Platinum complexes

Abstract

Platinum complexes of formula Ia or Ib where each A, is a leaving group and may be the same or different, which is suitably halo, especially chloro, hydroxy, carboxylate or together form a bi-dentate carboxylate or sulphate, each B, which may be the same or different, is halo, hydroxy, carboxylate, carbamate or carbonate ester, Z is a substituted amine wherein the substituent sterically hinders access of the Pt atom to a DNA strand of a tumour cell, and X is NH 3 or mono- or di-alkyl substituted NH 3 , are active against cancer cells, and appear to show a unique form of chemical and biological action.

1. A cis-platinum complex of general formula Ia or Ib 
                 
 
       where each A, is a leaving group and may be the same or different, or together form a bi-dentate carboxylate or sulphate, each B, which may be the same or different, is halo, hydroxy, carboxylate, carbamate or carbonate ester,
 Z is a substituted unsaturated cyclic amine coordinated to Pt through the amine nitrogen atom which amine may contain one or more other heteroatoms, wherein the amine is substituted by lower C 1   -C   4    alkyl or alkoxy adjacent to the amine nitrogen atom,  wherein the substituent sterically hinders access of the Pt atom to a DNA strand of a tumour ceil  cell, and  
 X is NH 3  or mono- or di-alkyl substituted NH 3  .  
 
     
     
       2. A complex according to  claim 1 , wherein Z is a 5- or 6- membered monocyclic or a 8 to 10-membered polycyclic tertiary amine. 
     
     
       3. A complex according to  claim 1 , wherein Z is a substituted pyridine or a bicyclic amine where the amine is coordinated through the nitrogen atom of a pyridine ring. 
     
     
       4. A complex according to  claim 1 , wherein Z is a pyridine substituted by lower alkyl or alkoxy  methyl in the 2 position. 
     
     
       5. A complex according to  claim 4 , wherein each A is halo, hydroxy, carboxylate or together form bi-dentate carboxylate or sulphate  chloro. 
     
     
       6. A cis-platinum complex selected from the group consisting of
 (SP-4-3)-amminedichloro(2-methylpyridine) platinum (II); (SP-4-3)-amminedichloro(2-ethylpyridine) platinum(II); (SP-4-3)-amminedichloro(2 -methyl-quinoline) platinum(II); (SP-4-3)-amminedichloro(2,4-dimethylpyridine) platinum(II); (SP -4-3)-ammine-dichloro(2-isopropylpyridine) platinum(II); (SP-4-3)-ammine-dichloro(2,6-dimethylpyridine) platinum(II); (OC-6-43)-amminedichlorodihydroxo-(2,4-dimethylpyridine) platinum(IV); (OC-6-43)-aminebisbutyratodichloro(2,4-dimethylpyridine) platinum(IV); and ammine(cyclobutane-1,1-dicarboxylato) (2,4-dimethylpyridine) platinum (II).  
 
     
     
       7. A pharmaceutical composition comprising as active ingredient a complex according to claim  1    5 , in admixture with a pharmaceutically acceptable diluent or carrier and optionally one or more other therapeutic agents. 
     
     
       8. A composition according to  claim 7 , in unit dosage form. 
     
     
       9. A composition according to  claim 7  or  8  for oral administration. 
     
     
       10. A method of treating cancer compsiring  comprising administering to a patient in need thereof a pharmaceutically effective amount of a complex according to claim  1    5 . 
     
     
       11. The cis- platinum complex of    claim 6   , that is  ( SP -   4   -   3   ) amminedichloro (   2   - methylpyridine ) platinum  ( II ). 
     
     
       12. A pharmaceutical composition comprising the complex according to  claim 11 , in admixture with a pharmaceutically acceptable diluent or carrier and optionally one or more other therapeutic agents. 
     
     
       13. The composition according to  claim 12 , in unit dosage form. 
     
     
       14. The composition according to  claim 12  or  13 , adapted for oral administration. 
     
     
       15. A method of treating cancer comprising administering to a patient in need thereof a pharmaceutically effective amount of the complex of  claim 11 .