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

A pharmaceutical composition, formed by suspending or dissolving a mixed metal complex of a compound of Formula I, or a salt thereof, in a liquid medium, optionally with one or more physiologically acceptable excipients, 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 R1 independently represents hydrogen or —CH2COR5;
• R5 represents hydroxy, ethylene glycol, glycerol, optionally hydroxylated alkoxy, amino or alkylamido;
• each R2 independently represents ZYR6 wherein Z represents a bond, CO, or a C1-3 alkylene or oxoalkylene group, optionally substituted by R7;
• Y represents a bond, an oxygen atom or NR6;
• R6 is a hydrogen atom, COOR8, alkyl, alkenyl, cycloalkyl, aryl or aralkyl group, optionally substituted by one or more groups selected from COOR8, CONR82, NR82, OR8, ═NR8, ═O, OP(O)(OR8)R7 and OSO3M;
• R7 is hydroxy, optionally hydroxylated, optionally alkoxylated alkyl or aminoalkyl group;
• R8 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;
• R3 represents a C1-8 alkylene, a 1,2-cykloalkylene, or a 1,2-arylene group, optionally substituted with R7;
• and
• each R4 independently represents hydrogen or C1-3 alkyl.

A method for treatment of a pathological condition caused by oxidative stress in a patient, the method comprising administering to the patient a pharmaceutical composition formed by suspending or dissolving a mixed metal complex of a compound of Formula I, or a salt thereof, in a liquid medium, the pharmaceutical composition being administered in an amount effective to reduce the oxidative stress,

• wherein the mixed metals comprise calcium and manganese,
• wherein the molar ratio of calcium to manganese is 1-10, and
• wherein the pathological condition is selected from the group consisting of a cytotoxic or cytostatic drug injury, acetaminophen-induced acute liver failure, non-small cell lung cancer, colorectal cancer, prostate cancer, breast cancer, pancreatic cancer, malignant melanoma, ischemia-reperfusion-induced injury, a pathological condition of iron or copper caused by oxidative stress, thalassemia, sickle cell anemia, transfusional hemosiderosis, Wilson's disease, hepatitis-induced liver cirrhosis, non-alcoholic steatohepatitis (NASH), viral-induced chronic hepatitis, or radiation-induced injury;
• or the pathological condition is caused by oxidative stress associated with a thrombolytic treatment, a cardiopulmonary bypass, percutaneous transluminal angioplasty, atherosclerosis or diabetes;
• or the pathological condition is a result of oxidative stress in cardiac or organ transplantation surgery or stroke,
• wherein
• X represents CH,
• each R1 independently represents hydrogen or —CH2COR5;
• R5 represents hydroxy;
• each R2 independently represents ZYR6 wherein Z represents a bond, or a C1-3 alkylene or oxoalkylene group, optionally substituted by R7;
• Y represents a bond or an oxygen atom;
• R6 is a hydrogen atom, COOR8, alkyl, alkenyl, cycloalkyl, aryl or aralkyl group, optionally substituted by one or more groups selected from COOR8, CONR82, NR82, OR8, ═NR8, ═O, OP(O)(OR8)R7 and OSO3M;
• R7 is hydroxy, optionally hydroxylated, optionally alkoxylated alkyl or aminoalkyl group;
• R8 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 ZYR6 includes a —CH2O— linkage to the respective pyridine ring;
• R3 represents ethylene;
• and
• each R4 independently represents hydrogen or C1-3 alkyl.