-C6-alkanoyloxy groups are introduced. (phenolic hydroxyl groups can can also be converted into benzoyloxy groups) Acylating reagents are acid halides of aliphatic C1-C6 carboxylic acids, mainly acid chlorides and benzoyl chloride for the C6H5COO substituent. Also the corresponding acid anhydrides, for example Acetic anhydride for the formation of the CH3COO substituent can be used. The C1-C6-alkanesulfonyl substituents are introduced accordingly, the latter for the Example with the help of the corresponding sulfonic acid chlorides. In these acylations the two aliphatic amino functions are expediently through imine formation, for example with benzaldehyde, protected. After the acylation, the imine group can cleaved back into the amino group, for example by hydrolysis with dilute Hcl will.

To represent compounds which have a carboxyl function in the B radical or have a carbonyl function, is derived from the corresponding methylenoxy-alkyl compounds went out. The ether linkage in the CH2OCH3 substituent remains throughout Synthesis route unchanged.

At the stage of diamine II, the ether cleavage becomes a CH2OH compound, carried out as described. With strong oxidizing agents, for example with CrO3, the CH2OH group can be converted into the carboxyl group.

The carboxyl group can be converted into carboxylate salts by neutralization with bases physiologically compatible cations are converted, for example with alkali hydroxides, in particular NaOH, KOH or alkaline earth metal hydroxides, in particular Mg (OH) 2, Ca (OH) 2. Instead of the alkali and alkaline earth hydroxides, other alkaline-reacting hydroxides can also be used Substances, for example the carbonates, can be used.

The ammonium ion NH4 and substituted ammonium ions NR4 (R = hydrogen, C1-C6-alkyl, phenyl or benzyl) can be introduced either by reacting the carboxyl compounds with the corresponding amines or by ion exchange with ion exudation in the NR4 + form.

The carboxyl group can be esterified with the aid of C1-C6 alcohols and by reaction with ammonia or amines NR3 (R = hydrogen, C1-C6-alkyl) convert into the corresponding acid amides. By the action of dehydrating Agents, for example P2O5, turn the carbonylamino group into the cyano group.

With the gentle oxidation of those obtained as described above Type II compounds with CH2OH groups, for example according to Oppenauer with acetone / aluminum isopropoxide, formyl derivatives are formed. If one uses the ether substituent in the representation CHR-O-CH3 (R = C1-C6-alkyl), the corresponding compounds can be passed through Ether cleavage and oxidation of the resulting alcoholic group into the C1-C6-carbonyl-substituted Convert connections.

Amino substituents NR2 (R = hydrogen, C1-C6-alkyl) are introduced, by starting the synthesis of diamines II with the appropriate amino substituents begins, but the substituents, provided they still contain NH bonds, by benzoylation, for example with benzoyl chloride, protects. The benzoyl groups on the amino substituent are reduced to benzyl groups during the LiAlH4 reduction. these can but hydrogenolytically, for example under the action of hydrogen with the aid of the platinum on carbon catalyst.

The NH groups of the amino substituents in NR groups (R = C1-C6-alkyl) are converted. Through exhaustive alkylation, for example with dimethyl sulfate, or by acidification with strong acids such as hydrochloric acid or sulfuric acid, all amino substituents NR2 can be converted into the corresponding Convert ammonium substituents NR3, in which R is hydrogen, C1-C6-alkyl can. Amino groups NH2 and NHR (R = C1-C6-alkyl) that still have one or two H atoms can contain, by acylation, as described for the OH compounds in converted the monoacylated substituents NHCOR 'and NRCOR' (R '= C1-C6-alkyl) will.

This happens after the production of the complexes I, in which the coordinated NH2 groups of the ethylenediamine molecule are strong against acylating agents have reduced reactivity. Instead of acylating agents, sulfonylating agents can also be used are used with the formation of C1-C6-alkanesulfonylamino groups.

The oxidation of an amino group on the aromatic ring of the benzyl substituent B can with the help of the methods given in Houben-Weyl, methods of organic Chemistry, nitrogen compounds I, part I, Thieme-Verlag Stuttgart 1971, pages 843-849 take place, for example with peracids such as peroxydisulfuric acid (e.g. ammonium peroxydisulfate), Peroximonosulphuric acid, peracetic acid, peroxitrifluoroacetic acid, peroximaleic acid. The reaction can take place in, for example, sulfuric acid, glacial acetic acid or halogenated hydrocarbons (CH2Cl2) at temperatures between 10-1500 C, preferably 10-800 C, in particular 10 - 200 C can be carried out.

The sulfo group survives in the form of the SO - anion that of the diamines II and the platinum complexes I leading reaction steps. It can be acidified with strong Acids can be converted into the SO3H form. adding Bases or substances with an alkaline reaction result in the corresponding sulfonates physiologically compatible cations (analogous to the carboxylates). Esterification of Sulpho group with C1-C6 alcohols or amidation with ammonia, primary amines RNH2 and secondary amines R2NH (R = C1 -C6-alkyl) leads to the diamine II stage to sulfonic acid esters and sulfonic acid amides with the substituents S03R, SO2NH2, SO2NHR, SO2NR2.

The C1 -C6 alkanesulfonyl substituents in the benzaldehyde at the start of the reaction are present in the reactions with the formation of the diamines II and the platinum complexes I not attacked.

For further explanation, reference is made to the preparation of some starting compounds of formula II following Examples 17-25 and referring to the diploma thesis von Ulrich Holzinger "Synthesis and investigation of N-alkyl substituted tumor-inhibiting 1,2-Diamino-3-phenylpropane-dichloroplatinum (II) complexes ", Department of Chemistry-Pharmacy of the University of Regensburg, 1985.

