Iron-pyridone complexes for anemia

Abstract

Pharmaceutical compositions containing an iron complex of a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group, or by an aliphatic hydrocarbon group substituted by one or, except in the case of ionizable groups, more than one substituent selected from aliphatic acyl, alkoxy, aliphatic amine, aliphatic amide, carboxy, aliphatic ester, halogen, hydroxy and sulpho groups and, optionally, in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by one of said substituents, by an aliphatic hydrocarbon group, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group, but excluding compounds in which said replacement of hydrogen atoms in the compound is effected only by aliphatic hydrocarbon groups, are of value for the treatment of iron deficiency anemia.

We claim: 
     
       1. A method for increasing the level of iron in the blood stream of a patient in need of such treatment which comprises administering to said patient an amount sufficient to elicit such an effect of a ferric iron complex of a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one compound in which the hydrogen atom attached to the nitrogen atom is replaced by an acyclic or cyclic aliphatic carboxylic acid acyl group or by an acyclic or cyclic aliphatic hydrocarbon group which can further be substituted by one or two substituents selected from acyclic or cyclic aliphatic carboxylic acid acyl, acyclic or cyclic alkoxy, acyclic or cyclic aliphatic amido, halo and hydroxy groups, and acyclic or cyclic aliphatic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hydrocarbyloxycarbonyl and hydrocarbyloxysulphonyl moieties, but excluding substitution by two hydroxy groups, and wherein one or more of the hydrogen atoms attached to ring carbon atoms can be replaced by one of said substituents or by an acyclic or cyclic aliphatic hydrocarbon group which can further be substituted by an acyclic or cyclic alkoxy, halo or hydroxy group, or an acyclic or cyclic aliphatic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hydrocarbyloxycarbonyl or hydrocarbyloxysulphonyl moiety, but excluding compounds in which said replacement of hydrogen atoms in the compound is effected only by unsubstituted acyclic or cyclic aliphatic hydrocarbon groups, wherein said compound when metal free has a partition coefficient between n-octanol and 20 mM tris hydrochloride, pH 7.4, of between 0.02 and 3.0 for the ratio (concentration of compound in organic phase)/(concentration of compound in aqueous phase). 
     
     
       2. The method according to claim 1, in which any replacement of a hydrogen atom attached to a ring carbon atom is effected by a C 1-4  acyclic or cyclic aliphatic hydrocarbon group. 
     
     
       3. A neutral 3:1 hydroxypyridone:iron(III) complex of 3-hydroxypyrid-2-one, 3-hydroxypyrid-4-one, 2-methyl-3-hydroxypyrid-4-one, 6-methyl-3-hydroxypyrid-4-one or 2,6-dimethyl-3-hydroxypyrid-4-one with the hydrogen atom attached to the nitrogen atom replaced by an acyclic aliphatic carboxylic acid acyl group --COR 1 , an acyclic aliphatic hydrocarbon group --(CH 2 ) n  -- carrying a terminal substituent group --COR 1 , --COXR 1 , --SO 2  XR 1 , --XCOR 1  or --XSO 2  R 1 , or an acyclic aliphatic hydrocarbon group --(CH 2 ) m  -- carrying a terminal substituent group --OH, wherein R 1  is a C 1-4  acyclic aliphatic hydrocarbon group, X is an oxy or imino group, n is an integer from 1 to 6, and m is an integer from 2 to 6. 
     
     
       4. The method according to claim 1, in which the 3-hydroxypyridone compound is substituted only on the nitrogen atom or is substituted on the nitrogen atom and on one of the ring carbon atoms. .[.5. A pharmaceutical composition comprising: (a) a ferric iron complex of a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one compound in which the hydrogen atom attached to the nitrogen atom is replaced by an acyclic or cyclic aliphatic carboxylic acid acyl group or by an acyclic or cyclic aliphatic hydrocarbon group which can further be substituted by one or two substituents selected from acyclic or cyclic aliphatic carboxylic acid acyl, acyclic or cyclic alkoxy, acyclic or cyclic aliphatic amido, halo and hydroxy groups, and acyclic or cyclic aliphatic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hydrocarbyloxycarbonyl and hydrocarbyloxysulphonyl moieties, but excluding substitution by two hydroxy groups, and wherein one or more of the hydrogen atoms attached to ring carbon atoms can be replaced by one of said substituents or by an acyclic or cyclic aliphatic hydrocarbon group which can be further substituted by an acyclic or cyclic alkoxy, halo or hydroxy group, or an acyclic or cyclic aliphatic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hydrocarbyloxycarbonyl or hydrocarbyloxysulphonyl moiety, but excluding compounds in which said replacement of hydrogen atoms in the compound is effected only by unsubstituted acyclic or cyclic aliphatic hydrocarbon groups and also excluding the compound 3-hydroxy-6-hydroxymethyl-1-methylpyrid-4-one, wherein said compound when metal free has a partition coefficient between n-octanol and 20 mM tris hydrochloride, pH 7.4, of between 0.02 and 3.0 for the ratio (concentration of compound in organic phase)/(concentration of compound in aqueous phase); and   
     
