# US 8,633,174 B2 · Compounds for use in the treatment of cancer

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- Number: US 8,633,174 B2
- Document ID: US8633174B2
- Status: Granted
- Kind: B2
- Application number: 13/769,298
- Filed: 2013-02-16
- Published: 2013-06-20
- Granted: 2014-01-21
- Earliest claimed: 2007-12-14
- Assignees: Pledpharma AB
- Applicants: PledPharma AB
- Inventors: Jan Olof G Karlsson; Tino Kurz; Rolf Andersson
- Web page: https://patentgrep.com/patent/US8633174B2

## CPC

- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61P 35/00: Antineoplastic agents
- 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

## Abstract

Pharmaceutical compositions comprise a first compound of Formula I or a physiologically acceptable salt thereof, and a cyto-protective amount of a manganese chelate of N,N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid (MnPLED): wherein R1, R2, R3, R4 and X are defined in the specification.

## Claims

### Claim 1

A pharmaceutical composition comprising a first compound of Formula I or a physiologically acceptable salt thereof, and a cyto-protective amount of a manganese chelate of N,N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid (MnPLED):
wherein
X is CH or N,
each R1 independently is hydrogen or —CH2COR5;
R5 is hydroxy, optionally hydroxylated alkoxy, amino or alkylamido;
each R2 independently is a group ZYR6;
Z is a bond, CO, or a C1-3 alkylene or oxoalkylene group optionally substituted by a group R7;
Y is a bond, an oxygen atom or a group NR6;
R6 is a hydrogen atom, COOR8, an 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, an 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 is a C1-8 alkylene group, a 1,2-cykloalkylene group, or a 1,2-arylene group, optionally substituted with R7; and
each R4 independently is hydrogen or C1-3 alkyl.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein in the first compound of Formula I:
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 a group of the formula OP(O) (OR8)R7; and
R7 is hydroxy, or an unsubstituted alkyl or aminoalkyl group.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein in the first compound of Formula I: R3 is ethylene and each group R1 represents —CH2COR5 in which R5 is hydroxy.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, wherein the first compound is N,N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid (PLED).

### Claim 5 (depends on 1)

The pharmaceutical composition of claim 1, wherein the first compound is N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid (DPDP).

### Claim 6 (depends on 5)

The pharmaceutical composition of claim 5, wherein the molar ratio of the MnPLED to DPDP is in the range of 1/100 to 99/100.

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1, wherein the molar ratio of the MnPLED to the first compound is in the range of 1/100 to 99/100.

### Claim 8

A kit comprising a preparation of a first active ingredient of Formula I, a preparation of a manganese chelate of N,N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid (MnPLED), and optionally instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof:
or a physiologically acceptable salt thereof, wherein
X is CH or N,
each R1 independently is hydrogen or —CH2COR5;
R5 is hydroxy, optionally hydroxylated alkoxy, amino or alkylamido;
each R2 independently is a group ZYR6;
Z is a bond, CO, or a C1-3 alkylene or oxoalkylene group optionally substituted by a group R7;
Y is a bond, an oxygen atom or a group NR6;
R6 is a hydrogen atom, COOR8, an 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, an 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 is a C1-8 alkylene group, a 1,2-cykloalkylene group, or a 1,2-arylene group, optionally substituted with R7; and
each R4 independently is hydrogen or C1-3 alkyl.

### Claim 9 (depends on 8)

The kit of claim 8, wherein in the first compound of Formula I:
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 a group of the formula OP(O) (OR8)R7; and
R7 is hydroxy, or an unsubstituted alkyl or aminoalkyl group.

### Claim 10 (depends on 8)

The kit of claim 8, wherein in the first compound of Formula I: R3 is ethylene and each group R1 represents —CH2COR5 in which R5 is hydroxy.

### Claim 11 (depends on 8)

The kit of claim 8, wherein the first compound is N,N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid (PLED).

### Claim 12 (depends on 8)

The kit of claim 8, wherein the first compound is N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid (DPDP).

### Claim 13 (depends on 12)

The kit of claim 12, wherein the molar ratio of the MnPLED to DPDP is in the range of 1/100 to 99/100.

### Claim 14 (depends on 8)

The kit of claim 8, wherein the molar ratio of the MnPLED to the first compound is in the range of 1/100 to 99/100.

### Claim 15 (depends on 1)

The pharmaceutical composition of claim 1, comprising a cancer-inhibiting amount of the first compound.

### Claim 16 (depends on 8)

The kit of claim 8, wherein the preparation of the first active ingredient comprises a cancer-inhibiting amount of the first compound.