CS273503B1 - Medicament with anticarcinomatous effect that contains platinum and method of active component production - Google Patents

Abstract

A medicament with anticancer effect that contains an atom of bivalent platinum consisting of an anion ligand made of organic hydroxy acid with at least one hydroxyl, whereas the platinum atom bound to the carboxyl oxygen atom and hydroxyl oxygen atom is part of a five or six member closed ring of general formula I or II, where at least one of the residues R contains ionogenic carboxyl and the others represent hydrogen, carboxyl, hydroxyl, alkyl, hydroxyalkyl or carboxyalkyl, whereas alkyl is formed by a chain with 1 to 6 carbon atoms in a row, and aminoligand A bound by coordination to the platinum atom, which is represented by two molecular monoamines from the group of ammoniac, alkyl amine, where alkyl is formed by a linear or branched chain containing l to 6 carbon atoms or cycloalkyl amine, where cycloalkyl is formed by 4 to 7 carbon atoms or diamine, whose carbon chain has a linear or branched structure containing 1 to 6 carbon atoms or 1,2-diamino-cycloalkylene, where cycloalkyl is formed by a ring structure containing 4 to 7 carbon atoms or diamine of general formula III, where R is cycloalkylene with 4 to 7 carbon atoms and m=0.1 or 2 a n=1 or 2 and various methods of their preparation.<IMAGE>

Description

OBROVSKY JAROSLAV ing.,

ŠTĚPÁNKOVÁ HELENA ing. CSc., PRAGUE (54)

(57) An anticancer drug containing a divalent platinum atom consists of an anionic ligand consisting of an organic hydroxy acid having at least one hydroxyl, the platinum atom being bound to the carboxyl oxygen atom and the hydroxyl oxygen atom. thus forming part of a five-membered or six-membered closed ring of formula I or II, wherein at least one of the radicals R contains an ionizable carboxyl group and the others represent hydrogen, carboxyl, hydroxyl, alkyl, hydroxyalkyl or carboxyalkyl, the alkyl being a chain of 1-6 carbon atoms; and an aminoligand A coordinated to a platinum atom, which is represented by two monoamine molecules from the group ammonia, an alkylamine wherein the alkyl is a linear or branched chain containing from 1 to 6 carbon atoms or a cycloalkylamine wherein the cycloalkyl is en having 4 to 7 carbon atoms or a diamine having a carbon chain having a linear or branched structure having 1 to 6 carbon atoms or 1,2-diaminocycloalkylene, wherein the cycloalkyl is a ring structure having 4 to 7 carbon atoms or a diamine of formula III, is cycloalkylene having a carbon number of 4 to 7 and m = 0, 1 or 2 and 1 or 2 and various methods for its preparation.

( ¹¹ ), (13) Bl (51) Int. Cl? C 07 P 15/00 // A 61 K 33/24

(and)

/ V (II)

-NI (CH.) - ™.,

CS 273503 Bl

The present invention relates to a medicament having an anti-cancer effect comprising a platinum atom and a process for the preparation of the active ingredient.

The simple inorganic compound cis-diamminedichloroplatium complex (generic name claplatin) has proven itself in practice in the treatment of various types of malingites. However, like any cytostatic, it has some side effects such as nephrotoxicity, nausea induction and vomiting, damage to hematopoiesis and some parts of the nervous system. Therefore, intensive research is ongoing in the field of analogous complexes of divalent and tetravalent platinum. Complexes in which the ammonia molecules are replaced by alkylamines with larger and hydrophobic alkyls are particularly promising. Due to this hydrophobicity, however, the solubility of these complexes in water decreases, which is a serious obstacle to practical use. There is therefore an attempt to increase solubility by a second, so-called leaving ligand, which is of an anionic nature. Therefore, a complex where the outgoing ligand is trimellitic acid is tested in the clinic. This tricarboxylic acid has two platinum-bonded carboxylates, while the third is ionized at physiological pH and provides acceptable solubility with such a hydrophobic aminoligand as 1,2-diaminocyclohexane (DACH). The disadvantage of this complex is its low stability.

The present inventors have now found that effective acceptable soluble complexes containing a hydrophobic aminoligand, for example 1,2-diaminocyclohexane (DACH), can be prepared by using a hydroxy acid containing at least two carboxyls and at least one hydroxyl, sterically arranged such that the atom Platinum may form a five- or six-membered ring with one carboxyl and one hydroxyl, with unoccupied carboxyl or carboxyls providing good solubility at physiological pH values.

The present invention provides an anticancer drug containing a divalent platinum atom, comprising an anionic ligand which is formed by an organic acid having at least two carboxyls and at least one hydroxyl per molecule, wherein the platinum atom is bound to a carboxyl oxygen atom and a hydroxyl oxygen atom it is thus part of a five or six-membered closed ring of formula (I) or (II)

wherein at least one of the radicals R contains an ionizable carboxyl and the others represent hydrogen, carboxyl, hydroxyl, alkyl, hydroxyalkyl or carboxyalkyl, wherein the alkyl is a chain of 1 to 6 carbon atoms in series, and an aminoligand A coordinated to a platinum atom which is represented by two monoamine molecules from the group of ammonia, an alkylamine wherein the alkyl is a linear or branched chain having 1 to 6 carbon atoms or a cycloalkylamine wherein the cycloalkyl is 4 to 7 carbon atoms or a diamine whose carbon chain has a linear or branched structure containing 1 to 6 carbon atoms; 6-carbon atoms or 1,2-diaminocycloalkyl, wherein the cycloalkyl is a ring structure containing 4 to 7 carbon atoms or a diamine of formula III

-NH ₂

R (CH ₂ ) _n -NH ₂ (III)

Wherein R is a cycloalkylene having a carbon number of 4 to 7 and m and 0.1 or 2 and n and 1 or 2.