     
       (b) a physiologically acceptable diluent or carrier..].6. The pharmaceutical composition according to claim 5, in which the hydrogen atoms attached to ring carbon atoms either are not replaced or are replaced by an aliphatic hydrocarbon group which is an acyclic alkyl group 
     
     
        of 1 to 4 carbon atoms. 7. The method according to claim 1, in which the 
     
     
        iron complex is the neutral 3:1 hydroxypyridone: iron(III) complex. 8. The pharmaceutical composition according to claim 5, which is adapted for oral administration. .[.9. The pharmaceutical composition according to claim 5, 
     
     
        which additionally contains folic acid..].10. A method for increasing the level of iron in the blood stream of a patient in need of such treatment which comprises administering to said patient an amount sufficient to elicit such an effect of a neutral 3:1 hydroxypyridone:iron(III) complex of a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one compound in which the nitrogen atom is substituted by a C 2-5  acylic or cyclic aliphatic hydrocarbon group substituted by a single substituent selected from C 2-5  acylic or cyclic alkylcarbonyl, C 1-4  acylic or cyclic alkoxy, halo, hydroxy and unsubstituted or C 1-4  acyclic or cyclic alkyl mono- or di-substituted amido groups, and C 1-4  acylic or cyclic alkylcarbonyloxy, alkylsulphonyloxy, alkoxycarbonyl and alkoxysulphonyl moieties and one or more of the ring carbon atoms can further be substituted by a C 1-4  acylic or cyclic aliphatic hydrocarbon group. 
     
     
          . The pharmaceutical composition according to claim 5, in which the iron 
     
     
        complex is in substantially pure form. 12. The pharmaceutical composition according to claim 5, which additionally contains an iron chelating agent selected from the group consisting of (1) 3-hydroxypyrid-2-one and 3-hydroxypyrid-4-one compounds in which the hydrogen atom attached to the nitrogen atom is replaced by an acyclic or cyclic aliphatic hydrocarbon group and in which one or more of the hydrogen atoms attached to ring carbon atoms can be replaced by an acyclic or cyclic aliphatic hydrocarbon group and salts thereof containing a physiologically acceptable cation and (2) 3-hydroxypyrid-2-one and 3-hydroxypyrid-4-one compounds as defined in claim 5 and salts thereof containing a physiologically acceptable cation. 
     
     
         3. The pharmaceutical composition according to claim 12, in which the iron chelating agent is the same hydroxypyridone as in the iron complex, or a salt thereof containing a physiologically acceptable cation in 
     
     
        uncomplexed form. 14. The pharmaceutical composition according to claim 13, in which the molar proportion of uncomplexed hydroxypyridone:iron 
     
     
        complex is from 1:1 to 10:1. 15. A pharmaceutical composition according to claim 5, in which the diluent is water or a medium containing an organic solvent and the composition has the form of a solution, suspension or 
     
     
        emulsion. 16. The pharmaceutical composition according to claim 15, in 
     
     
        which said diluent consists in whole or in part of a glycol. 17. The pharmaceutical composition according to claim 15, in sterile injectable 
     
     
        form. 18. The pharmaceutical composition according to claim 5, in which 
     
     
        the carrier is a physiologically acceptable solid carrier. 19. The pharmaceutical composition according to claim 18 in tablet or capsule 
     
     
        form. 20. The pharmaceutical composition according to claim 5 in delayed 
     
     
        release form. 21. The pharmaceutical composition according to claim 5 which is adapted to release of the iron complex in the intestine rather 
     
     
        than in the stomach. 22. The pharmaceutical composition according to claim 21, in which the iron complex is encapsulated by a material resistant to 
     
     
        dissociation under acidic aqueous conditions. 23. The pharmaceutical composition according to claim 22, in which the iron complex is encapaulated by a solid material which is resistant to dissociation under acidic aqueous conditions but which is adapted for dissociation under 
     
