Platinum coordination compounds

Abstract: Platinum IV coordination compounds of general formula I, where A is chlorine or hydroxyl and A is an alkylamine, other than cyclohexylamine when X is chlorine, have activity against tumour cells, and some show activity against cisplatin and tetraplatin resistant cells.

Description: This invention concerns platinum coordination compounds indicated for chemotherapeutic use. More especially, it concerns platinum (IV) coordination compounds. Certain platinum coordination compounds have become accepted for chemotherapeutic use against a variety of tumours. The best-known compound is "cisplatin", cis-diammine-dichloro-platinum (II), which has activity against a broad spectrum of tumours. The toxicity of cisplatin, however, leads to unpleasant side-effects or possibly the rejection by the patient of chemotherapy. A further platinum (II) compound, carboplatin, has recently been introduced, and which exhibits considerably less toxicity. There remains, however, a need for chemotherapeutic agents which are of relatively low toxicity and/or are active against tumours which are unaffected by or resistant to existing platinum chemotherapeutic agents. CH-A 633961 and related GB-A 1,585,103 disclose Pt(IV) coordination compounds of a broad class, and the disclosures thereof are incorporated herein by reference. In these specifications, bis-n-alkylamine Pt(IV) compounds alone were exemplified and the preparative method disclosed was only suitable for the preparation of bis-alkylamine compounds. USP 4,329,299, discloses mixed amine Pt (II) and Pt (IV) compounds as chemotherapeutic agents. Only Pt (II) compounds were exemplified and tested. European Specification EP 0 147 926A is directed to the use of platinum (II) and (IV) compounds for oral treatment; only one Pt (IV) compound is mentioned cis-amminetetrachloro (cyclohexylamine)-platinum(IV) which was stated to be known per se . We have now discovered that certain platinum (IV) coordination compounds have unexpected activity in in vitro cytotoxicity tests, especially against cisplatin-resistant and Tetraplatin-resistant tumour cells, which indicates potential clinical utility. Accordingly, the present invention provides a platinum (IV) coordination compound of the general formula I, in which X is a chlorine atom or hydroxyl group, and A is an amine of the general formula R-NH₂ wherein R is a straight chain alkyl of 2 or 3 carbon atoms, alicyclic of 3 to 7 carbon atoms, or branched chain alkyl of 3 or 4 carbon atoms, provided that where X is a chlorine atom R is not cyclohexyl. Preferred compounds are those of formula Ia, in which Y is an amine of the formula R'-NH₂ wherein R' is branched chain alkyl of 3 or 4 carbon atoms or alicyclic of 3 to 5 or 7 carbon atoms. Other preferred compounds are those of formula Ib, in which Z is an amine of the formula R''-NH₂ wherein R'' is branched chain alkyl of 3 or 4 carbon atoms or alicyclic of 3 to 7 carbon atoms. Especially preferred compounds are those of formula Ia or Ib wherein R' or R'' respectively are alicyclic or isopropyl. The compounds of formula I, Ia and Ib are believed to be novel, although falling within prior generic disclosures. They may suitably be prepared from the initial starting material potassium amminetrichloroplatinate (II). The invention provides a method for the preparation of compounds of the formula I, comprising (a) reacting a platinum (II) complex of the general formula II, in which A is as defined above, with chlorine to form a compound of formula I as defined above but in which X is a chlorine atom, and (b) where a compound of formula I in which X is a hydroxyl group is desired, treating the dichloro compound of formula II with hydrogen peroxide. The compound of formula II may be prepared by converting the starting material K[PtCl₃(NH₃)] into the appropriate alkylamine ammine diiodo complex by solution in water, and adding potassium iodide and the appropriate alkylamine. The diiodo complex is then treated with silver nitrate and stirred for 2 hours in the dark, charcoal is added and the mixture filtered. The filtrate is tested for free silver ion and, if necessary, sodium chloride solution added until silver ion cannot be detected. The filtrate is then added to excess concentrated hydrochloric acid and stirred, and the compound of formula II is collected by filtration. Step (a) of the method may be suitably carried out by suspending the compound of formula II in water, and passing chlorine gas