SI8910016A - Process for obtaining of 1,2-bis (aminomethyl) cyclobutane-platinum complexes - Google Patents

Abstract

1,2-bis (aminomethyl) cyclobutane platinum complex with the general formula I ch2 - nhr5 X Pt Z \ CK2 - NHR6 X or II wherein the residues, identical or different, are Ri, R2, R3, R4, R5 and R6 are hydrogen, C1-C6-alkyl, phenyl, phenyl-C1-C6-alkyl, C1-C6-alkyl, which may be substituted by halogens, with hydroxyl, with C2-C6-alkanoyloxy, or C1-C6-alkoxy halogen-substituted phenyl group, s hydroxyl, with C2-C6-alkanoyloxy, or with C1-C6-alkoxy a group or phenyl-C1-C6-alkyl which is in the phenyl moiety substituted by halogen, by hydroxyl, by C2-C6-alkanoyloxy, or with a C1-C6-alkoxy group and X is equivalent of some physiologically acceptable anion, or however, X can be one molecule of water and is in it case the existing positive charge of the platinum atom is right so saturated with some physiologically acceptable anion, and salts thereof, and processes for the manufacture of these compounds comprising the reaction of tetrachloro-platinum (11l) acid, tetrahalogeno-platinum (ll) complex salts with two monovalent, or single divalent cations, or of platinum (11l) halide with a compound of formula II, or with one the salt of this compound, or the oxidation of the compound of formula I '. The compounds of the invention have a good antitumor effect (for example in vitro on AH 135 tumor, on melanoma B 16, at colon 115; in vivo, for example, on P 388 leukemia in mice). The compounds of the invention are furthermore very a little toxic. Notably, they have no cumulative toxicity and are not nephrotoxic. Further it is for bone brain toxicity minor and thrombocytopenia which to flog her, not to perform.

Description

ASTA PHARMA AG

PRODUCTION PROCEDURE for 1,2 - bis (aminomethyl) cyclobutane-platinum complexes

For example, US 2 024 823 discloses, for example, 1,1-bis (aminomethyl) -cyclobutane platinum complexes. These compounds are recommended in the treatment of cancers.

The compounds of the invention have a good antitumor effect (for example in vitro AH 135 tumor, melanoma B 16, colon 115; in vivo, for example P 388 leukemia in mice. The compounds of the invention are also very toxic. In particular, they have no cumulative toxicity and are not nephrotoxic.For bone marrow toxicity is negligible and thrombocytopenia, which is feared, does not occur.

Moreover, as a surprise, the compounds of the invention are well soluble in water.

The following characteristics relate to preferred embodiments of the invention:

The resulting C 1 -C 8 alkyl groups, alkoxy groups and C ₂ -C ₆ alkanoyloxy groups may be straight or branched. The alkyl or alkoxy groups are predominantly from 1 to 4 C atoms and the alkanoyloxy groups are predominantly from 2 to 4 C atoms. The same applies if the components of the Ο, -Οθ alkyl groups are of another functional group. As alkanoyloxy groups, the acetoxy groups are especially considered. Halogen substituents are particularly suitable for bromine, chlorine and / or fluorine. In the case of phenyl-C1-C8-alkyl groups, the alkyl moiety is predominantly of one, two or three C-atoms, preferably a benzyl group or a 1-phenylethyl group, the phenyl moiety being always substituted as indicated.

The phenyl residues formed can be substituted by said residues once, twice or three times, the light residues being the same or different, such that, for example, such a phenyl residue may contain 1 or 2 halogen atoms (as chlorine), preferably in position 2 and / or position 6 as well as an additional hydroxyl group (preferably in position 4).

The compounds given by the formulas l ^z or l ^zz have a particularly advantageous effect, in which all residues R ₁ to R _{6 are} hydrogen or where residues R 1 to R ₄ are hydrogen and where one or both of residues R _s and / or R _{6 is} an alkyl group and in particular a methyl group.

Formulas I 'and I

Pt /

Pt

The residues X, which may be the same or different, represent the known and customary physiologically acceptable and pharmaceutically usable anions of one or more valent acids as well as hydroxide anions. In case these acids have asymmetric C atoms, they can therefore be present as racemates, as optically pure forms or in the form of suitable diastereoisomers.

