Calmangafodipir, a new chemical entity, and other mixed metal complexes, methods of preparation, compositions, and methods of treatment
AssigneePledpharma AB
InventorsJan-Olof Karlsson, Karl Reineke, Tino Kurz, Rolf Andersson, Michael Hall, Christina McLaughlin, Sven Jacobsson, Jacques Näsström
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Abstract
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, R1, R2, R3, and R4 are as defined herein.
Claims40
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 R1 independently represents hydrogen or —CH2COOH;
- each R2 independently represents ZYR6 wherein Z represents a bond, CH2 or CH2O;
- 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.
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 R1 independently represents hydrogen or —CH2COOH;
- each R2 independently represents ZYR6 wherein Z represents a bond, CH2 or CH2O;
- 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.
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 R1 independently represents hydrogen or —CH2COOH;
- each R2 independently represents ZYR6 wherein Z represents a bond, CH2 or CH2O;
- 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.
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 R1 independently represents hydrogen or —CH2COOH;
- each R2 independently represents ZYR6 wherein Z represents a bond, CH2 or CH2O;
- 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.
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 R1 independently represents hydrogen or —CH2COOH;
- each R2 independently represents ZYR6 wherein Z represents a bond, CH2 or CH2O;
- 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.
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 R1 independently represents hydrogen or —CH2COOH;
- each R2 independently represents ZYR6 wherein Z represents a bond, CH2 or CH2O;
- 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;
- 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 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 R1 independently represents hydrogen or —CH2COOH;
- each R2 independently represents ZYR6 wherein Z represents a bond, CH2 or CH2O;
- 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.
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 R1 independently represents hydrogen or —CH2COOH;
- each R2 independently represents ZYR6 wherein Z represents a bond, CH2 or CH2O;
- 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.
Dependencies are inferred from the claim text.