     
        non-acidic aqueous conditions. 24. A pharmaceutical composition according to claim 5 in unit dosage form. .[.25. A ferric iron complex of a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one compound in which the hydrogen atom attached to the nitrogen atom is replaced by an acyclic or cyclic aliphatic carboxylic acid acyl group or by an acyclic or cyclic aliphatic hydrocarbon group which can further be substituted by one or two substituents selected from acyclic or cyclic aliphatic carboxylic acid acyl, acyclic or cyclic alkoxy, acyclic or cyclic aliphatic amido, halo and hydroxy groups, and acyclic or cyclic aliphatic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hydrocarbyloxycarbonyl and hydrocarbyloxysulphonyl moieties, but excluding substitution by two hydroxy groups, and wherein one or more of the hydrogen atoms attached to ring carbon atoms can be replaced by one of said substituents or by an acyclic or cyclic aliphatic hydrocarbon group which can be further substituted by acyclic or cyclic alkoxy, halo or hydroxy groups, or an acyclic or cyclic aliphatic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hydrocarbyloxycarbonyl or hydrocarbyloxysulphonyl moiety, but excluding compounds in which said replacement of hydrogen atoms in the compound is effected only by unsubstituted acyclic or cyclic aliphatic hydrocarbon groups, and also excluding the compound 3-hydroxy-6-hydroxymethyl-1-methylpyrid-4-one, wherein said compound when metal free has a partition coefficient between n-octanol and 20 mM tris hydrochloride, pH 7.4, of between 0.02 and 3.0 for the ratio (concentration of compound in organic phase)/(concentration of compound in 
     
     
        aqueous phase)..].26. The ferric complex according to claim 25, in which any replacement of a hydrogen atom attached to a ring carbon atom is effected by a C 1-4  acyclic or cyclic aliphatic hydrocarbon group. 
     
     
            The complex according to claim 25, in which the 3-hydroxypyridone compound is substituted only on the nitrogen atom or is substituted on the 
     
     
        nitrogen atom and one one of the ring carbon atoms. 28. A neutral 3:1 hydroxypyridone:iron(III) complex of 3-hydroxypyrid-2-one, 3-hydroxypyrid-4-one or a 2-alkyl-3-hydroxypyrid-4-one, 6-alkyl-3-hydroxypyrid-4-one or 2,6-dialkyl-3-hydroxypyrid-4-one, the alkyl groups being acylic or cyclic, with the hydrogen atom attached to the nitrogen atom replaced by a C 2-5  acylic or cyclic alkylcarbonyl group or by a C 1-6  acylic or cyclic aliphatic hydrocarbon group substituted by a single substituent selected from C 2-5  acylic or cyclic alkylcarbonyl, C 1-4  acylic or cyclic alkoxy, halo, hydroxy, and unsubstituted or C 1-4  acyclic or cyclic alkyl mono- or di-substituted amido groups, and C 1-4  acylic or cyclic alkylcarbonyloxy, alkylsulphonyloxy, alkoxycarbonyl and alkoxysulphonyl 
     
     
        moieties. 29. The ferric complex according to claim 28, in which the alkyl group or groups at the 2-, 6-, or 2- and 6-positions of the 
     
     
        3-hydroxypyridone are C 1-3  acyclic groups. 30. The complex according to claim 3, in which the nitrogen atom of the 3-hydroxypyridone compound is substituted by a group --(CH 2 ) n  --COXR 1  wherein --(CH 2 ) n  -- and R 1  together contain 3 to 7 carbon atoms. 
     
     
            The ferric complex according to claim 3, in which R 1  and R 2  are each an acyclic alkyl group of 1 to 4 carbon atoms, n is an integer from 1 to 4 with the number of carbon atoms in --(CH 2 ) n  -- and 
     
     
        R 1  being 3 to 7 carbon atoms, and m is an integer from 3 to 6. 32. The ferric complex according to claim 25, in which the hydroxypyridone is a 3-hydroxypyrid-2-one N-substituted by a group --(CH 2 ) n  COXR 1  or a 3-hydroxy-2-methylpyrid-4-one N-substituted by a group --(CH 2 ) n  COXR 1  or --(CH 2 ) m  XH wherein R 1  is a acyclic alkyl group of 1 to 4 carbon atoms, X is an oxy group, n is an integer from 1 to 4 with the number of carbon atoms in --(CH 2 ) n  -- and R 1  being 3 to 7 carbon atoms, and m is an integer from 3 to 6. 
     