The production of other starting materials can be carried out in an analogous manner.

The starting compound II, in which B is the 4-chloro-phenyl radical and the R1, R2, R3 and R4 radicals are hydrogen can be prepared, for example, as follows (the production of other corresponding starting materials can be carried out in the same way): 4-Chlorophenylalanine methyl ester hydrochloride: 0.14 mol (10 ml, 16.5 g) thionyl chloride are added dropwise to 100 ml of methanol at -5 ° C. After adding 0.11 mol (22 g) of 4-chlorophenylalanine is refluxed for 15 hours. After the solvent has been removed, the white residue dried in a high vacuum.

The implementation is quantitative. The ester formation can be determined by IR spectroscopy can be followed by the appearance of a band at around 1750 cm 1. The product comes without further purification used in the next stage.

4-chlorophenylalanine amide: 0.1 mole (25 g) 4-chlorophenylalanine methyl ester hydrochloride are dissolved in 250 ml of methanol. Then ammonia is added several times at 0 ° C. each time to saturation initiated. The reaction is ended after 4 days.

The solvent is drawn off and the white residue is dried. The product is used in this form in the next stage.

1,2-diamino-3- (4-chlorophenyl) propane: 0.1 mole (20 g) of 4-chlorophenylalanine amide or hydrochloride are mixed well in small portions Added suspension of 0.3 mol of LiAlH4 in 250 ml of dry tetrahydrofuran. The mixture is stirred for 24 hours under reflux and then dropwise with ice-cooling hydrolyzed with 1.2 moles of H20.

After stirring for a further hour at room temperature, the The hydrolysis product obtained as a sludge-like solid is filtered off. This residue is extracted with 125 ml of tetrahydrofuran for 24 hours. Filtrate and extract are united.

1,2-diamino-3- (4-chlorophenyl) propane dihydrochloride (starting material II): The representation can be done according to two different methods: a) The combined tetrahydrofuran solutions (filtrate and extract) are up to half concentrated and then added dropwise with concentrated HCl while cooling with ice offset. The precipitated dihydrochloride is filtered off and dried.

b) The combined tetrahydrofuran solutions are concentrated and the oily residue dissolved in 5-10 ml of absolute ethanol. Thereupon is under ice cooling and vigorous stirring with 20 ml of ethereal hydrochloric acid added dropwise. The dihydrochloride After the addition of 20 ml of ether, it separates out at -400 ° C. as a fine white solid from (m.p. 249 - 2520 C, decomposition from 240 ° C).

The compounds of the invention are useful for the manufacture of pharmaceuticals Compositions suitable. The pharmaceutical compositions respectively Medicines can be one or more of the compounds according to the invention or else Contain mixtures thereof with other pharmaceutically active substances.

For the production of the pharmaceutical preparations, the usual pharmaceutical carriers and excipients are used. The medicines can for example enteral, parenteral (for example intravenous, intramuscular, subcutaneous) or used orally. For example, administration in the form of tablets, Capsules, pills, coated tablets or suppositories can be made. For example, liquids are used in question: Oily or aqueous solutions or suspensions (for example in sesame seeds or olive oil), emulsions, injectable aqueous and oily solutions or suspensions. Furthermore, for example, dry ampoules, which as an active ingredient the invention Compound I contain, are prepared, the contents of such before use Dry ampoules, for example in physiological saline solution or mixtures physiological saline solution and, for example, dimethyl sulfoxide is dissolved.

The compounds according to the invention are shown, for example, on M 5076 Reticular cell sarcoma (mouse), on the P 388 leukemia (mouse), on the L 5222 leukemia (Rat) and good anti-tumor activity on the MDA-MB 231 human breast cancer cell line. For example, the compound according to Example 4 is used in reticular cell sarcoma (Mouse) when administered subcutaneously at a dose of 30.0 mg / kg body weight / mouse a decrease in the initial tumor size is achieved. When testing on the hormone-independent human mammary tumor line MDA-MB 231 (see dissertation by Manfred Schmidt, University of Regensburg 1984, page 78, 168ff) show the compounds according to the invention in vitro, for example, in concentrations between 1 and 5. 1-6 moles / liter, in particular 1.3 - 2.5.10'6 mol / liter a 50% growth inhibition on this cell line. In the same The inhibition of the / H / -thymidine incorporation is on the order of magnitude. In the cell culture experiment with of mouse leukemia L 1210 show the compounds according to the invention, for example a 50% growth inhibition in doses between 0.01-0.2 μg / ml.

The direction of action of the compounds according to the invention is with the known remedy comparable to cisplatin.

However, in the case of the compounds according to the invention, for example the toxic side effects are considerably lower.

The lowest effective dose for reticular cell sarcoma For example, mouse is 5. 3.2 mg / kg intraperitoneally. As a general dose range for the effect (reticular cell sarcoma / mouse), for example: 3.2 - 30.0 mg / kg intraperitoneally or intravenously, in particular 15 mg / kg.

Indications for which the compounds according to the invention in The following can be considered: tumor diseases, especially breast cancer, leukemia, reticular cell sarcoma, also ovarian, prostate and endometrial sarcoma.

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 to 200 mg, preferably 150 mg, b) in the case of parenteral dosage forms (for example intravenous, intramuscular) between 100 to 200 mg / m2 body surface, preferably 150 mg / m2 body surface, c) in drug forms for rectal or vaginal application between 1 to 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 to 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 mg; 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 mg / kg; Miller and Tainter method; Proc. Soc. Exper. Biol. A. Med.

57 (1944) 261) is for example intraperitoneal application at 464 mg / kg.

The medicaments can be used in human medicine and in veterinary medicine alone or in admixture with other pharmacologically active substances.

