Calmangafodipir, a new chemical entity, and other mixed metal complexes, methods of preparation, compositions, and methods of treatment

1. A mixed metal complex of a compound of Formula I, or a salt thereof, wherein the mixed metals comprise calcium and manganese and wherein the molar ratio of calcium to manganese is 1-10:

wherein

X represents CH or N,

each R 1 independently represents hydrogen or —CH 2 COR 5 ;

R 5 represents hydroxy, ethylene glycol, glycerol, optionally hydroxylated alkoxy, amino or alkylamido;

each R 2 independently represents ZYR 6 wherein Z represents a bond, CO, or a C 1-3 alkylene or oxoalkylene group, optionally substituted by R 7 ;

Y represents a bond, an oxygen atom or NR 6 ;

R 6 is a hydrogen atom, COOR 8 , alkyl, alkenyl, cycloalkyl, aryl or aralkyl group, optionally substituted by one or more groups selected from COOR 8 , CONR 8 2 , NR 8 2 , OR 8 , ═NR 8 , ═O, OP(O)(OR 8 )R 7 and OSO 3 M;

R 7 is hydroxy, optionally hydroxylated, optionally alkoxylated alkyl or aminoalkyl group;

R 8 is a hydrogen atom or an optionally hydroxylated, optionally alkoxylated alkyl group;

M is a hydrogen atom or one equivalent of a physiologically tolerable cation;

R 3 represents a C 1-8 alkylene, a 1,2-cykloalkylene, or a 1,2-arylene group, optionally substituted with R 7 ; and

each R 4 independently represents hydrogen or C 1-3 alkyl.

2. A mixed metal complex according to claim 1 , wherein R 5 is hydroxy, C 1-8 alkoxy, ethylene glycol, glycerol, amino or C 1-8 alkylamido; Z is a bond or a group selected from CH 2 , (CH 2 ) 2 , CO, CH 2 CO, CH 2 CH 2 CO and CH 2 COCH 2 ; Y is a bond; R 6 is a mono- or poly(hydroxy or alkoxylated) alkyl group or of the formula OP(O)(OR 8 )R 7 ; and R 7 is hydroxy, or an unsubstituted alkyl or aminoalkyl group.

3. A mixed metal complex according to claim 1 , wherein R 3 is ethylene and each group R 1 represents —CH 2 COR 5 in which R 5 is hydroxy.

4. A mixed metal complex according to claim 1 , wherein the compound of Formula I is N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid (DPDP) or N,N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid (PLED), or a pharmaceutically acceptable salt thereof.

5. A mixed metal complex according to claim 1 , having a Ca 2+ /Mn 2+ molar ratio of about 4.

6. A mixed metal complex according to claim 1 , wherein the mixed metal complex is a mixed metal complex of a sodium salt of a compound of Formula I.

7. A mixed metal complex according to claim 2 , having a Ca 2+ /Mn 2+ molar ratio of about 4.

8. A mixed metal complex according to claim 3 , having a Ca 2+ /Mn 2+ molar ratio of about 4.

9. A mixed metal complex according to claim 4 , having a Ca 2+ /Mn 2+ molar ratio of about 4.

10. A mixed metal complex according to claim 1 , wherein the complex is freeze dried.

11. A pharmaceutical composition comprising a mixed metal complex according to claim 1 and one or more physiologically acceptable carriers and/or excipients.

12. A method of producing a mixed metal complex according to claim 1 , comprising a one-step crystallization from a solution of calcium, manganese, and a compound of Formula I, or a salt thereof.

13. A method for treatment of a cytotoxic or cytostatic drug injury in a patient, comprising administering to the patient an effective amount of a mixed metal complex according to claim 1 .

14. A method according to claim 13 , wherein the cytotoxic or cytostatic drug is a cancer treatment drug.

15. A method according to claim 13 , wherein the cytotoxic or cytostatic drug comprises at least one of doxorubicin, epirubicin, oxaliplatin, carboplatin, cisplatin, 5-fluorouracil, docetaxel or paclitaxel.