Particularly suitable, for example, are the anions of the following acids: HBr, HCl, HJ, HF, HNO ₃ , H ₂ SO ₄ , (SO ₄ ''); H ₃ PO ₄ , (HPO ₄ ''); H ₂ CO ₃ , (CO ₃ '');HSCN; caffeine sulfonic acid, aliphatic, or aromatic sulfonic acid, for example C 1 -C 8 alkylsulfonic acid (for example methanesulfonic acid, ethane, propane or hexansulfonic acid), benzene or naphthalenesulfonic acid, which may be optionally substituted once or twice by methyl groups (toluenesulfonic acid, especially o- or p-toluenesulfonic acid), aliphatic θΐθ20 -monocarboxylic acids, especially C ^ C ^ -monocarboxylic acids, which are optionally substituted once, twice or three times by atoms

-3 halogens (especially with Cl, F) e.g. formic acid, acetic acid, propionic acid, palmitic acid, stearic acid, chloroacetic acid, dichloroacetic acid, trifluoroacetic acid, trichloroacetic acid; aliphatic C ₂ -C ₁₁ -dicarboxylic acids having a double bond (for example: oxalic acid, malonic acid, 2-amino-malonic acid, malonic acid substituted in position 2 by a benzyl group or by one or two C ₁ -C ₄ -alkyl groups, maleic acid, fumaric acid, succinic acid); aliphatic monohydroxy and dihydroxymonocarboxylic acids of two to 8, especially 2 to 6 carbon atoms, preferably α-monohydroxycarboxylic acids such as lactic acid, glyceric acid, or glycolic acid; di- and tricarboxylic acids of 3 to 8 carbon atoms, especially 3 to 6 carbon atoms (for example malic acid, tartaric acid, malonic acid), which may be optionally substituted on one C atom by a hydroxyl group and / or optionally by A C1-C4 alkyl group (isocitronic acid, citric acid); phthalic acid, which may be optionally substituted by one carboxyl group (especially in position 4); glucuronic acid; azetidinecarboxylic acid; quadratic acid (3,4-dihydroxy-3-cyclobutene-1,2-dione); natural? -amino acids (for example L-aspartic acid); 1,1-cyclobutanedicarboxylic acid; organophosphoric acids such as aldose- and ketosophosphoric acids (eg corresponding mono and diphosphoric acids) for example aldose-6-phosphoric acid such as Dali L-glucose-6-phosphoric acid, aD-glucose-1-phosphoric acid, D-fructose-6 -phosphoric acid, D-galactose-6-phosphoric acid, D-ribose-5-phosphoric acid, D-fructose-1,6-diphosphoric acid; glycerolphosphoric acid (wherein the phosphoric acid residue is attached to one of the terminal or middle oxygen atoms of glycerol) as aD, L-glycerolphosphoric acid, β-glycerolphosphoric acid; N-phosphonoacetylaspartic acid.

Preferably, X is always chlorine, bromine, iodine or -SCN (rhodanide), or the anion X is derived from a hydroxycarboxylic acid of the structure R ₅ -CH (OH) - (CH ₂ ) _n -CO ₂ H, where n may be 0 , 1, 2, 3 or 4, and R ₅ denotes hydrogen, halogen, hydroxyl, C ₂ -C ₆ alkanoyloxy, C 1 -C 8 alkoxy group, C 1 -C 8 alkyl or phenyl which may be optionally substituted by halogen , hydroxyl, C1-C8-alkoxy, C1-C8-alkyl or with a C1-C8-alkanoyloxy group.

In the case of such oxycarboxylic acid, it has a complex part X

the following structure

II

- CH

X is preferably derived from lactic acid or glycolic acid (always racemate, D-form, L-form).

The acids for the X anions are further considered aromatic carboxylic acids containing one or more carboxylic groups and in addition one or more (for example one, two, three, four or five) C 1 -C 4 alkoxy groups and / or hydroxyl groups. In case more than one carboxyl group is present on an aromatic residue (for example a benzene ring), at least two carboxyl groups are preferably located at adjacent positions. If, for example, a benzene ring contains four or five carboxylic groups, complexes may be formed containing two moles of the platinum component per mole of the benzene carboxylic acid anion. 2 adjacent carboxyl groups neutralize each mole of the platinum component each time by neutralizing, for example, benzene pentacarboxylic acids at positions 1 and 2 as well as positions 4 and 5, each mole of the platinum component (ie a total of 2 moles). while at the 3- position, the free group is free or in the form of a salt of some physiologically acceptable cation (for example, an alkaline cation, especially a sodium cation). This is generally the case if X anions also have additional acid functional groups that are not used for platinum saturation. The same applies to the case of benzenehexacarboxylic acid, in which case one mole of this acid can neutralize 3 moles of platinum.

Examples of such acids are: benzenmonocarboxylic acid, benzendicarboxylic acids, benzentricarboxylic acids (for example trimellic acid), benzentetracarboxylic acids, benzenpentacarboxylic acids, benzenhexacarboxylic acids; syringic acid, orotic acid.