EXAMPLES General procedure for the preparation of cis-diaminedichloroplatinum (II) complexes of the formula wherein B has the meanings according to claim 1.

Examples 1 to 16 of Table 1.

1 mmol (415 mg) of potassium tetrachloroplatinate (II) is dissolved in 5 ml of water solved. The reaction flask is protected against incidence of light with aluminum foil. Under A solution of 1 mmol of compound II (as di- or monohydrochloride) was added dropwise in 5 ml of water. The solution will be on about 500 ° C., the pH value is adjusted to about 6 with 0.5 N NaOH and by means of a pH meter or pH indicator paper checked and if necessary kept at 6 by the addition of 0.5 N NaOH. After about 5 hours, the precipitate appears filtered off and washed with plenty of H2O and ethanol. The mostly yellow solids are dried at 800 ° C. in a high vacuum. The filtrate, which is often still orange, will still be Stirred for 20 hours, considerable amounts of precipitate still falling out. After again Filtering off, the process is partly repeated one more time. The manufactured Complex compounds are listed in Table 1. The melting points of everyone in the platinum complexes listed in Table 1 are above 2500 C.

Unless otherwise stated in Table 1, it is the complexes and the DL forms (racemates).

The complexes listed in Table 1 have a light yellow color.

Table 1 E k - Grue -CH2-B Characteristic IR oscillation marks in ffi ß g No. No n mo o Pt-Cl I 'Y cu N In ooom E, P (mmm .R ER 3 1 U3 Ln ao olp, 8 Vf ir> I Ln lr! = 1 rr] rn tn cn sr! l'z Ln 3265 vs, 3195 s, 3110 N n o: tq gg XO bo | a - NX t # = Stretching vibration # = deformation vibration s = strong, vs = very strong, m = medium strength, sh = shoulder, br = broad, w = weak Table 1 (continued) 4Z group H2-B icharacteristic iR-Sicinunganden in ooo hE 71 b tD OD am 0 7 uO n In u) % fr oooo fP (t \ o Y: mm E m z 3270 vs, 3195 vs, 3110 4 1565 E 570 325 m, W 300 m, br z Y: VI L 6 -CH2CF3 3265 O 3195 O 3110 o 1565 o 560 300 m, br v1 bn sn rl 3 crl m 7 X 3270 vs, 3200 s, 3120 mnn g X g 6th mo In o Ln mn v7 n X t UU 8 g 2 t V tt aA - W> X Table 1 (continued) 3 E. No. NH SN-H Pt-N Pt-Cl OH 9 2OH 3280 vs, 3220 vs, 3140 m 1575 s 10> 3260 s, 3190 s, 3105 W 1560 m, br 520 w 320 w, sh, 300 w 1 O o Cl S 0 z X o \ OCH3 3280 vs, 3200 vs, 3120 VB, 1570 VB j br 12 Cr, oW X g a "ffi" «OW ? 8 E 080 ff 1E 9 T3 UV aA O v N Table 1 (continued) vvvui 0 a Hm O FhrPI 2-B Characteristic 1R oscillation bands in @ g. . . I mm IU) UI 19th E. 3 O X VB, 3220 VB, 3110 m O -g .U e OX n O Ta Y, O Cr) mo I m I q g - b vs, br, oo O 1585s, br 615 m 325 m ,, 310 br cY NI;?; m m 1 I. CH2 3260 VB, 3190 VB, 3110 1575 B, 1565 sc c k A | æz rs 8 oWs Examples 17 - 25 General preparation procedure: The platinum (II) complexes of the following formula listed in Table 2 are then prepared: The complexes are obtained as light yellow, finely crystalline powders, which are very easily charged electrostatically. For example, they are insoluble in H2O, ether, ethyl acetate and similar agents, while the low solubility in CHCl3, CH2Cl2, acetone, methanol and ethanol increases with the number of alkyl substituents on the nitrogen.

The complexes are readily soluble in dimethylformamide and dimethyl sulfoxide.

The complexes of Examples 17, 20, 21, 23, 24, 25 and 26 are like prepared as follows: 1 mmol (415 mg) potassium tetrachloroplatinate (II) are in 5 ml Dissolved water. A neutralized one is added dropwise at room temperature with stirring Solution (pH 6 - 7) of 1 mmol ligand (diamine or diamine dihydrochloride) in 5 - 10 ml of water was added. The solution is heated to about 500 C and the pH becomes continuously checked.

If necessary, it is adjusted to pH = with 1N HCl or 1N NaOH 6 adjusted.

After 10-30 minutes a light yellow precipitate begins to separate out. After stirring for 4 hours, the solid which has formed up to that point is filtered off, with plenty of water and a little (0.5 ml) of ethanol. The yellow solids are im Dried under high vacuum at 800.degree. The filtrate, which is still orange in color, continues at Stirred at room temperature, with only small amounts of further product often being obtained. The complexes according to Examples 17, 20, 23, 24 and 25 melt above 2500 C. The platinum complex according to Example 21 decomposes at 1900 C; the platinum complex according to example 26 melts at 1750 C.

The complexes of Examples 18, 19, 22, 27 and 28 are as follows prepared: 1 mmol (415 mg) K2PtCl4 are dissolved in 5 ml water and stirred added dropwise to a solution of 1 mmol of ligand diamine in 6 ml of dimethylformamide. Should some ligand precipitate, more dimethylformamide is added (approx. 5-10 ml). To Adding 1 ml of dimethyl sulfoxide changes the color within 10 minutes from orange to yellow. The mixture is concentrated in a high vacuum at room temperature and mixed the oily residue with about 50 ml of water. The yellow complexes fail immediately and become crystalline after prolonged stirring at room temperature (approx. 1 day). The solids are suctioned off, washed with a lot of water and a little ethanol and in a high vacuum dried at 800 C.

