A PROCESS FOR PREPARING PLATINUM-(II)-CIS-DICHLOROBIS-(TRISHYDROXYMETHYLPHOSPHINE)

Abstract: The invention relates to a process for preparing Platinum(II) cis-dichlorobis(trishydroxymethyl­ phosphine) having the formula (I): and to pharmaceutical compositions containing the compound (I). This compound is useful for treating tumor diseases.

Description: The present invention relates to a process for preparing Platinum(II) cis-dichlorobis(trishydroxymethylphosphine) of formula (I): and to pharmaceutical compositions containing this compound. The compound of this invention, Platinum(II) cis-dichlorobis(trishydroxymethylphosphine), is used as an intermediate in the preparation of the antitumor compounds disclosed in European Patent Application No. 86112285.1. In addition, applicants have found out that the aforesaid intermediate has a significant antitumor activity. The compound of this invention has already been described by J. Chatt et al (J.Chem.Soc.-Dalton-, 2021-8,1973) who prepared it by reacting potassium chloroplatinite with tris(hydroxymethyl)phosphine. However, these authors did not mention any antitumor activity for the compound. Applicants have found out that the preparation of Platinum(II) cis-dichlorobis(trishydroxymethylphosphine) can be carried out in a different way from that known so far, which consists in reacting platinum(II) dichloro (1,5-cyclooctadiene) with tris(hydroxymethyl)phosphine in a medium comprising a solvent selected from low molecular weight alkanols having 1 to 6 carbon atoms or their mixtures; methanol and ethanol or their mixtures are preferred. Applicants have found out that when methanol and ethanol ratios range from 1: 0.8 to 1: 1.2 respectively, the reaction occurs suitably to give a better yield. This finding as well as the fact that the aforesaid compound has surprisingly proved to be an active antitumor compound account for the main purpose of the present invention. Moreover, the present invention provides a process described in such detailed terms as to enable any person skilled in the art to make and use the same, while the process by J. Chatt et al is not described experimentally and, consequently, it is difficult to be reproduced both on a small scale and on a large scale. A practical way to determine the toxicity and activity on DNA in the screening for potential anti-tumor agents consists in testing selected compounds against bacterial cells. Thus, the toxicity, effect on bacterial DNA and SOS induction ability of the compound of the invention was tested against E.coli and showed an unmistakable anti-tumor activity. Escherichia coli K12 strains in LB culture medium grown at 37°C with aeration were used (J.H. Miller: Experiments in Molecular Genetics. Cold Spring Harbor Laboratory, New York, 1972). Culture aliquots of AB1157 and AB2463 E.coli were poured onto tubes containing different doses of compound (I). Two hours after incubation at 37°C with aeration, the specimens were placed on LB medium in the presence of streptomycin (75 µg/ml). Under these experimental conditions, compound (I) resulted more active than carboplatin. In addition, the toxicity increased when the bacterial strains were RecA which makes evident the participation of the SOS system in the restoration of the lesion produced by compound (I). Therefore, Platinum(II) cis-dichlorobis(trishydroxymethylphosphine) is useful as a medication in the treatment of tumors and may be administered, mixed with suitable carriers, orally in the form of tablets, capsules, coated-tablets, granules, syrup, solution, etc., or by injection at daily doses ranging from 10 to 600 mg/m². An example will now be described in non-limitative manner to illustrate the invention. Example 1 Platinum(II) cis-dichlorobis(trishydroxymethylphosphine) (I) 2.5 g (6.0 mmole) of potassium tetrachloroplatinite (K₂PtCl₄) are dissolved in 40 ml of water and filtered off. To the red filtrate, 60 ml of glacial acetic acid and 2.5 ml (20 mmole) of 1,5-cyclooctadiene are added. The mixture is immediately stirred and heated at nearly 90°C in a water bath. After 30 minutes approximately, the red solution slowly becomes light yellow and fine crystals are formed. The solution volume is reduced to about 30 ml by evaporation under reduced pressure. Light yellow needles are collected and washed successively with 50 ml of water, ethanol and ether. After drying for 1 hour at 100°C, 2.16 g of platinum(II) dichloro (1,5-cyclooctadiene) are obtained which decomposes without melting between 250 and 280°C. 4.60 g (12.29 mmole) of platinum(II) dichloro(1,5-cyclooctadiene) in 100 ml of ethanol are stirred and added to 3.92 g (31.59 mmole) of 95% tris(hydroxymethyl)phosphine dissolved in 200 ml of ethanol:methanol (1: 3) under nitrogen atmosphere. The mixture is stirred until all solids have dissolved, filtered off and concentrated to dryness, then washed with carbon tetrachloride. Finally, the mixture is treated with absolute ethanol to remove any reacted phosphine residue. 3.5 g of Platinum(II) cis-dichlorobis(trishydroxymethylphosphine) are obtained. Yield: 55%. Melting point: 122-126°C. IR Spectrum (KBr), cm⁻¹: 3500-3000, 1360, 1020. NMR Spectrum (D₂O) δ: 4.39 (t) J= 24.41Hz.

Claims: 1. A process for preparing Platinum(II) cis-dichlorobis (trishydroxymethylphosphine) having the formula (I): characterized in that platinum(II) dichloro(1,5-cyclooctadiene) is reacted with tris(hydroxymethyl) phosphine in a medium comprising a solvent selected from low molecular weight alkanols having 1 to 6 carbon atoms or their mixtures. 2. A process as claimed in Claim 1, wherein said low molecular weight alkanols are mixtures of methanol and ethanol in a ratio of 1: 0.8 to 1: 1.2. 3. Pharmaceutical compositions comprising the compound of Claim 1, optionally together with pharmaceutical carriers and/or adjuvants. 4. The use of the compound of Claim 1 for the preparation of pharmaceutical compositions for treating tumor diseases. 5. The compound of formula I for pharmaceutical use.

Inventors: BONAL, JOAQUIN, CASTELLO, JOSEP M., CAYUELA, SALVADOR, DE ANDRES, LUIS, FOGUET, RAFAEL, ORTIZ, JOSE A., SAMPEDRO, FEDERICO, Castelló, Josep M., de Andrés, Luis, Ortiz, José A.
Applicants: FERRER INTERNACIONAL, S.A.
Application year: 1986
Main classification: C07F15
IPC codes: C07F15