The acids forming anions of X are also considered amino acids or amino acid derivatives, in which the basic amino groups are protected by an acid group. For example, these are amino acids with the following structure:

-5R ^z - CH - CO ₂ H

I NH ₂ where R represents ^the hydrogen, a phenyl radical, indolyl (3) -methyl radical, imidazolyl (4) -methyl radical,

-alkyl group, or a C 1 -C 6 -alkyl group substituted by a hydroxyl group, a carboxyl group, a C ₁ -C ₆ alkoxy group, a mercapto group, a C ₁ -C ₆ -alkylthio group, a phenyl group, with a hydroxyphenyl group, a C ₂ -C ₆ alkanolamine group, or a C ₁ -C ₆ alkoxycarbonyl group.

The basic amino group is then protected in position 2 by a conventional amino acid protecting group (acylated), for example, a C ₂ -C ₆ -alkanol residue or a butyloxycarbonyl residue.

In the above formula, R is ^an alkyl group, it is preferably a C 1 -C 8 alkyl group, for example in the 2-, 3-, 4-, 5-, or 6- positions (starting at the junction point an alkyl residue with a molecular residue) contains a C ₂ -C ₆ -alkanoylamino group, an imidazolyl- (4) -methyl residue, or an indolyl- (3) -methyl residue. Some examples of such amino acids are: leucine (preferably D- or Lobyl), valine (preferably D- or L-form), phenylalanine (preferably D- or L-form), phenylglycine (preferably D- or L-form), alanine (preferably D or L form), isoleucine (preferably D or L form) asparagine (preferably D or L form), lysine (preferably D or L form), tryptophan (preferably D or L form) ), tyrosine (preferably D- or L-form), ornithine (preferably D- or L-form), hydroxyproline (D- or L-form).

In doing so, the basic amino groups are blocked by some conventional acylamino protecting group, in particular by the acetyl group, chloroacetyl group or butyloxycarbonyl group.

Appropriate acid addition salts may optionally also be prepared using physiologically acceptable acids, provided they contain exchangeable groups X of the basic group (for example, amino groups).

In case X is a water molecule, the positive charge of the platinum atom of said acids is considered to be of particular potency, preferably H ₂ SO ₄ .

The formula l ^z or l ^zz also includes possible enantiomers and dia stereoisomers. To the extent that the compounds are racemates, they can then be cleaved into the optically active isomers by a known method, for example, with an optically active acid or with a chiral phase. It is also possible to initially add enantio-6omeric or possibly diastereoisomeric starting materials. The result is a suitably pure optically active or diastereoisomeric compound as a final product. Independently of the structure, the residue X may optionally also contain a cyclobutane moiety of the asymmetric carbon atom and may therefore be in racemic form or also in some optically active or diastereoisomeric form.

Additional forms are formed by stereochemistry on cyclobutane, where both aminomethyl groups as well as residues R to R _{4 may} be in the cis or trans position. Further, additional forms may be formed via different enantiomeric or diastereoisomeric forms of X residues.

The compounds of the invention of formula l ^with or with respect to the platinum atom are primarily cis compounds.

The starting amine II is used, for example, as a racemate, as a pure right or left succulent form, as a cisali trans form (depending on the position of the aminomethyl groups) or in some other diastereoisomeric form. These configurations also remain in the production of the platinum complex.

Formula II

• CH ₂ - NHR ₅

CH ₂ - NHR ₀

II

The process for the production of compound l ^z of the invention is carried out in a solvent at temperatures between 10 and 80 ° C, preferably 20 to 40 ° C and especially 25 to 30 ° C.

Suitable solvents include, for example: water, C1-C8-alkanols (methanol, ethanol, tertiary butanol), cyclic ethers such as uranium tetrahydrofoil, dioxane, saturated ethers of one or more valent alcohols, such as ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, lower saturated ketones (acetone, methylethylketone), aprotic substances such as dimethylsulfoxide or dialkylamides of lower aliphatic carboxylic acids (formic acid, acetic acid) with Ο, -Cg alkyl residues, such as dimethylmethylethamide and, for example, dimethylformamide amide , especially their mixtures with water.

Both reaction components (platinum compound and compound II) are preferably used in equimolar amounts. The pH of the reaction solution should be between 6 and 9, preferably at pH 8.

-7The pH adjustment is carried out mainly by the addition of alkali, preferably with an aqueous solution of sodium or potassium hydroxide, or, for example, with sodium carbonate, or with the addition of acids, preferably with an aqueous hydrochloric acid solution. PH adjustments can also be performed with ion exchangers.

The cotetrachalogen-platinum (II) compounds (acids as well as complex salts) are suitable tetrachloro-, tetrabromo- and tetrahodo compounds. When platinum (II) halides are used as starting components, atoms of the same halogens are considered.