The complexes according to Examples 18 and 19 melt above 2500 C. The complex according to example 22 decomposes at 2100 C. The complexes according to example 27 and 28 melt at 125 and 1100 C.

Table 2 At- R3 R4 R1 R2 Characteristic IR vibration bands in cm-1 (KBr) play #NH #CH #NH # C = C #CH # Pt-N # Pt-Cl No. 17 HH CH3 H 3290 m 3070 m 2940 w 1580 m 1610 s 750 s 580 w 310 m 3180 s 3040 m 1500 s 700 s 465 w 3130 vs. 18 CH3 HHH 3280 w 3040 w 2960 w 1580 m 1605 w 745 s 580 w 310 m 3200 m 1500 m 730 s 545 w 3120 vs 695 s 450 w 19 CH3 H CH3 H 3120 vs 3040 w 2950 w 1585 vw 1605 w 745 s 565 w 310 m 2870 vw 1500 m 700 s 450 vw 20 HH CH3 CH3 3210 vs 3020 m 2940 m 1585 m 1605 w 755 s 585 m 310 s 3180 vs 2870 vw 1500 s 705 s 545 m 3120 s 460 m 21 CH3 CH3 HH 3120 vs 3030 m 2940 m 1585 w 1605 m 740 s 580 m 310 s 2860 w 1500 s 700 s 450 m Continuation of table 2 rl: E 8 U) tn Inui rn c 8 / mm mm Tc, m 8 8 mm 3 3 t 8 Yg Pk I onou, mz: In, Esl mcr, aJ Ip oDCV Ln In nrn up r I. Bei- R3 o ur ou) o S sr o ur o game bb bb rr hNN bb --- -------- - - 22 CH3 CH3 fi 3030 w 2940 s V) g, 1605 3 740 VB 580 w CH3 CH3 3000 W 2850 m 00 m oc mo ° oo 3 rP rr rr -C I'C 8th .S vs 1500 m 700 s 465 s tn vi 3 a ZHH 3280 m 3040 w | s 1605 o 750 Q, 3200 vs 44 m 700 r 460 w 1 25 CH <CH3) 2 H CH (CH3) 2 H 3275 m 3040 5 2980 vs 1580 s 1610 w 750 580 m 31 3190 1500 700 460 3130 mge 3> S 3 vs. 26 CH3 H cHCH, H 3150 s 2980 æ 1580 w 1605 w 750 s 585 VW m 3060 m OD w 1,900 740 s 520 w 3 NNN «NN« NN 3E 3 3 m EE I Bm UI 88 "o H 3230 2990 v 1590 wtoo co O .d oo ooo oo oo k mm c 3040 X g XX> g WEP e X uuo õ m Xo no z »@ r NG Nt. N U 0> q4 ne ne nen nn N Pr f ~ m HE l ~% m P: 6 mmmmm NN ~ t 8 8 m Z fm 8 8 en bt | N ff) NNN ts Continuation of table 2 At- R3 R4 R1 R2 Characteristic IR vibration bands in cm-1 (KBr) play #NH #CH #NH # C = C #CH # Pt-N # Pt-C No. 28 CH2C6H5 HHH 3230 s 3040 s 2920 m 1590 w 1610 m 750 s 575 vw 320 # 3190 s 3070 s 1500 m 700 vs 440 m Preparation of starting amines for Examples 17-28 a) (S) -2-Amino-1-N-methylamino-3-phenylpropane While cooling with ice, 10 mmol (1.78 g) (L) -phenylalanine methylamide are stirred in small portions Suspension of 30 mmol (1.14 gd LiAlH4 in approx.

Add 50 ml of dry tetrahydrofuran. The mixture will last 24 hours heated to reflux. In order to hydrolyze excess LiAlH4 one gives after the Cool to 0 ° C., add 120 mmol (2.16 ml) of water dropwise. It is filtered through a suction filter and concentrates the filtrate. The residue is extracted overnight with 150 ml of tetrahydroaurane in a Soxhlet apparatus. Combine the extract with the filtrate and the solvent is distilled off in vacuo. The slightly yellowish one The crude product is distilled in a high vacuum (10-4 Torr) at an air bath temperature of 75 ° C. F. Dihydrochloride 890 C.

The (L) -phenylalanine methylamide used here is obtained as follows: 50 mmol (8.96 g) of (L) -phenylalanine methyl ester are dissolved in 75 ml of absolute methanol dissolved and cooled to -10 ° C in the egg-boiling salt bath. Then the solution with dry Methylamine (boiling point -70 C) saturated and stirred overnight. Cooling down and Initiation is repeated twice. The solvent is distilled off in vacuo, and the oily product obtained is treated with an ethyl acetate - ether mixture (1: 1) recrystallized. A white solid crystallizes on standing at -20 ° C the end. F 570 C.

b) (S) -2-Amino-1-N, N-dimethylamino-3-phenylpropane The representation from 12.5 mmol (3.41 g) (L) -phenylalanine dimethylamide hydrobromide (preparation is given below) and 37.5 mmol (1.42 g) LiAlH4 is carried out analogously to a). Vacuum distillation at 100 ° C / 10-4 Torr (air bath temperature).

The compound obtained is a colorless oil.

N-Benzyloxazarbonyl- (L) -phenylalanine 100 mmol (16.51 g) (L) -phenylalanine are dissolved in 50 ml of 2N NaOH, cooled in an ice bath and added dropwise with 106 mmol (15.04 ml) benzyl chloroformate were added.