Method of preparing a complex of the invention consists in that the aquo-complex of bivalent platinum bound amino ligand A in the cis-position of Formula IV ^ p _t 2+ χΐ jXH «2 ° (IV) wherein A is as defined above, for pH 2 to 7, preferably 4.5 to 5.5, is contacted with the appropriate hydroxy acid or polyhydroxy diacid or hydroxypolyacid having a carbon number of 2 to 10 and allowed to react at 10 to 80 ° C with optional pH control for a period of time 12 to 72 hours, then the product is stabilized by adding an excess of the acid used, up to 100% equivalent, and allowed to crystallize or lyophilize. In the latter case, a better soluble product is obtained. Crystallization is necessary if the aquo-complex solution contains undesirable impurities such as nitrates and must be repeated several times in this case. Therefore, it is preferable to start with aquo complexes prepared by a method other than the hydrolysis of nitrates, for example by means of ion exchangers.

Complexes can also be prepared by reacting a divalent platinum halide complex with an aminoligand A in the cis position of formula V (V), wherein X is chlorine, bromine or iodine and A is as defined above, reacted in the dark for 12 to 72 hours. temperature of 10 to 80 ° C with two equivalents of silver ions in the form of a silver salt of the corresponding hydroxy acid or polyhydroxy acid or hydroxypolyacid having a carbon number of 2 to 10 or in the form of a mixture of this salt with the appropriate acid or alkali metal salt thereof platinum comprises 1 to 2, preferably 1.05 to 1.1, acid molecules and then the product is purified by crystallization until the reaction to silver disappears.

The complexes of the invention can also be prepared by _: contacting the halogen complex of formula (V) with wet silver oxide, colloidal or fixed on a solid particle to obtain a solution of the hydroxy-complex of formula (VII)

A OH

XiPt (VII)

A ^x OH where A is as defined above. Since this solution is not very stable, a solution of the appropriate hydroxy acid or polyhydroxy acid or hydroxypolyacid having a number of atoms in the chain of 2 to 10 should be added at the same time as the complex IV or as soon as possible to achieve a final pH of 2 to 7. , 05 to 2 molecules per platinum atom. It is allowed to react in the dark at a temperature of 10 to 80 ° C for 12 to 72 hours, filtered, concentrated, again allowed to stand as necessary and repeatedly filtered.

Finally, the filtrate is lyophilized.

ii &

«Tí.

CS 273503 Bl

The following examples illustrate the invention without limiting it.

Claims (2)

Example 1 3.49 g (9.2 mM) of 1,2-trans-diaminocyclohexane dichloroplatinate complex was suspended in 50 ml of an aqueous solution of 2.88 g (17 mM) of silver nitrate. It is then allowed to react in the dark at room temperature for 24 hours with stirring. The solution is then filtered and lyophilized; 3.68 g (8.5 mM) of the lyophilized product, the dinitrate complex, is dissolved in 20 ml of an aqueous solution containing 1.79 g (110% equiv., 9.35 mM) of citric acid and adjusted to pH 5.0 with sodium hydroxide. The reaction mixture was concentrated for 48 hours, concentrated and crystallized by addition of 100 ml of methanol. The product is dissolved in a minimum amount of water and crystallized again. The product thus prepared is a 1,2-trans-diaminecyclohexane citrate platinum (II) complex stabilized with an approximately 5% excess of citric acid which, according to the kinetics of the ligand exchange reactions, is a mixture of structures VIIIa and VIIIb or their salts (depending on the reaction of the solution). 0b3ah% Theory Found coo C H N Pt ———— 25.62 3.23 4.98 34.68 —---—— ——— ———— 25.25 3.78 4.81 34.23 8,17 nost. (Willow) (VlIIb) Example 2 A solution of the 1,2-trans-diaminooyclohexane-dinitratoplatinum (II) complex was prepared as in Example 1. After filtration, it was poured over an ion exchange column in the OH phase. The effluent was directly introduced into an aqueous solution of 1.79 g citric acid. Allow to stand at room temperature for 48 hours and lyophilize the solution. Again, the product is complex VIII, stabilized at ca. 10% excess citric acid (82% yield on platinum loaded). CS 273503 Bl Content% C Η N Pt Theory 27.79 3.89 5.40 37.62 Found 27.05 4.09 5> 08 Example 3 0.847 g of a silver salt of glucaric acid (sugar) and 50 mg of potassium hydrogen glucan are suspended in 60 ml of water. Add 0.761 g of 1,2-trans-diaminocyclobexanedichloroplatinate complex. Stirred at 45 ° C in the dark for 36 hours. The filtrate was concentrated and crystallized by addition of methanol. The product was recrystallized again. The result is 1,2-trans-diaminocyclohexane-glucaratoplatinum (IX) according to the ligand exchange reactivity of structures (IXa) and (IXb) (IXa) CH • CH „ BOY In (boys) (IXb) CH CH. COO Content % C H N Pt Theory 27.85 4.28. 5.41 37.72 Found 27.04 .4,44 5.21 37.60 Example 4 θ> 847 g of silver glucaric acid salt and 50 mg of potassium hydrogen glucan are suspended in 60 ml of water. 600 mg of cis-diaminodichloroplatinum (II) complex was added and made up to 100 ml with water. Stirred at room temperature for 48 hours. The resulting complex was