# US 8,377,969 B2 · Compounds for use in the treatment of cancer

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- Number: US 8,377,969 B2
- Document ID: US8377969B2
- Status: Granted
- Kind: B2
- Application number: 12/808,144
- Filed: 2008-12-12
- Published: 2010-11-25
- Granted: 2013-02-19
- Earliest claimed: 2007-12-14
- Assignees: Pledpharma AB
- Applicants: Jan Olof G. Karlsson; Tino Kurz; Rolf Andersson
- Inventors: Jan Olof G. Karlsson; Tino Kurz; Rolf Andersson
- Web page: https://patentgrep.com/patent/US8377969B2

## 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

Compound of Formula I or a salt thereof for treating cancer, wherein X represents CH or N; R1 represents hydrogen or —CH2COR5; R5 represents hydroxy, optionally hydroxylated alkoxy, amino or alkylamido; R2 represents ZYR6; Z represents a bond, 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, an alkyl, alkenyl, cycloalkyl, aryl or aralkyl group optionally substituted by one or more 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 represents C1-8 alkylene, 1,2-cykloalkylene, or 1,2-arylene, optionally substituted with R7; and R4 represents hydrogen or C1-3 alkyl.

## Claims

### Claim 1

A method for treatment of cancer selected from lymphoma, colorectal cancer and/or metastases thereof, and breast cancer and/or metastases thereof, in a human or non-human body, said method comprising administrating to said body a cancer-inhibiting amount of a first compound of Formula I:
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, 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, ═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 method of claim 1, wherein:
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 2)

The method of claim 2, wherein R3 is ethylene and each group R1 represents —CH2COR5 in which R5 is hydroxy.

### Claim 4 (depends on 1)

The method of claim 1, wherein the first compound is N,N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid.

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

The method of claim 1, wherein the cancer is colon cancer and/or metastases thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein the cancer is breast cancer and/or metastases thereof.

### Claim 8 (depends on 1)

The method of claim 1, wherein the cancer is lymphoma,

### Claim 9 (depends on 1)

The method of claim 1, wherein the first compound is administered with a cyto-protective amount of a metal chelate of a compound of Formula I.

### Claim 10 (depends on 9)

The method of claim 9, wherein said metal chelate has a Ka value in the range of from 108 to 1024.

### Claim 11 (depends on 9)

The method of claim 9, wherein said metal chelate has a lower Ka value than the Ka value of an iron (Fe3+) chelate of a compound of Formula I, by a factor of at least 103.

### Claim 12 (depends on 9)

The method of claim 9, wherein the metal chelate is a manganese (Mn2+ or Mn3+) or copper (Cu+ or Cu2+) chelate.

### Claim 13 (depends on 9)

The method of claim 9, wherein the first compound is N,N′-dipyridoxyl ethylenediamine-N,N′-diacetic acid and metal chelate is a metal chelate of N,N′-dipyridoxyl ethylenediainine-N,N′-diacetic acid.

### Claim 14 (depends on 9)

The method of claim 9, wherein the first compound is N,N′-bis-(pyridoxal-5-phosphate)-ethylenediamine-N,N′-diacetic acid and the metal chelate is a metal chelate of N,N′-dipyridoxyl ethylenediamine-N,N′-diaretic acid.

### Claim 15 (depends on 1)

The method of claim 1, wherein the first compound is administered together with one or more other anti-cancer drugs selected from the group consisting of doxorubicin, epirubicin, cisplatin, carboplatin, paclitaxel, 5-fluorouracil, cyclophosphamide, gemcitabine, irinotecan, and methotrexate.

### Claim 16 (depends on 15)

The method of claim 15, wherein the first compound and the one or more other anti-cancer drug(s) are administered simultaneously, separately or sequentially to said patient.

### Claim 17 (depends on 1)

The method of claim 1, wherein the first compound is administered in combination with radiation therapy.