The mixture is stirred for 30 minutes at room temperature. If the product already fails, enough water is added until a clear solution is achieved. Man drips Add 4N hydrochloric acid to acidic reaction (pH = 4) and shake three times with ethyl acetate the end. The organic phases are dried over sodium sulfate and removed in vacuo Freed solvent. A colorless, oily product is obtained.

It is dissolved in 200 ml of chloroform by adding 400 ml of petroleum ether precipitated in the cold and sucked off in a large suction filter. Colorless crystals.

Benzyloxycarbonyl- {L) -phenylalanine dimethylamide 20 mmol (5.99 g) N-benzyloxycarbonyl- (L) -phenylalanine and 24 mmol (2.76 g) of N-hydroxysuccinimide are dissolved in 30 ml of chloroform and taken under Ice cooling and stirring with 22 mmol (4.34 g) dicyclohexylcarbodiimide, dissolved in approx. 10 ml of chloroform, added. After stirring for 10 minutes, place in an ice-salt bath cooled to -100 C and 20 mmol (0.90 g) condensed, dry dimethylamine (Boiling point + 7 ° C) added. The mixture is stirred for 24 hours while slowly moving the cooling bath can thaw. The precipitate formed is filtered off and the filtrate one after the other washed with 20 ml each of 2N hydrochloric acid, saturated NaHCO3 solution and water. To obtained by drying over sodium sulfate and stripping off the solvent in vacuo one an oily product. It is at 2400 C air bath temperature in a high vacuum (10 4 Torr) distilled.

Colorless, very viscous oil.

(L) -Phenylalanine dimethylamide - hydrobromide 13 mmol (4.28 g) benzyloxycarbonyl- (L) -phenylalanine dimethylamide 10 ml of ice-cold saturated HBr glacial acetic acid solution (40%) are poured over them and stirred for 60 minutes at room temperature. The reaction mixture is in vacuo concentrated The colorless, oily product is mixed with about 150 ml of ether and 15 Left to stand at -20 ° C for hours. A white crystalline solid forms. It is filtered off with suction, dried and, without further purification, for subsequent reduction used.

c) (S) -2-Amino-1-N-isopropylamino-3-phenyl-propane The representation from 20 mmol (5.74 g) (11) -phenylalanine isopropylamide - hydrobromide (for preparation see below) and 60 mmol (2.28 g) LiAlHd is carried out analogously to a). High vacuum distillation at 1450 c / 10 Torr (air bath temperature). The amine is a colorless oil.

N-Benzyloxycarbonyl- (L) -phenylalanine isopropylamide 20 mmol (5.99 g) N-benzyloxycarbonyl- (L) -phenylalanine and 24 mmol (2.76 g) N-hydroxysuccinimide dissolved in 30 ml of chloroform and, with ice-cooling and stirring, with 22 mmol (4.54 g) Dicyclohexylcarbodiimide, dissolved in approx. 10 ml of chloroform, added. After 10 minutes Stirring at room temperature, 20 mmol (1.71 ml) isopropylamine are added. To The precipitate formed is filtered off for 24 hours and the filtrate one after the other with 20 ml of dilute hydrochloric acid, saturated NaHCO3 solution and water, Der obtained after drying over sodium sulfate and distilling off the solvent waxy residue is recrystallized with ethyl acetate / petroleum ether.

Colorless, crystalline substance.

(L) -phenylalanine-isopropylamide - hydrobromide 20 mmol (6.81 g) N-benzyloxycarbonyl- (L) -phenylalanine isopropylamide 15 ml of ice-cold saturated HBr solution (approx. 40%) are poured over them and 60 Stirred minutes at room temperature. The reaction mixture is concentrated in vacuo. The colorless, oily product is mixed with about 150 ml of ether and 15 hours at -200 C left to stand. A very hygroscopic, white, crystalline one forms Solid. It is suctioned off through a suction filter, dried and without further cleaning used for the subsequent reduction (colorless crystals).

d) (5) -2- N -methylamino-1- (N- (5) -i-phenylethylamino) -3-phenylpropane The preparation from 18.2 mmol (7.30 g) N-benzyloxycarbonyl- (L) -phenylalanine- (S) -1-phenylethylamide (For preparation see below) and 164 mmol (6.22 g) LiAlH4 is carried out analogously to a). It is hydrolyzed with 656 mmol (11.80 ml) of water while cooling with ice. In a high vacuum The benzyl alcohol formed is first distilled off (approx. 1000 C). The diamine is boiling at approx.

1500 C / 10 4 Torr (air bath temperature). Colorless oil.

N-Benzyloxycarbonyl- (L) -phenylalanine- (S) -1-phenylethyl amide The representation from 20 mmol (5.99 g) N-benzyloxycarbonyl- (L) -phenylalanine, 24 mmol (2.76 g) N-hydroxysuccinimide, 22 mmol (4.54 g) dicyclohexylcarbodiimide and 20 mmol (2.53 g) (S) -1-phenylethylamine takes place analogously to c). Colorless solid, m.p. 990 C.

e) 1-Amino- (S) -2-N-methylamino-3-phenylpropane To an ice-cold Suspension of 90 mmol (3.41 g) LiAlH4 in 100 ml tetrahydrofuran are in small 10 mmol (2.36 g) portions of N-ethyloxycarbonyl- (L) -phenylalanine amide (preparation from (L) -phenylalanine amide and ethyl chloroformate in the presence of Na CO in an ice bath). It is refluxed for 24 hours. Is hydrolyzed under Ice cooling with 360 mmol (6.50 ml) water.

Further work-up analogous to a). It is at 750 C air bath temperature distilled in a high vacuum (10 4 Torr). Colorless liquid.