     
        3. The ferric complex according to claim 25, in which the hydrogen atom attached to the nitrogen atom is replaced by an acyclic or cyclic aliphatic hydrocarbon group and the hydrogen atom attached to a ring carbon atom at the 6-position is replaced by an acyclic or cyclic 
     
     
        alkoxymethyl, halomethyl, or hydroxymethyl group. 34. The ferric complex according to claim 33, in which the aliphatic hydrocarbon group is an 
     
     
        acyclic alkyl group of 1 to 4 carbon atoms. 35. The ferric complex according to claim 25, in which the ferric complex is the neutral 3:1 
     
     
        hydroxypyridone:iron(III) complex. 36. The pharmaceutical composition according to claim 30, in which the neutral 3:1 complex is substantially free from complexes containing other proportions of the hydroxypyridone 
     
     
        and iron. 37. A method for increasing the level of iron in the bloodstream of a patient in need of such treatment which comprises administering to said patient an amount sufficient to elicit such an effect of a neutral 3:1 hydroxypyridone:iron(III) complex of 3-hydroxypyrid-2-one, 3-hydroxypyrid-4-one, 3-hydroxy-2-methylpyrid-4-one, 3-hydroxy-6-methylpyrid-4-one or 3-hydroxy-2,6-dimethylpyrid-4-one with the hydrogen atom attached to the nitrogen atom replaced by an acyclic aliphatic carboxylic acid acyl group --COR 1 , an acyclic aliphatic hydrocarbon group --(CH 2 ) n  -- carrying a terminal substituent group --COR 1 , --COXR 1 , --SO 2  XR 1 , --XCOR 1  or --XSO 2  R 1 , or an acyclic aliphatic hydrocarbon group --(CH 2 ) m  -- carrying a terminal substituent group --OH, wherein R 1  is a C 1-4  acyclic alkyl group, X is an oxy or imino group, n 
     
     
        is an integer from 1 to 4 and m is an integer from 3 to 6. 38. A pharmaceutical composition comprising: (a) a neutral 3:1 hydroxypyridone:iron(III) complex of a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one compound in which the nitrogen atom is substituted by a C 2-5  acylic or cyclic aliphatic hydrocarbon group substituted by a single substituent selected from C 2-5  acylic or cyclic alkylcarbonyl, C 1-4  acylic or cyclic alkoxy, halo, hydroxy, and unsubstituted or C 1-4  acyclic or cyclic alkyl mono- or di-substituted amido groups, and C 1-4  acylic or cyclic alkylcarbonyloxy, alkylsulphonyloxy, alkoxycarbonyl and alkoxysulphonyl moieties, and one or more of the ring carbon atoms can further be substituted by a C 1-4  acylic or cyclic aliphatic hydrocarbon group; and   
     
     
       (b) a physiologically acceptable diluent or carrier. 39. A pharmaceutical composition comprising: (a) a neutral 3:1 hydroxypyridone:iron(III) complex of 3-hydroxypyrid-2-one, 3-hydroxypyrid-4-one, 3-hydroxy-2-methylpyrid-4-one, 3-hydroxy-6-methylpyrid-4-one or 3-hydroxy-2,6-dimethylpyrid-4-one with the hydrogen atom attached to the nitrogen atom replaced by an acyclic aliphatic carboxylic acid acyl group --COR 1 , an acyclic aliphatic hydrocarbon group --(CH 2 ) n  -- carrying a terminal substituent group --COR 1 , --COXR 1 , --SO 2  XR 1 , --XCOR 1  or --XSO 2  R 1 , or an acyclic aliphatic hydrocarbon group --(CH 2 ) m  -- carrying a terminal substituent group --XH, wherein R 1  is a C 1-4  acyclic alkyl group, X is an oxy or imino group, n is an integer from 1 to 4 and m is an integer from 3 to 6; and   
     
     
       (b) a physiologically acceptable diluent or carrier. 40. The pharmaceutical composition according to claim 5, in which the iron complex is the neutral 
     