The following are considered monovalent cations: alkali ions, especially sodium and potassium; however, lithium, rubidium, cesium and also NH /, NR /, PR /, or AsR / may be used, wherein R is a C 1 -C 8 alkyl residue, or a phenyl residue. Divalent cations can be: ions of alkaline earth metals, in particular Mg ²⁺ and Ca ²⁺ , as well as Zn ²⁺ . As platinum (II) halides, PtCI ₂ , PtBr ₂ and PtJ _{2 are considered} suitable.

Compound (II) is used either in the form of a diamine or in the form of an acid addition salt: for example as monohydrochloride, or dihydrochloride, mono- or dihydrobromide, mono- or dihydroiodide, or as a salt with some other conventional inorganic or organic acid . Particularly suitable are acids whose anions form residues of X. Further, diamine can be used in the form of acetate or diacetate, with potassium chloride (for example 2 moles per mole of compound II) being added before mixing the reaction components. Diamine II may also be used, for example in the form of hydrochloride, carbonate, oxalate, or malonate.

The process for the production of platinum (IV) complexes of formula (I) is carried out, for example, in the same means as the process for the production of platinum (IV) complexes of formula (li). ° C. The following are considered oxidizing agents: halogens such as chlorine (gas), bromine, iodine, hydrogen peroxide (for example 3-60%); preferably 10-40% -en, and in particular 35% -en, dirodane (gaseous), halogen hydrogen acids (HCl, HBr, HJ). In the case of oxidation with halogens, dirodane, or halogen hydrogen acids, the additional presence of a compound HX is not necessarily required.

The replacement of ligand X with another ligand may be carried out, for example, by precipitation of silver halide. To this end, for example, a compound of the dihalogen-1,2-bis (aminomethyl) cyclobutane-platinum (II) of formula I ⁷ reacts, or optionally a compound of formula I ⁷⁷ , wherein X is halogen (chlorine , bromine, or iodine) in a solvent, or suspension medium, with a silver salt of another acid corresponding to the meaning of X, at temperatures between 0 and 90 ° C, preferably 10

-8 to 50 ° C, especially 30 to 40 ° C and especially at 40 ° C. Silver nitrate (for example an aqueous solution of silver nitrate) may also be used as the silver salt to give (if compound l ^z is the starting material) an ionic diac complex of the formula

CH ₂ CH ₂

R ₃ HN x NO ₃

Pt

H ₂ 0 h ₂ o

From this complex, poorly bound iigand water can be displaced by higher-affinity anions (for example Cl ', Br' in the form of NaCl, KCI, NaBr, KBr, malonate ² ', chloroacetate *' ¹ , oxalate ² ', anion ² '1,1-Cyclobutanedicarboxylic acids) as well as with other of the foregoing acidic residues X used in the form of acids, or salts thereof, and in particular their alkali salts.

The same compounds can also be obtained by the following procedure: by treating the aforementioned diacetate nitrate complex with an anion exchanger in hydroxide form (for example Dowex 1 - 8X), wherein two water molecules are replaced by OH and the complex compound thus obtained ((X) = always OH) reacts with an equimolar amount of HX, where X represents a physiologically acceptable acid anion.

Replacement of the starting group (for example, SO ₄ ² 'or oxalate anion ² ') is also possible in the case of sulfatoosyme oxalato-1,2-bis (aminomethyl) -cyclobutane-platinum (III) compounds by reaction with alkaline earth metal salts containing the desired X-ligands (for example, glyceric acid) to the extent that the resulting complex is soluble in water and thus permits the dissolution of the water-soluble alkaline sulphates or oxalates in water.

Suitable X-ligands for this process are preferably hydroxycarboxylic acid anions, sulfonic

-9 acids, halogenoacetic acids and nitric (V) acids.

The solvent or suspension agent mentioned in the process for the manufacture of compound I is also suitable for the substitution reaction (water, dimethylformamide, dimethylacetamide, dimethylsulfoxide, methanol, ethanol, tertiary butanol, acetone, methylethyl ketone are particularly suitable). For example, the substitution reaction is carried out in the range of pH 3 to 9.

The production of the unknown starting amines of formula II may take place, for example, as described in Example 1, from the corresponding known cyclobutane-1,2-dicarboxylic acids (with the substituents R _in R ₂ in position 3 as well as R ₃ and R ₄ in position 4).

Cyclobutane-1,2-dicarboxylic acid substituted in the cyclobutane ring with residues R _p R ₂ , R ₃ , R ₄ is converted with the corresponding acid dihalide (chloride, bromide), with ammonia, or with the amines NHR _S or NHR ₆ to known manner to the corresponding amide, and this is then reduced in the known manner here by hydration (for example by catalytic hydrogenation or by complex hydrides such as LiAIH ₄ ) to the diamine of formula II.