F. Hydrochloride 1600 C.

f) 1-Amino- (S) -2-N, N-dimethyamino-3-phenylpropane In 100 mmol (3.85 ml) 98% but formic acid becomes 20 mmol (3.28 g) (L) -phenylalanine amide with stirring dissolved and treated with 60 mmol (4.47 ml) 37% aqueous formaldehyde solution. It is briefly heated until the evolution of carbon dioxide begins (approx.

2 to 3 minutes), and then continue stirring without adding heat. Sounds like the evolution of gas ceases, the mixture is refluxed at 1000 ° C. for a further 15 minutes.

After cooling, 20 ml of 2N hydrochloric acid are added and on a rotary evaporator freed from excess starting materials and water. The yellow, oily one Residue is taken up in 7 ml of water and the amine by adding 5 ml of 18N sodium hydroxide solution released. The organic phase is separated off and the aqueous phase twice shaken out with 10 ml of ethyl acetate. The combined organic phases are dried over potassium carbonate and freed from solvent. 17.3 mmol are obtained (3.32 g) N, N-dimethylamino- (L) -phenylalanine amide as a yellow colored oil.

This is added in portions to an ice-cold suspension of 69 mmol (2.62 g) LiAlH4 in approx. 100 ml tetrahydrofuran and refluxed for 24 hours heated.

It is hydrolyzed with 276 mmol (4.97 ml) of water while cooling with ice. Further work-up analogous to a). The product is in a high vacuum (10-4 Torr) at 90 ° C air bath temperature distilled (colorless oil).

g) l-Amino- (5) -2-N-isopropylamino-3-phenylpropane 20 mmol (3.20 g) (L) -Phenylalanine amide are dissolved in 125 ml of benzene, with 20 mmol (1.47 ml) of acetone and a spatula tip p-toluenesulphonic acid added, and in a Soxhlet apparatus, which is filled with CaSO4 1/2 H20 as a desiccant, refluxed for 12 hours. After the solvent has been stripped off in vacuo, an air-sensitive, viscous one is obtained Oil as a condensation product. This becomes a suspension of while cooling with ice 100 mmol (3.79 g) LiAlH4 in 100 ml tetrahydrofuran and refluxed overnight heated. The excess LiAlH4 is hydrolyzed by slowly adding dropwise 400 mmol (7.20 ml) water (in an ice bath). It is filtered off through a suction filter and concentrated the filtrate. The residue is extracted overnight with 150 ml of tetrahydrofuran in a Soxhlet apparatus. The extract is combined with the filtrate and the Solvent is distilled off in vacuo. The yellowish oil obtained is in a high vacuum at 809 C air bath temperature distilled (colorless liquid).

Instead of 20 mmol (1.47 ml) acetone 20 mmol (2.33 ml) acetophenone or 20 mmol (2.02 ml) benzaldehyde used, the compounds 1-amino- (S) -2- (N- (R, S) -1-phenylethylamino) -3-phenylpropane are formed (Distillation at 1500 C air bath temperature in a high vacuum; colorless liquid) or 1-Amino- (S) -2-N-benzylamino-3-phenyl-propane (distillation at 1450 C air bath temperature in a high vacuum; colorless liquid).

h) (5) -1,2-bis (N-methylamino) -3-phenylpropane. 225 mmol (9.00 g) NaOH dissolved in 45 ml water, cooled in an ice bath and with 49 mmol (7.35 g) (S) -1,2-diamino-3-phenylpropane, dissolved in about 45 ml of benzene, added. While stirring a solution of 108 mmol (10.3 ml) ethyl chloroformate is added dropwise within 30 minutes in 45 ml of benzene, and stir at room temperature for 3 hours. The organic The phase is separated off and the aqueous solution is extracted twice with 20 ml of benzene. The combined phases are dried over sodium sulfate and removed from the solvent freed. 40.33 mmol (11.87 g) of colorless, crystalline solid L (S) -1,2-bis (N-ethyloxazarbonylamino) -3-phenylpropane are obtained.

This becomes an ice-cold suspension in small portions of 370 mmol (14.0 g) of LiAlH4 in 300 ml of tetrahydrofuran. After 24 hours Heating under reflux is careful with ice-cooling with 1.5 mol (27 ml) of water hydrolyzed. The hydrolysis products are filtered off and the filtrate is concentrated. The The residue is extracted for 12 hours with 150 ml of tetrahydrofuran in a Soxhlet apparatus. One unites that Extract with the filtrate and distilled in vacuo the solvent off. The slightly brownish liquid becomes in a high vacuum at 850 C distilled. Colorless liquid.

i) (5) -1,2-bis (N -isopropylamino) -3-phenylpropane 21.2 mmol (3.18 g) (S) -1,2-diamino-3-phenylpropane are dissolved in 125 ml of benzene, with 42.4 mmol (3.11 ml) acetone and a spatula tip of p-tolene sulfonic acid are added. In a Soxhlet apparatus, which is filled with calcined calcium sulfate as a desiccant, will last 12 hours heated to reflux. After the solvent has been stripped off in vacuo, a slightly yellowish oil. It is dissolved in 50 ml of methanol, in an ice-salt bath to -10 ° C cooled and treated with 80.0 mmol (3.03 g) NaBH4. The mixture is allowed to stir while stirring Come room temperature and reflux for a further 12 hours. After cooling down The solvent is distilled off in vacuo and hydrolyzed with 30 ml of water. It is extracted with 150 ml of ether and the organic phase with twice more washed 30 ml of water each time. After drying over sodium sulfate, the ether is drawn off and the brownish oil obtained is distilled in a high vacuum at 1000 C air bath temperature.

Colorless oil.

Representation of the diamine dihydrochloride Can be used for cleaning purposes the diamines are converted into their dihydrochlorides. The best results were at Introducing dry hydrogen chloride gas into a well-cooled ethereal solution Obtaining the diamine: approx. 2 g of diamine are dissolved in 5 ml of ethanol with 50 ml of ether added and cooled to -15 ° C in an ice-salt bath.

