Calmangafodipir, a new chemical entity, and other mixed metal complexes, methods of preparation, compositions, and methods of treatment
Methods for treatment of a pathological condition caused by oxidative stress in a patient comprise administering to the patient a mixed metal complex of a compound of Formula I, or a salt thereof, in an amount effective to reduce the oxidative stress. The mixed metals comprise calcium and manganese in a molar ratio of calcium to manganese in the range of 1-10: wherein X, R 1 , R 2 , R 3 , and R 4 are as defined herein.
1. A method for treatment of oxidative stress associated with a pathological condition in a patient, the method comprising administering to the patient a mixed metal complex of a compound of Formula I, or a salt thereof, in an amount effective to reduce the oxidative stress, wherein the mixed metals comprise calcium and manganese, and wherein the molar ratio of calcium to manganese is 1-10:
wherein
X represents CH,
each R 1 independently represents hydrogen or —CH 2 COOH;
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 , 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;
provided that each ZYR 6 includes a —CH 2 O— linkage to the respective pyridine ring;
R 3 represents ethylene; and
each R 4 independently represents hydrogen or C 1-3 alkyl.
2. A method according to claim 1 , wherein in the mixed metal complex, 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 method 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.
4. A method according to claim 3 , wherein the mixed metal complex has a Ca 2+ /Mn 2+ molar ratio of about 4.
5. A method according to claim 3 , wherein the mixed metal complex is a mixed metal complex of a sodium salt of a compound of Formula I.
6. A method according to claim 3 , wherein the mixed metal complex is administered in a pharmaceutical composition comprising the mixed metal complex and one or more physiologically acceptable carriers and/or excipients.
7. A method according to claim 1 , wherein the mixed metal complex has a Ca 2+ /Mn 2+ molar ratio of about 4.
8. A method according to claim 1 , wherein the mixed metal complex is a mixed metal complex of a sodium salt of a compound of Formula I.
9. A method according to claim 1 , wherein the mixed metal complex is freeze dried.
10. A method according to claim 1 , wherein the mixed metal complex is administered in a pharmaceutical composition comprising the mixed metal complex and one or more physiologically acceptable carriers and/or excipients.
11. A method according to claim 1 , comprising administering about 0.01 to 50 μmol/kg body weight of the mixed metal complex.
12. A method according to claim 1 , comprising administering about 0.1 to 10 μmol/kg body weight of the mixed metal complex.
13. A method according to claim 1 , comprising administering about 0.1 to 5 μmol/kg body weight of the mixed metal complex.
14. A method according to claim 1 , wherein the pathological condition is an ischemia-reperfusion-induced injury.
15. A method according to claim 1 , wherein the pathological condition is associated with atherosclerosis.
16. A method according to claim 1 , wherein the pathological condition is associated with diabetes.
17. A method according to claim 1 , wherein the pathological condition is associated with a thrombolytic treatment, a cardiopulmonary bypass, or percutaneous transluminal angioplasty.
18. A method according to claim 1 , wherein the pathological condition is a result of cardiac or organ transplantation surgery.
19. A method according to claim 1 , wherein the pathological condition is a result of stroke.
20. A method according to claim 1 , wherein the pathological condition is a pathological condition of iron or copper.
21. A method according to claim 1 , wherein the pathological condition is thalassemia, sickle cell anemia, transfusional hemosiderosis, or Wilson's disease.
22. A method according to claim 1 , wherein the pathological condition is hepatitis-induced liver cirrhosis, non-alcoholic steatohepatitis (NASH), or viral-induced chronic hepatitis.
23. A method according to claim 1 , wherein the pathological condition is a radiation-induced injury.
24. A method according to claim 1 , wherein the pathological condition is cancer.
25. A method according to claim 1 , wherein the pathological condition is non-small cell lung cancer, colorectal cancer, prostate cancer, breast cancer, pancreatic cancer, or malignant melanoma.