Furthermore, the production of such starting amines is possible by the following methods: by catalytic hydrogenation of the corresponding dician compounds in the presence of conventional metal catalysts according to British Patent I 121 413; by reduction with lithium aluminum hydride in diethyl ether or tetrahydrofuran; by conversion to the corresponding formic acid amides with formic acid / HCl and then reduction with lithium aluminum hydride in tetrahydrofuran; by Curtius decomposition of the corresponding acid azides; by degradation by the method of K. H. Schmidt (see, for example, J. Am. Soc. 64 (1942), pp. 269-98).

The amino substituents R ₅ and / or R ₆ are introduced when the synthesis of diamine II begins with the corresponding amino substituents. Further explanation can be seen in the above examples of the production of the starting compounds of formula II.

The compounds of the invention exhibit a good antitumor effect, for example, in P388 leukemia in mice. Thus, for example, a 77% increase in survival time was achieved with the above-mentioned experimental method at an intraperitoneal dose of 10-30 mg / kg body weight of mice. The lowest but still effective dose was in the above animal experiment, for example:

mg / kg orally

0.5 mg / kg intraperitoneally

-100.5 mg / kg intravenously

As a general dosage field with the desired effect (animal experiment as above), it is appropriate, for example:

2-2000 mg / kg orally, especially 50-200 mg / kg

0.5-1000 mg / kg intraperitoneally, especially 2-100 mg / kg

0.5-1000 mg / kg intravenously, especially 2-100 mg / kg.

The direction of effect of the compounds of the invention can be compared with the effect of known cis-platinum active agents, but the differences are particularly the following: the effect of action is better, the spectrum of action is different, and the kidneys are almost non-toxic.

The following may be indicated as indications for the compounds of the invention: chemotherapy in cancer.

The pharmaceutical compositions generally contain from 1 to 2000 and preferably from 10 to 1000 mg of active ingredients according to the invention.

Use may be in the form of tablets, capsules, pills, dragees, suppositories, ointments, jellies, creams, powders, powders, aerosols, or in liquid form. Liquid applications include, for example, oily, alcoholic or aqueous solutions, as well as suspensions and emulsions. The preferred form of administration is tablets containing between 100 and 1000 mg of active substance, or lyophilisate (for example, for the manufacture of solutions containing between 10 and 200 mg of active substance).

An individual dose of the active components according to the invention may be, for example:

a) when administered orally between 10 and 2000 mg, preferably 10 to 1000 mg;

b) between 1 and 1000, preferably 5 to 200 mg, for parenteral administration (for example intravenous or intramuscular).

For example, one to four tablets containing from 10 to 500 mg of the active substance may be recommended three times daily, or one ampoule of 1 to 200 mg of the active substance may be given intravenously 1 to 4 times daily. For oral administration, the minimum daily dose, for example, is 1 mg;

the maximum daily dose for oral administration should not exceed 2000 mg.

-11When treating dogs and cats, the single oral dose is generally between 10 and 500 mg / kg body weight; and the parenteral dose is between 1 and 500 mg / kg body weight.

For the treatment of horses and cattle, the single oral dose is generally between about 10 and 500 mg / kg, and the individual parenteral dose is between about 1 and 500 mg / kg body weight.

The acute toxicity of the compound according to the invention to mice (expressed by LD 50 mg / kg; Miller and Tainter method: Off. Soc. Exper. Biol. Med. 57 (1944) 261, for example, in intraperitoneal administration is between 5 and 1000 mg / kg.

It may be used in human medicine, veterinary medicine and also in agriculture, alone or in admixture with other pharmacological agents.

The compounds of the invention are suitable for the manufacture of pharmaceutical preparations. The pharmaceutical compositions or medicaments may contain one or more compounds according to the invention, or also mixtures thereof with other pharmaceutical ingredients. When using pharmaceutical preparations, conventional pharmaceutical carriers and excipients may also be used for their manufacture. For example, the drugs may be administered enterally, parenterally (for example intravenously, intramuscularly, intraperitoneally, subcutaneously), or orally. For example, administration may take the form of tablets, capsules, pills, dragees, or suppositories. Liquid preparations include, for example, oily or aqueous solutions, or suspensions (for example, in sesame or olive oil), emulsions, aqueous and oily solutions, or suspensions for injection. Furthermore, dry ampoules containing the compound I according to the invention can be produced, whereby the contents of these dry ampoules are dissolved, for example, in saline, or a mixture of saline, for example dimethyl sulfoxide.

Example 1

Dichloro-1,2-bis (aminomethyl) cyclobutane-platinum (III) (trans form)

-12V solution of 3.05 g (0.0073 mol) of potassium tetrachloroplatinate in 10 ml of water was added 0.81 g (0.014 mol) of KOH and 1.5 g (0.0073 mol) of 1,2-bis (aminomethyl) cyclobutane at 50 ° C and stir for 3 hours. After cooling to room temperature, they are sucked off and washed with water and a 1: 1 mixture of acetone and diethyl ether. Yield: 1.0 g.