Then a slow stream of dry HCl gas is poured up to the Separation of a white, crystalline precipitate initiated. When it is too big Excess HCl, the precipitate is oily. The mostly very moisture-sensitive Dihydrochloride is filtered off with suction and dried in a high vacuum.

Conversion of the dihydrochlorides into the diamines Approx. 10 mmol of dihydrochloride are refluxed for 30 minutes with 20 ml of ether and 10 ml of triethylamine.

The precipitated triethylammonium chloride is filtered off and the filtrate freed from excess solvent and triethylamine in vacuo. The received Oils are distilled in a high vacuum.

Table 3 below with Examples 29 to 36 again relates to platinum complexes of the formula These compounds are prepared according to the instructions given for Examples 1 to 16. Table 3 b 2 kk 3 ß-cH2-B Characteristic IR-8xiinguug bands 5 cm (KBr) No. -4 NH Pt-N, ftl S) ooooo gmm 0 mb 29 -CH2 '\ 3280 cm1, vs 1560 cm1, 5 570 cm1, w 305 cm1, m, br . cml, r - A lll toooo u -cH '3270 = 1, - 1560 cml, r 560 cml, w 300 cm1, m, br 2 3190 cm1, sb i. . El 31 g Cl 3270 cm1, 5 g Q e vle rn g X for 3rn - 3200 cm1, s titie tiaa m 000 000 000 000 cm1, 5 590 GNc -1 32 ai 2260 cm1, X 1570 tn m 310 cm c 3 br 2 2190 cm1, vs 440 cm, m 2120 cm1, d f OD WO Ak tf pG f 8 «NO Continuation of table 3 ti bC4C CI ~ Group H Characteristic IR oscillations in 18 (KBr) XO Õ VO- 'O P1 m cr, 3 s EE 3 1.1 Br 33227000 cm11.5 '' cm1, 5 S oo oo oo 7 coor SE Inir In Ln Ln I at the h -CH2 / \ F 3270 cm1 vs 1565 cm1 580 cm1 m 300 cml m br - 3190 cm-1, 5 490 cm-1; m 3120 cm, w rn o In oo rl o D \ r, a, b - 3190 cm1, vs. 3110 cm, w ; u mE 3mE m pm -1 -1 36 Cl 3270 cm1, 5 1580 'ddl I "leli 3200 2tr v5 z 3120 cm, 5 ON mnm mm mmm X e XX ts na 8 i iN 8 aM XXX n Example 37 Replacement of the anion X by other anions 1 mmol (416.2 mg) of the dichloro complex (DL form) of the formula is suspended in 5 to 10 ml H20 and mixed with 2 mmol (339.7 mg) AgNO3, dissolved in 5 ml H20. The reaction mixture is stirred in the dark. After just a few hours, the gradual transition from the initially yellow color of the dichloro complex to the white-gray color of the silver chloride formed shows that the reaction is progressing. After about two to seven days, the silver chloride is filtered off, the pH is brought to 4 to 5 by adding 0.5 molar ammonia solution and the clear filtrate is treated with 1 mmol of the acids 1,1-cyclobutanedicarboxylic acid, malonic acid, hydroxymalonic acid, benzenesulfonic acid, tartaric acid , o <-Chloroacetic acid, aspartic acid, phthalic acid and 4-carboxyphthalic acid or the salts sodium oxalate and sodium isocitrate in solid form. In most cases, the yellow or white complexes begin to separate out after a few hours and are stirred for a further 20 hours.

It is then filtered off, washed with ice-cold water and in a high vacuum dried at 800 C.

In this way, for example, complexes of the above formula obtained in which the two chlorine anions by the divalent anions of following Acids are replaced: oxalic acid (white powder, F.> 2500 C); 1,1-cyclobutanedicarboxylic acid (white powder, m.p. 2500 C); Malonic acid (white Powder, m.p.> 2500 C); Hydroxymalonic acid (white powder, m.p.> 2500 C); 4-carboxy-phthalic acid (white powder, m.p. 2220 C, decomposition); Phthalic acid (white powder, m.p. 1850 C, decomposition); Isocitric acid (light yellow powder, m.p. 2260 C, decomposition); Tartaric acid (white powder, M.p. 2150 C, decomposition); Aspartic acid (white powder, m.p. 1300 C, decomposition).

Because of the good water solubility of the dibenzenesulfonate complex, the α-chloroacetate nitrate complex and the dinitrate complex was in these Cases concentrated in a high vacuum until a viscous residue is formed, which with Ether was added. After brief stirring, these complexes also precipitated as white Solids on, which were filtered off and dried in a high vacuum.

The benzenesulfonate complex (X = C6H5SO3) is a white powder that melts at 1700 C with decomposition.

The «-chloroacetate-nitrate complex (one X = NO3, the other X = CH3Cl-CO2) is a beige powder that melts at 1480 C with decomposition.

The dinitrate complex (with 2 mol H2O) is a yellow powder, F. 2500 C.

From the dichloro complex (DL form) of the formula For example, complexes are obtained in an analogous manner, where the two anions X have the following meaning: The two anions X together form the malonic acid anion (# O2C-CH2-CO2 #).

The complex is a colorless solid; Decomposition point 3070 C.

The two anions X together form the hydroxymalonic acid anion (# O2C-CH (OH) -CO2 #).

The complex is a colorless solid, soluble in water; Decomposition point 2700 C.

Complex with the tetra-anion of 1,2,3,4,5-benzene pentacarboxylic acid (it is a bis complex, where 1 mole of the anionic compound is connected to 2 moles of the platinum component): The complex is a white powder that melts above 1600 C with decomposition.