through the suspension, conveniently for 1 hour at a reaction temperature of 60°C. The reaction mixture may then be boiled to remove excess chlorine, and cooled, and the tetrachloro complex collected by filtration, washed and dried in vacuo . Step (b) of the method may be suitably carried out by suspending the dichloro complex of formula II in water, adding hydrogen peroxide, eg 30% w/v, and stirring, conveniently at 60°C for two hours. After cooling, the product may be collected by filtration, washed with water and recrystallised from water. The present invention further provides a pharmaceutical composition comprising a compound of formula I, Ia or Ib, in association with a pharmaceutically acceptable diluent or carrier. The invention additionally provides a pharmaceutical composition in unit dosage form, comprising an effective unit dose of a compound of formula I, Ia or Ib, in association with a pharmaceutically acceptable carrier or diluent. Preferred unit doses may be in the range 10mg to 1g of active compound. If desired, other pharmaceutically active compounds may be combined with the compound of formula I, Ia or Ib. Pharmaceutical compositions and unit doses may be prepared by methods and in forms generally known in the pharmaceutical art. Suitable carriers or diluents are well known, and additional components such as binders, excipients, lubricants, flavouring agents etc may be used depending on the desired dosage form, eg tablets, capsules, syrups or suspensions for oral administration, or solutions for intra-peritoneal administration. The invention will now be described by way of example only. A selection of compounds according to the invention were prepared by the above-described method, and were characterised by elemental analysis and infra red spectroscopy. The compounds were compared against known compounds and against each other for activity against the ADJ/PC6 tumour in mice, when given by the intraperitoneal route and the results are tabulated below. Several of the compounds according to the invention were also tested in vitro for activity against L1210 leukaemia cell lines and against L1210 cell lines which had been bred to be resistant to cisplatin and Tetraplatin. The results are tabulated below: The IC₅₀ values are defined as the concentration of each compound required to reduce cell counts to 50% of control values after 48 hours continuous exposure. It can readily be seen that the hydroxy components according to the invention are surprisingly effective against cells which are resistant to treatment by other platinum coordination compounds. In addition the following compound has been prepared and characterised: PtCl₄(NH₃)(c-C₃H₅ NH₂)

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A platinum (IV) coordination compound of the general formula I, in which X is a chlorine atom or hydroxyl group, and A is an amine of the general formula R-NH₂ wherein R is straight chain alkyl of 2 or 3 carbon atoms, alicyclic of 3 to 7 carbon atoms or branched chain alkyl of 3 or 4 carbon atoms, provided that where X is a chlorine atom R is not cyclohexyl. A compound according to claim 1, wherein X is chlorine and A is a branched chain alkylamine of 3 or 4 carbon atoms or an alicyclic amine of 3 to 5 or 7 carbon atoms. A compound according to claim 1, wherein X is hydroxyl and A is a branched chain alkylamine of 3 or 4 carbon atoms or an alicyclic amine of 3 to 7 carbon atoms. A pharmaceutical composition comprising a platinum compound according to any one of claims 1 to 3, in association with a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition comprising a platinum compound according to any one of claims 1 to 3, in unit dosage form, comprising an effective unit dose of the platinum compound in association with a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition according to claim 4, for the treatment of tumours resistant to treatment by platinum coordination compounds of different structure. A process for the production of a compound according to any one of claims 1 to 3, comprising (a) reacting a platinum (II) complex of the general formula II, in which A is as defined in claim 1, with chlorine to form a compound of formula I as defined in claim 1 but in which X is a chlorine atom, and (b) where a compound of formula I in which X is a hydroxyl group is desired, treating the dichloro compound of formula II with hydrogen peroxide. Claims for the following Contracting State : ES A process for the production of a platinum (IV) coordination compound of the general formula I, in which X is a chlorine atom or hydroxyl group, and A is an amine of the general formula R-NH₂ wherein R is a straight chain alkyl of 2 or 3 carbon atoms, alicyclic of 3 to 7 carbon atoms or branched chain alkyl of 3 or 4 carbon atoms, provided that where X is a chlorine atom R is not cyclohexyl, the process comprising reacting a platinum (II) complex of the general formula II, in which A is as defined above, either with chlorine to form a compound of formula I in which X is a chlorine atom, or with hydrogen peroxide to form a compound of formula I in which X is a hydroxyl group. A process according to Claim 1 in which the complex (II) is reacted with chlorine, wherein A is a branched chain alkylamine of 3 or 4 carbon atoms or an alicyclic amine of 3 to 5 or 7 carbon atoms. A process according to Claim 1 in which the complex (II) is reacted with hydrogen peroxide, wherein A is a branched chain alkylamine of 3 or 4 carbon atoms or an alicyclic amine of 3 to 7 carbon atoms. A process according to Claim 1 or Claim 2, in which the complex (II) is suspended in water and chlorine gas is passed through the suspension, the reaction mixture boiled if necessary to remove excess chlorine, and the tetrachloro complex is collected by filtration. A process according to Claim 1 or Claim 3, in which the complex (II) is suspended in water, hydrogen peroxide solution is added to the suspension with stirring and the product is collected by filtration. A process according to any preceding claim, in which the complex (II) is prepared by converting K[PtCl₃(NH₃] into the appropriate alkylamine ammine diiodo complex by dissolution in water and addition of potassium iodide and the appropriate alkylamine, treating the diiodo complex with silver nitrate and adding excess concentrated hydrochloric acid. A process for the preparation of a pharmaceutical composition, the process comprising addition of a compound of formula (I) as defined in Claim 1 when prepared by a process according to any preceding claim to a pharmaceutically acceptable carrier or diluent. Claims for the following Contracting State : GR A platinum (IV) coordination compound of the general formula I, in which X is a chlorine atom or hydroxyl group, and A is an amine of the general formula R-NH₂ wherein R is straight chain alkyl of 2 or 3 carbon atoms, alicyclic of 3 to 7 carbon atoms or branched chain alkyl of 3 or 4 carbon atoms, provided that where X is a chlorine atom R is not cyclohexyl. A compound according to claim 1, wherein X is chlorine and A is a branched chain alkylamine of 3 or 4 carbon atoms or an alicyclic amine of 3 to 5 or 7 carbon atoms. A compound according to claim 1, wherein X is hydroxyl and A is a branched chain alkylamine of 3 or 4 carbon atoms or an alicyclic amine of 3 to 7 carbon atoms. A process for the production of a compound according to any one of Claims 1 to 3, comprising reacting a platinum (II) complex of the general formula II, in which A is defined in Claim 1, either with chlorine to form a compound of formula I as defined in Claim 1 in which X is a chlorine atom, or with hydrogen peroxide to form a compound of formula I in which X is a hydroxyl group. A process according to Claim 4, in which the complex (II) is suspended in water and chlorine gas is passed through the suspension, the reaction mixture boiled if necessary to remove excess chlorine, and the tetrachloro complex is collected by filtration. A process according to Claim 4, in which the complex (II) is suspended in water, hydrogen peroxide solution is added to the suspension with stirring and the product is collected by filtration. A process according to any preceding claim, in which the complex (II) is prepared by converting K[PtCl₃(NH₃] into the appropriate alkylamine ammine diiodo complex by dissolution in water and addition of potassium iodide and the appropriate alkylamine, treating the diiodo complex with silver nitrate and adding excess concentrated hydrochloric acid. A process for the preparation of a pharmaceutical composition, the process comprising addition of a compound of formula (I) as defined in Claim 1 to a pharmaceutically acceptable carrier or diluent.

Inventors: BARNARD CHRISTOPHER FRANCIS JA, HYDES PAUL CEDRIC, BARNARD, CHRISTOPHER FRANCIS JAMES, HYDES, PAUL CEDRIC
Applicants: JOHNSON MATTHEY PLC, JOHNSON MATTHEY PUBLIC LIMITED COMPANY
Application year: 1989
Main classification: C07F15
IPC codes: C07F15, A61K33, A61K31, C07C211, A61P35