Melting point: 225-226 (decomposition).

Production of starting amine II

A) 5 g (0.028 mol) of trans-cyclobutane-1,2-dichloride of dicarboxylic acid are added dropwise to a mixture of 50 ml of concentrated ammonia solution and 50 ml of ice. After this addition, the mixture is stirred for an additional hour and then the precipitate (acid amide) is sucked off, washed with water and recrystallized from 150 ml of ethanol.

Yield: 2.5 g.

Melting point: 231-233 ° C.

The acid amide thus obtained is then reduced with lithium aluminum hydride to diamine II:

g (0.21 mol) of lithium aluminum hydride is suspended in nitrogen atmosphere in 200 ml of anhydrous tetrahydrofuran. At 0 ° C, 5 g (0.035 mol) of amide are carefully added portionwise. After this addition, the mixture was stirred again at room temperature and then heated under reflux for 4 hours. After overnight standing, ethyl acetate was added first and then water and then the precipitate was separated by filtration. The filtrate was dried with magnesium sulfate and concentrated in a rotary evaporator. The residue was bound with isopropyl alcohol, and the salt was precipitated with 7 g (0.07 mol) of oxalic acid and recrystallized from ethanol. (Yield: 4.7 g).

The dioxalate melts at 160 ° C upon decomposition.

B) 115 g (3 moles) of LiAIH ₄ at -10 ° C in 1500 ml of diethyl ether are mixed with a solution of 53 g (0.5 mol) of 1,2-dicycocyclobutane (dissolved in 500 ml of diethyl ether). Allow to stand overnight and then hydrolyse with 185 ml of ethyl acetate and 350 ml of water. The precipitate was filtered off with suction, washed with ether and the filtrate concentrated to dryness in a rotary evaporator.

38 g of 1,2-bis (aminomethyl) cyclobutane are obtained, which is dissolved in 550 ml of ethanol and then mixed with 50.4 g of oxalic acid. The precipitate was filtered off and washed with a little ether. 58 g of dioxalate are obtained. Melting point: 160 ° C (decomposition).

-13Display of the lactate complex (Example 1 a).

3.8 g (0.01 mol) of the chloro complex are suspended in 20 ml of water and heated to 40 ° C. To this was added 3.39 g (0.02 mol) of silver nitrate and stirred for 1.5 hours. After cooling the mixture in a refrigerator, suction off a precipitate of silver chloride and wash with 10 ml of water. The filtrate was percolated through a column with 100 ml of basic ion exchanger and added dropwise into 1 g (0.01 mol) of L-lactic acid. After stirring for 3 days at room temperature, it thickens, the residue is dissolved in methanol and stirred with activated charcoal. After filtration, the mixture was stirred with diethyl ether to allow it to evaporate and allowed to crystallize overnight in the refrigerator. The urgently collected crystals after suction are washed with diethyl ether and dried at 40 ° C. Yield: 1.2 g.

Melting point: 220 ° C (decomposition).

Examples of other 1,2-bis (aminomethyl) -cyclobutane-platinum (II) complexes with different X anions.

General method of production:

3.8 g (0.01 mol) of dichloro-1,2-bis (aminomethyl) cyclobutan-platinum (II) were suspended in 20 ml of water, to which 1 ml of ethanol was added and mixed with 3.39 g (0.02 mol) AgNO ₃ . After heating to 40 ° C, it was stirred at the indicated temperature for about 5 hours. After cooling to 15 ° C (in the refrigerator), the filtered AgCI precipitate was washed with 10 ml of water. After percolating dropwise through a column with 100 ml of a basic ion exchanger (OH-type), the filtrate is run into a solution of 0.01 mol of the new starting group (X) in 5 ml of water. The mixture thus obtained was stirred overnight, then concentrated and purified by silica gel column chromatography with a mixture of acetone and water.

The resulting complexes are listed in Table 1:

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-18Production of complexes in accordance with m) is carried out according to the following regulation:

2.9 g of dichloro-1,2-bis (aminomethyl) cyclobutane-platinum (11 l) was suspended in 50 ml of water and mixed with 2.6 g of silver nitrate. This was stirred for 4 hours at 50 ° C, then the silver chloride precipitate was sucked off, 2 g of N-acetyl-alanine and 0.085 g of KOH were added to the colorless filtrate and stirred for a further 5 hours at 30 ° C. The reaction mixture was freeze-dried and the residue was recrystallized from ethanol.

Example 2

Dichloro-1,2-bis (methylamino-methyl) cyclobutane-platinum (11l)

ch ₃

1.79 g (0.0043 mol) of potassium tetrachloroplatinate (1 l) was dissolved in 5 ml of water at 50 ° C and mixed with 0.5 g (0.0086 mol) of KOH and 1 g (0.0043 mol) of 1.2 -bis (methylamino-methyl) cyclobutane. After stirring for 2 hours, cool to room temperature and vacuum.

