Calmangafodipir, a New Chemical Entity, and Other Mixed Metal Complexes, Methods of Preparation, Compositions, and Methods of Treatment

A method of treatment of prostate cancer, breast cancer, pancreatic cancer, or malignant melanoma, the method comprising administering to the patient 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 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 of treatment of a pathological condition in a patient, wherein the pathological condition is ischemia-reperfusion-induced injury;

• associated with a thrombolytic treatment, a cardiopulmonary bypass, percutaneous transluminal angioplasty, atherosclerosis and/or diabetes;
• is a result of cardiac or organ transplantation surgery;
• or stroke,
• the method comprising administering to the patient 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 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 of treatment of a pathological condition of iron or copper, the method comprising administering to the patient 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 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 of treatment of a pathological condition in a patient, wherein the pathological condition is thalassemia, sickle cell anemia, transfusional hemosiderosis, or Wilson's disease,

• the method comprising administering to the patient 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 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 of treatment of a pathological condition in a patient, wherein the pathological condition is hepatitis-induced liver cirrhosis, non-alcoholic steatohepatitis (NASH), or viral-induced chronic hepatitis,

• the method comprising administering to the patient 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 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 of treatment of radiation-induced injury in a patient, the method comprising administering to the patient 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 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.