Each anion X is the anion of the amino acid ornithine (L-form, whose both amino groups are acetylated.

The complex is a white powder; Melting point 1150 C (with decomposition).

Examples of pharmaceutical preparations Coated tablets: 200 g Compound according to Example 3, 300 g of lactose D 10, 130 g of corn starch and 10 g of magnesium stearate are passed through a sieve with a mesh size of 0.8 mm and homogenized.

This mass is made into convex tablets of 100 in a known manner mg weight pressed.

These cores are used to produce coated tablets a spray device in a known manner with a gastric or small intestinal soluble Provided coating made of a suitable polymeric film former such as Esters of acrylates or methacrylates and suitable auxiliaries such as wetting agents, Plasticizers, dyes, lubricants, etc. can consist. The kernels can too can be processed into coated tablets in the usual way. A film-coated tablet respectively a dragee contain 20 mg of active ingredient.

Lyophilisate: Add 800 ml of water for injections while stirring 50 g mannitol and 5 g (D, L) -dibenzenesulfonato- (1-benzylethylenediamine) -platinum II (compound according to Example 37) and with water for injections the volume to 1 liter filled up.

This solution is passed through a membrane filter under aseptic conditions 0.22 μm pore size sterile-filtered 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 seal the bottles in the plant. The stoppers are secured with a crimp cap.

For intravenous use, the lyophilisate is dissolved in 10 ml of water for injection reconstituted.

1 ml of solution contains 5 mg of active ingredient.

Claims (5)

Tumor-inhibiting (1-benzyl-ethylenediamine) platinum (II) complexes Patent claims: 1. (1-Benzyl-ethylenediamine) platinum (II) complexes of the general formula in which the radicals R1, R2, R3 and R4 are identical or different and are hydrogen, a C1-C6-alkyl group, a benzyl group or a phenylethyl group, and B is a thienyl radical, an indolyl radical, an imidazolyl radical or one of the radicals R5, R6 and R7 is a substituted phenyl radical and the radicals R5, R6 and R7 are identical or different and are hydrogen, halogen, trihalomethyl, C1-C6-alkyl, hydroxy, C1-C6-alkoxy, phenoxy, benzyloxy, C1-C6-alkanoyloxy, benzoylcxy, CX C6-alkanesulfonyloxy carboxy, C1-C6-carbalkoxy, cyano, aminocarbonyl, aminocarbonyl, which contains one or two C1-C6-alkyl radicals, C1-C6-alkylcarbonyl, nitro, amino, C1-C6-alkylamino, di-C1-C6 -Alkylamino, (C1-C6-alkyl) 3N, C1-C6-alkanoylamino, C1-C6-alkyl-C1-C6-alkanoylamino, C1-C6-alkasulfonylamino, C1-C6-alkyl-C1 -C6-alkanesulfonylamino, aminosulfonyl, Aminosulfonyl, which contains one or two C1-C6-alkyl radicals, C1-C6-alkoxysulfonyl (-S02-0-C1-C6-alkyl), sulfo (-S03H) or C1-C6-alkanesulfonyl and z Because these radicals can also be the methylenedioxy group and X stands for the equivalent of a physiologically compatible anion, and optionally their salts with physiologically compatible cations or anions. 2. Process for the preparation of (1-benzyl-ethylenediamine) -platinum (II) complexes of the general formula in which the radicals R1, R2, R3 and R4 are identical or different and are hydrogen, a C1-C6 -alkyl group, a benzyl group or a phenylethyl group, and B is a thienyl radical, an indolyl radical, an imidazolyl radical or one of the radicals R5, R6 and R7 is a substituted phenyl radical and the radicals R5, R6 and R7 are identical or different and are hydrogen, halogen, trihalomethyl, C1-C6-alkyl, hydroxy, C1-C6-alkoxy, phenoxy, benzyloxy, C1-C6-alkanoyloxy, benzoyloxy, C1 -C6-alkanesulfonyloxy, carboxy, C1-C6-CarbalRoxy, cyano, aminocarbonyl, aminocarbonyl, which contains one or two C1-C6-alkali radicals, C1-C6-alkylcarbonyl, nitro, amino, C-C6-alkylamino, Di-C - C -C alkylamino. (C1-C6-alkyl) 3N, C1-C6-alkanoylanino, C1-C6-alkyl-C1-C6-alkanoylamino, C1-C6-alkanesulfonylamino, C1-C6-alkyl-C1-C6-alkanesulfonylamino, aminosulfonyl, aminosulfonyl, which contains one or two C1-C6-alkyl radicals, C1-C6-alkoxysulfonyl (-S02-O-C1-C 6-alkyl), sulfo (-SO3H) or C1-C6-alkanesulfonyl and two of these radicals can also be the methylenedioxy group and X stands for the equivalent of a physiologically acceptable anion, and optionally salts thereof, characterized in that a tetrahalogenoplatinum (II) acid, a tetrahalogenoplatinum (II) complex salt with two monovalent or divalent cations or a platinum is used (II) halide with a compound of the formula or a salt of the compound II is reacted with a physiologically acceptable counterion or an acid addition salt of the compound II, where the radicals R1, R2, R3, R4 and B have the meanings given, optionally in hydroxyl groups or amino groups of the radical B by acylation one or more C1 Introduces -C6-alkanoyl groups, C1-C6-alkanesulfonyl groups or benzoyl groups, optionally existing amino groups of the radical B oxidized to nitro groups, and optionally exchanging the radical X or the radicals X for other physiologically compatible anions in a compound of the formula I obtained and / or any compounds obtained are converted into the salts with physiologically acceptable anions or cations. 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.