26. A method of treatment of prostate cancer, breast cancer, pancreatic cancer, or malignant melanoma, the method comprising administering to the patient an effective amount of 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,
each R 1 independently represents hydrogen or —CH 2 COOH;
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 , 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;
provided that each ZYR 6 includes a —CH 2 O— linkage to the respective pyridine ring;
R 3 represents ethylene; and
each R 4 independently represents hydrogen or C 1-3 alkyl.
27. A method of treatment of a pathological condition in a patient, wherein the pathological condition is ischemia-reperfusion-induced injury; is caused by oxidative stress in a thrombolytic treatment, a cardiopulmonary bypass, percutaneous transluminal angioplasty, and/or atherosclerosis; or is a result of oxidative stress in cardiac or organ transplantation surgery or stroke,
the method comprising administering to the patient an effective amount of 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,
each R 1 independently represents hydrogen or —CH 2 COOH;
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 , 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;
provided that each ZYR 6 includes a —CH 2 O— linkage to the respective pyridine ring;
R 3 represents ethylene; and
each R 4 independently represents hydrogen or C 1-3 alkyl.
28. A method of treatment of a pathological condition of iron or copper and caused by oxidative stress, the method comprising administering to the patient an effective amount of 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,
each R 1 independently represents hydrogen or —CH 2 COOH;
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 , 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;
provided that each ZYR 6 includes a —CH 2 O— linkage to the respective pyridine ring;
R 3 represents ethylene; and
each R 4 independently represents hydrogen or C 1-3 alkyl.
29. A method of treatment of thalassemia, sickle cell anemia, transfusional hemosiderosis, or Wilson's disease, in a patient,
the method comprising administering to the patient an effective amount of 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,
each R 1 independently represents hydrogen or —CH 2 COOH;
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 , 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;
provided that each ZYR 6 includes a —CH 2 O— linkage to the respective pyridine ring;
R 3 represents ethylene; and
each R 4 independently represents hydrogen or C 1-3 alkyl.
30. A method of treatment of hepatitis-induced liver cirrhosis, non-alcoholic steatohepatitis (NASH), or viral-induced chronic hepatitis, in a patient,
the method comprising administering to the patient an effective amount of 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,
each R 1 independently represents hydrogen or —CH 2 COOH;
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 , 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;
provided that each ZYR 6 includes a —CH 2 O— linkage to the respective pyridine ring;
R 3 represents; and
each R 4 independently represents hydrogen or C 1-3 alkyl.
31. A method of treatment of radiation-induced injury in a patient, the method comprising administering to the patient an effective amount of 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,
each R 1 independently represents hydrogen or —CH 2 COOH;
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 , 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;
provided that each ZYR 6 includes a —CH 2 O— linkage to the respective pyridine ring;
R 3 represents ethylene; and
each R 4 independently represents hydrogen or C 1-3 alkyl.
32. A method of treatment of a pathological condition associated with diabetes in a patient,
the method comprising administering to the patient an effective amount of 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,
each R 1 independently represents hydrogen or —CH 2 COOH;
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 , 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;
provided that each ZYR 6 includes a —CH 2 O— linkage to the respective pyridine ring;
R 3 represents ethylene; and
each R 4 independently represents hydrogen or C 1-3 alkyl.
33. A method according to claim 1 , wherein each R 2 independently represents —CH 2 —OP(O)(OR 8 )R 7 .
34. A method according to claim 26 , wherein each R 2 independently represents —CH 2 —OP(O)(OR 8 )R 7 .
35. A method according to claim 27 , wherein each R 2 independently represents —CH 2 —OP(O)(OR 8 )R 7 .
36. A method according to claim 28 , wherein each R 2 independently represents —CH 2 —OP(O)(OR 8 )R 7 .
37. A method according to claim 29 , wherein each R 2 independently represents —CH 2 —OP(O)(OR 8 )R 7 .
38. A method according to claim 30 , wherein each R 2 independently represents —CH 2 —OP(O)(OR 8 )R 7 .
39. A method according to claim 31 , wherein each R 2 independently represents —CH 2 —OP(O)(OR 8 )R 7 .
40. A method according to claim 32 , wherein each R 2 independently represents —CH 2 —OP(O)(OR 8 )R 7 .