Yield: 0.53 g

For example, the starting amine can be obtained as follows:

g of cyclobutane-1,2-dichloride of dicarboxylic acid are added dropwise under ice-cooling in 200 ml of saturated methylamine solution. After stirring at room temperature for 4 hours, it was concentrated in a rotary evaporator and the residue was recrystallized from 900 ml of ethyl acetate.

5.6 g of cyclobutane-1,2-methyl-amide of dicarboxylic acid are obtained.

Melting point: 180-181 ° C.

7.06 g (0.186 mol) of LiAIH ₄ in 173 ml of tetrahydrofuran (cooled in an ice bath) were added in small portions of 5.3 g (0.031 mol) of the amide thus obtained. After stirring for one hour, and with the continued addition of 93 ml of tetrahydrofuran, boil under reflux. By condition over

-19 at night and after cooling with ice, decompose the obtained first with ethyl acetate and then add water. After stirring for one hour, it is filtered and dried over K ₂ CO ₃ and concentrated in a rotary evaporator. The residue was bound with ethanol and mixed with 6.5 g of oxalic acid (dissolved in 20 ml of water). The precipitated product was recrystallized once from ethanol. Oxalate (2 moles of oxalic acid per 1 mol of amine) was melted at 145-147 ° C (1.3 g).

Example 3 (Pt (IV) complex)

Dichloro-dihydroxy-1,2,2-bis (aminomethyl) cytobutane-platinum (IV)

0.5 g (0.0013 mol) of dichloro-1,2-bis (aminomethyl) cyclobutan-platinum (1 l) were suspended in 10 ml of water at 70 ° C and 5 ml of H ₂ O ₂ (35%) was added dropwise. solution). This was stirred for 4 hours at 70 ° C (pH 4) and allowed to cool overnight. The orange-yellow precipitate is sucked off and washed with a little water. To remove unused hydrogen peroxide, 200 mg of platinum on activated charcoal was added to the filtrate and stirred at room temperature for 3 hours, and then the platinum on activated charcoal was filtered off. The filtrate is concentrated to dryness.

Yield: 200 mg of yellow powder.

-20Example 4 (Pt (IV) complex)

Tetrachloro- ¢ 1,2-bis (aminomethyl) cyclobutane || -platinum (IV)

\ ch ₂ nh ₂ nh ₂

g (0.0053 mol) of dichloro-1,2-bis (aminomethyl) cyclobutane-platinum (11 l) was suspended in 250 ml of water and stirred at room temperature with (gas) chlorine. Chlorine is introduced for 4 hours; this produces a solution from which, in the further course of the reaction, the orange-yellow product is precipitated, which is sucked off, washed with water and dried at vacuum at 40 ° C.

Yield: 0.85 g

Example 5 (Pt (IV) complex)

Dihydroxy-lactato- (1,2-bis (aminomethyl) cyclobutane [-platinum (IV) /

\

Dissolve 0,5 g of lactato-1,2-bis (aminomethyl) cyclobutane] -platinum (II) in 10 ml of water at 70 ° C and mix with 5 ml of H ₂ O ₂ solution (35%). After stirring at 70 ° C (pH 5) for 4 hours, it was allowed to cool overnight. The excess H ₂ O ₂ decomposes with platinum on activated charcoal, the activated charcoal is sucked off and the filtrate is concentrated to dryness.

Yield: 200 mg of yellow powder.

-21Preparations for pharmaceutical preparations

Example for capsules kg of lactate complex according to Example 1 a, 625 g of microcrystalline cellulose and 11 g of highly dispersed silica are sieved through a sieve with apertures of 0.8 mm and homogenized. 39 g of magnesium stearate (sieved to 0.8 mm) are then added to this mixture and stirred once more for one minute.

For capsule production, the capsule mixture, in a known manner, is filled into a 00 hard capsule-making machine of hard gelatin. The amount of charge per capsule is 670 mg, which corresponds to 400 mg of the active substance.

Primer for lyophilisate

Dissolve 20 ml of lactate complex in 900 ml of water for injection according to Example 1a. The solution is then filled up to 1 liter with water for injection.

This solution is sterile filtered under aseptic conditions through a 0.22 pm pore size membrane filter and filled with 2 ml into 10 ml injection bottles. The bottles are hydrolytic grade

I. The contents of the stoppers fitted with bottles are frozen and dried (lyophilized) in a suitable device. After drying, sterile, dry nitrogen is sucked in and the bottles are closed in the device. Secure the stoppers with a cap to prevent the bottles from opening. For intravenous use, the lyophilisate is dissolved in 4 ml of water for injection for injection purposes.