16. A method according to claim 13 , wherein the cytotoxic or cytostatic drug injury is myelosuppression.

17. A method for treatment of acetaminophen-induced acute liver failure in a patient, comprising administering to the patient an effective amount of a mixed metal complex according to claim 1 .

18. A method for treatment of non-small cell lung cancer or colorectal cancer in a patient, comprising administering to the patient an effective amount of a mixed metal complex according to claim 1 .

19. A method according to claim 13 , comprising administering about 0.01 to 50 μmol/kg body weight of the mixed metal complex.

20. A method according to claim 13 , comprising administering about 0.1 to 10 μmol/kg body weight of the mixed metal complex.

21. A method according to claim 20 , having a Ca 2+ /Mn 2+ molar ratio of about 4.

22. A method according to claim 21 , wherein the mixed metal complex is a mixed metal complex of a sodium salt of a compound of Formula I.

23. A method according to claim 13 , comprising administering about 0.1 to 5 μmol/kg μmol/kg body weight of the mixed metal complex.

24. A method according to claim 18 , comprising administering about 0.01 to 50 μmol/kg body weight of the mixed metal complex.

25. A method according to claim 18 , comprising administering about 0.1 to 10 μmol/kg body weight of the mixed metal complex.

26. A method according to claim 25 , having a Ca 2+ /Mn 2+ molar ratio of about 4.

27. A method according to claim 26 , wherein the mixed metal complex is a mixed metal complex of a sodium salt of a compound of Formula I.

28. A method according to claim 18 , comprising administering about 0.1 to 5 μmol/kg μmol/kg body weight of the mixed metal complex.

29. A method according to claim 13 , wherein the cytotoxic or cytostatic drug injury is neurotoxicity.

30. A method according to claim 29 , wherein the cytotoxic or cytostatic drug comprises oxaliplatin.

31. A method according to claim 29 , comprising administering about 0.01 to 50 μmol/kg body weight of the mixed metal complex.

32. A method according to claim 29 , comprising administering about 0.1 to 10 μmol/kg body weight of the mixed metal complex.

33. A method according to claim 32 , having a Ca 2+ /Mn 2+ molar ratio of about 4.

34. A method according to claim 33 , wherein the mixed metal complex is a mixed metal complex of a sodium salt of a compound of Formula I.

35. A method according to claim 29 , comprising administering about 0.1 to 5 μmol/kg μmol/kg body weight of the mixed metal complex.

36. A method according to claim 17 , comprising administering about 0.01 to 50 μmol/kg body weight of the mixed metal complex.

37. A method according to claim 17 , comprising administering about 0.1 to 10 μmol/kg body weight of the mixed metal complex.

38. A method according to claim 37 , having a Ca 2+ /Mn 2+ molar ratio of about 4.

39. A method according to claim 38 , wherein the mixed metal complex is a mixed metal complex of a sodium salt of a compound of Formula I.

40. A method according to claim 17 , comprising administering about 0.1 to 5 μmol/kg μmol/kg body weight of the mixed metal complex.

41. A mixed metal complex according to claim 1 , wherein

X represents CH,

each R 1 represents —CH 2 COR 5 ;

R 5 represents hydroxy;

each R 2 independently represents ZYR 6 wherein Z represents a bond, —CH 2 — or —CH 2 O—;

Y represents a bond or an oxygen atom;

R 6 is a hydrogen atom, COOR 8 , C 1 -C 8 alkyl, or C 1 -C 8 alkenyl group optionally substituted by one or more groups selected from COOR 8 , CONR 8 2 , NR 8 2 , OR 8 , ═NR 8 , ═O, OP(O)(OR 8 )R 7 and OSO 3 M;

R 7 is hydroxy, optionally hydroxylated, optionally C 1 -C 8 alkoxylated C 1 -C 8 alkyl or amino-C 1 -C 8 -alkyl group; and

R 8 is a hydrogen atom or an optionally hydroxylated, optionally C 1 -C 8 alkoxylated C 1 -C 8 alkyl group;

provided that each ZYR 6 includes a —CH 2 O— linkage to the respective pyridine ring;

M is a hydrogen atom or one equivalent of a physiologically tolerable cation;

R 3 represents ethylene; and

each R 4 independently represents hydrogen or C 1-3 alkyl.