# US 10,111,893 B2 · Calmangafodipir, a new chemical entity, and other mixed metal complexes, methods of preparation, compositions, and methods of treatment

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- Number: US 10,111,893 B2
- Document ID: US10111893B2
- Status: Granted
- Kind: B2
- Application number: 15/445,588
- Filed: 2017-02-28
- Published: 2017-06-15
- Granted: 2018-10-30
- Earliest claimed: 2012-01-05
- Assignees: Pledpharma AB
- Applicants: PledPharma AB
- Inventors: Jan-Olof Karlsson; Karl Reineke; Tino Kurz; Rolf Andersson; Michael Hall; Christina McLaughlin; Sven Jacobsson; Jacques Näsström
- Web page: https://patentgrep.com/patent/US10111893B2

## CPC

- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/08: of the prostate
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/00: Drugs for skeletal disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61P 39/02: Antidotes
- A61P 39/06: Free radical scavengers or antioxidants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07F 13/005: {Compounds without a metal-carbon linkage}
- C07F 19/00: Metal compounds according to more than one of main groups C07F1/00 - C07F17/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## 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. Pharmaceutical compositions are 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. 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.

## Claims

### Claim 1

A method for treatment of oxidative stress associated with a pathological condition 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, and wherein the molar ratio of calcium to manganese is 1-10:
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.

### Claim 2 (depends on 1)

A method according to claim 1, wherein in the mixed metal complex, Z is a bond or a group selected from CH2, (CH2)2, CH2CO, CH2CH2CO and CH2COCH2; Y is a bond; R6 is a mono- or poly(hydroxy or alkoxylated) alkyl group or of the formula OP(O)(OR8)R7; and R7 is hydroxy, or an unsubstituted alkyl or aminoalkyl group.

### Claim 3 (depends on 1)

A method according to claim 1, wherein in the mixed metal complex, each group R4 is methyl.

### Claim 4 (depends on 1)

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.

### Claim 5 (depends on 4)

A method according to claim 4, wherein the mixed metal complex has a Ca2+/Mn2+ molar ratio of about 4.

### Claim 6 (depends on 4)

A method according to claim 4, wherein the mixed metal complex is a mixed metal complex of a sodium salt of a compound of Formula I.

### Claim 7 (depends on 4)

A method according to claim 4, wherein the pharmaceutical composition comprises one or more physiologically acceptable carriers and/or excipients.

### Claim 8 (depends on 1)

A method according to claim 1, wherein the mixed metal complex has a Ca2+/Mn2+ molar ratio of about 4.

### Claim 9 (depends on 1)

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.

### Claim 10

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.

### Claim 11 (depends on 10)

A pharmaceutical composition according to claim 10, wherein in the mixed metal complex, R5 is hydroxy, C1-8 alkoxy, ethylene glycol, glycerol, amino or C1-8 alkylamido; Z is a bond or a group selected from CH2, (CH2)2, CO, CH2CO, CH2CH2CO and CH2COCH2; Y is a bond; R6 is a mono- or poly(hydroxy or alkoxylated) alkyl group or of the formula OP(O)(OR8)R7; and R7 is hydroxy, or an unsubstituted alkyl or aminoalkyl group.

### Claim 12 (depends on 10)

A pharmaceutical composition according to claim 10, wherein in the mixed metal complex, R3 is ethylene and each group le represents —CH2COR5 in which R5 is hydroxy.

### Claim 13 (depends on 10)

A pharmaceutical composition according to claim 10, 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.

### Claim 14 (depends on 13)

A pharmaceutical composition according to claim 13, wherein the mixed metal complex has a Ca2+/Mn2+ molar ratio of about 4.

### Claim 15 (depends on 13)

A pharmaceutical composition according to claim 13, wherein the mixed metal complex is a mixed metal complex of a sodium salt of a compound of Formula I.

### Claim 16 (depends on 10)

A pharmaceutical composition according to claim 10, wherein the mixed metal complex has a Ca2+/Mn2+ molar ratio of about 4.

### Claim 17 (depends on 10)

A pharmaceutical composition according to claim 10, wherein the mixed metal complex is a mixed metal complex of a sodium salt of a compound of Formula I.

### Claim 18

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.

### Claim 19 (depends on 18)

The method according to claim 18, wherein the mixed metal complex has a Ca2+/Mn2+ molar ratio of about 4.

### Claim 20 (depends on 19)

The method according to claim 19, wherein the pathological condition is a cytotoxic or cytostatic drug injury.

### Claim 21 (depends on 19)

The method according to claim 19, wherein the pathological condition is acetaminophen-induced acute liver failure.

### Claim 22 (depends on 19)

The method according to claim 19, wherein the pathological condition is non-small cell lung cancer, colorectal cancer, prostate cancer, breast cancer, pancreatic cancer, or malignant melanoma.