The injection bottle contains 40 mg of the compound according to Example 1a, 1 ml of solution contains 10 mg of the active substance. \

Claims (4)

PATENT APPLICATIONS 1.1, 2-bis (aminomethyl) cyclobutane platinum complexes of the general formula ah in which the residues R _r R ₂ , R ₃ , R ₄ , R _s and R ₆ are the same or different and represent hydrogen, C ₁ -O ₆ -alkyl, phenyl , phenyl-C ₁ -C ₆ -alkyl, halogen-substituted C ₁ -C ₆ -alkyl, hydroxyl, C ₂ -C ₆ -alkanoyloxy, or a C ₁ -C ₆ -alkoxy group, phenyl substituted with halogen, with hydroxyl, with C ₂ -C ₆ -alkanoyloxy, or with a C ₁ -C ₆ -alkoxy group, or phenyl-C 1 -C 6 -alkyl substituted by halogen in the phenyl moiety, with hydroxyl, with C ₂ -C _6- alkanoyloxy, or a C 1 -C 8 alkoxy group, and X represents the equivalent of a physiologically acceptable anion, or X may be a water molecule, in which case the existing positive charge of the platinum atom is also neutralized by some physiologically acceptable anion, and their salts. -232. Process for the production of 1,2-bis (amionomethyl) cyclobutane-platinum (II) complexes of the general formula i g n n i \ 5 Pt I 'in which the residues R _{1 (} R ₂ , R _3> R ₄ , R ₅ and R ₆ are the same or different and represent hydrogen, C ₁ -C ₆ -alkyl, phenyl, phenyl-C 1 -C 8 -alkyl, C ₁ - C ₆ -alkyl, which is substituted by halogen, hydroxyl, C ₂ -C ₆ alkanoyloxy, or by CfCg alkoxy group, phenyl, which is substituted by halogen, hydroxyl, C ₂ -C ₆ alkanoyloxy, or a C ₁ -C ₆ alkoxy group, or a phenyl-C ₁ -C ₆ alkyl which is substituted by halogen in the phenyl moiety, by hydroxyl, by a C ₂ -C ₆ alkanoyloxy, or by a C ₁ -C ₆ alkoxy group, and represents X the equivalent of some physiologically acceptable anion, or X may also represent a water molecule, in which case the existing positive charge of the platinum atom is also neutralized by some physiologically acceptable anion, and, if necessary, their salts, characterized in that tetrahalogen-platinum (11l) acid, tetrhalogen-platinum (II) complex salt with two monovalent or one divalent cation, or platinum (II) -halogen reacts with a compound of the formula CH ₂ - NHR ₅ ch ₂ - NHR ₀ Ii -24or the salt of compound II with a physiologically acceptable counter ion, or with a salt of the addition acids of compound II, wherein the residues R, R ₆ have the meanings indicated and, if necessary, in the resulting compound of formula oziroma, residue X or residues X are replaced by others physiologically acceptable anions and / or, where appropriate, the compounds obtained are converted into salts with physiologically acceptable anions, or cations. 3. A process for the production of 1,2-bis (aminomethyl) -cyclobutane-platinum (1 /) complexes of the general formula wherein the residues R _p R ₂ , R ₃ , R ₄ , R _s , and R ₆ are the same, or different and represent hydrogen, Cl-Cs-alkyl, phenyl, phenyl-C-Cs-alkyl, CR-Cs-alkyl, which is substituted by halogen, hydroxyl, C ₂ -C ₆ alkanoyloxy, or alkoxy CfCg a group halogen-substituted phenyl, hydroxyl, C ₂ -C ₆ alkanoyloxy, or a C ₁ -C ₆ alkoxy group, or phenyl-C ₁ -C ₆ -alkyl substituted in the phenyl moiety , with hydroxyl, with C ₂ -C ₆ -alkanoyloxy, or with a C ₁ -C ₆ alkoxy group, and X represents the equivalent of a physiologically acceptable anion, or X may also represent a water molecule, in which case the existing positive charge of the platinum atom is also saturated with to certain physiologically acceptable anions, as well as their salts, if necessary, characterized in that the compound of the platinum complex of formula l ^z , in which the residues R ₁ to R ₆ as well as X have the meanings indicated, is oxidized by the pathway are present in the presence of a compound HX and, if necessary, in the reaction product thus obtained, one or more residues X is replaced by other physiologically acceptable anions and / or, if necessary, the compounds obtained are converted into salts with physiologically acceptable anions, or cations. A process for the manufacture of a medicament, characterized in that the compound of general formula I ⁷ or l is treated with conventional pharmaceutical carriers, or diluents or other excipients, in pharmaceutical formulations or in some therapeutically useful form. '