     
        3:1 hydroxypyridone:iron(III) complex. 41. The ferric complex according to 
     
     
        claim 29, in which the acyclic alkyl groups are methyl. .Iadd.42.  A pharmaceutical composition comprising: (a) a ferric iron complex of a 3-hydroxypyrid-2-one or 3-hyroxypyrid-4-one compound in which the hydrogen atom attached to the nitrogen atom is replaced by an acyclic aliphatic carboxylic acid acyl group --COR 1  wherein R 1  is a C 1-4  acyclic aliphatic hydrocarbon group, or by an acyclic or cyclic aliphatic hydrocarbon group which can further be substituted by one or two substituents selected from acyclic aliphatic carboxylic acid acyl --COR 1  wherein R 1  is a C 1-4  acyclic aliphatic hydrocarbon group, acyclic or cyclic alkoxy, acyclic or cyclic aliphatic amido, halo and hydroxy groups, and acyclic or cyclic aliphatic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hyrocarbyloxycarbonyl and hydrocarbyloxysulphonyl moieties, but excluding substitution by two hydroxy groups, and wherein one or more of the hydrogen atoms attached to ring carbon atoms can be replaced by one of said substituents with the exception of halo groups or by an acyclic or cyclic aliphatic hydrocarbon group which can be further substituted by an acyclic or cyclic alkoxy, halo or hydroxy group, or an acyclic or cyclic aliphatic hydrocarbylcarbonyloxy, hydrocarbysulphonyloxy, hydrocarbyloxycarbonyl or hydrocarbyloxysulphonyl moiety, but excluding compounds in which said replacement of hydrogen atoms in the compound is effected only by unsubstituted acyclic or cyclic aliphatic hydrocarbon groups and also excluding the compound 3-hydroxy-6-hydroxymethyl-1-methylpyrid-4-one, wherein said compound when metal free has a partition coefficient between n-octanol and 20 mM tris hydrochloride, pH 7.4, of between 0.02 and 3.0 for the ratio (concentration of compound in organic phase)/(concentration of compound in aqueous phase); and   (b) a physiologically acceptable diluent or carrier. .Iaddend..Iadd.43. A ferric iron complex of a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one compound in which the hydrogen atom attached to the nitrogen atom is replaced by an acyclic aliphatic carboxylic acid acyl group --COR 1  wherein R 1  is a C 1-4  acyclic aliphatic hydrocarbon group, or by an acyclic or cyclic aliphatic hydrocarbon group which can further be substituted by one or two substituents selected from acyclic aliphatic carboxylic acid acyl --COR 1  wherein R 1  is a C 1-4  acyclic aliphatic hydrocarbon group, acyclic or cyclic alkoxy, acyclic or cyclic aliphatic amido, halo and hydroxy groups, and acyclic or cyclic aliphatic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hydrocarbyloxycarbonyl and hydrocarbyloxysulphonyl moieties, but excluding substitution by two hydroxy groups, and wherein one or more of the hydrogen atoms attached to ring carbon atoms can be replaced by one of said substituents with the exception of halo groups or by an acyclic or cyclic aliphatic hydrocarbon group which can be further substituted by acyclic or cyclic alkoxy, halo or hydroxy groups, or an acyclic or cyclic aliphatic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hydrocarbyloxycarbonyl or hydrocarbyloxysulphonyl moiety, but excluding compounds in which said replacement of hydrogen atoms in the compound is effected only by unsubstituted acyclic or cyclic aliphatic hydrocarbon groups, and also excluding the compound 3-hydroxy-6-hydroxymethyl-1-methylpyrid-4-one, wherein said compound when metal free has a partition coefficient between n-octanol and 20 mM tris hydrochloride, pH 7.4, of between 0.02 and 3.0 for the ratio (concentration of compound in organic phase)/-(concentration of compound in aqueous phase). .Iaddend..Iadd.44. A pharmaceutical composition comprising:   (a) a ferric iron complex of a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one compound in which the hydrogen atom attached to the nitrogen atom is replaced by an acyclic aliphatic carboxylic acid acyl group --COR 1  wherein R 1  is a C 1-4  acyclic aliphatic hydrocarbon group, or by an acyclic or cyclic aliphatic hydrocarbon group which can further be substituted by one or two substituents selected from acyclic aliphatic carboxylic acid acyl --COR 1  wherein R 1  is a C 1-4  acyclic aliphatic hydrocarbon group, acyclic or cyclic alkoxy, acyclic or cyclic aliphatic amido, halo and hydroxy groups and acyclic or cyclic aliphatic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hydrocarbyloxycarbonyl and hydrocarbyloxysulphonyl moieties, but excluding substitution by two hydroxy groups, and wherein one or more of the hydrogen atoms attached to the ring carbon atoms can be replaced by any one of said substituents or by an acyclic or cyclic aliphatic hydrocarbon group which can be further substituted by an acyclic or cyclic alkoxy, halo or hydroxy group, or an acyclic or cyclic aliphatic hydrocarbylcarbonyloxy, hydrocarbylsulphonyloxy, hydrocarbyloxycarbonyl or hydrocarbyloxysulphonyl moiety, but excluding compounds in which said replacement of hydrogen atoms in the compound is effected only by unsubstituted acyclic or cyclic aliphatic hydrocarbon groups and also excluding the compound 3-hydroxy-6-hydroxymethyl-1-methylpyrid-4-one, wherein said compound when metal free has a partition coefficient between n-octanol and 20 mM tris hydrochloride, pH 7.4, of between 0.02 and 3.0 for the ratio (concentration of compound in organic phase)/(concentration of compound in aqueous phase);   (b) folic acid; and (c) a physiologically acceptable diluent or carrier. .Iaddend.