# US 7,410,985 B2 · Cycloalkyl derivatives of 3-hydroxy-4-pyridinones

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- Number: US 7,410,985 B2
- Document ID: US7410985B2
- Status: Granted
- Kind: B2
- Application number: 10/580,011
- Filed: 2004-11-18
- Published: 2007-04-12
- Granted: 2008-08-12
- Earliest claimed: 2003-11-20
- Assignees: Apotex Inc.
- Inventors: Tim Fat Tam; Michael Spino; Wanren Li; Yingsheng Wang; Yanqing Zhao; Birenkumar Hasmukhbhai Shah
- Web page: https://patentgrep.com/patent/US7410985B2

## CPC

- C07D 213/81: Amides; Imides
- A61P 39/00: General protective or antinoxious agents
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides an cycloalkyl derivative of 3-hydroxy-4-pyridinone which is useful for the chelation of metal ions such as iron. Its preparation and use is described. In particular, the invention concerns the removal of iron in chemical and biological systems including chelating agents having the formula (I); wherein R1 is X with the proviso that R2 is Y; or R1 is T with the proviso that R2 is W; or R1 is X with the proviso that R2 R5 N when taken together form a heterocyclic ring selected from piperidinyl, morpholinyl, pyrrolidinyl or piperazinyl, wherein the group piperidinyl, morpholinyl, pyrrolidinyl or piperazinyl is either unsubstituted or substituted with one to three C1 to C6 alkyl groups. X is C3-C6 cycloalkyl; Y is selected from the group consisting of C1 to C6 cycloalkyl; C1 to C6 alkyl, and C1 to C6 alkyl monosubstituted with a C3-C6 cycloalkyl; T is C1 to C6 alkyl; W is C3-C6 cycloalkyl; R3 is selected from the group consisting of hydrogen and C1 to C6 alkyl; R4 is selected from the group consisting of hydrogen and C1 to C6 alkyl; R5 is selected from the group consisting of hydrogen and C1 to C6 alkyl; and its pharmaceutically acceptable salt thereof. Pharmaceutical compositions of such compounds are useful in the removal of excess body iron from patients with iron overload diseases.

## Claims

### Claim 1

A 3-hydroxypyridin-4-one compound of formula I:
wherein:
R1 is X with the proviso that R2 is Y; or
R1 is T with the proviso that R2 is W;
X is C3-C6 cycloalkyl;
Y is selected from the group consisting of C3-C6 cycloalkyl, C1 to C6 alkyl and C1 to C6 alkyl monosubstituted with a C3-C6 cycloalkyl;
T is C1 to C6 alkyl;
W is C3-C6 cycloalkyl;
R3 is selected from the group consisting of hydrogen and C1 to C6 alkyl;
R4 is selected from the group consisting of hydrogen and C1 to C6 alkyl;
R5 is selected from the group consisting of hydrogen and C1 to C6 alkyl;
and/or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein R1 is X with the proviso that R2 is Y.

### Claim 3 (depends on 2)

A compound of claim 2 wherein X is C3-C6 cycloalkyl, Y is C1 to C6 alkyl and R5 is hydrogen or methyl.

### Claim 4 (depends on 3)

A compound of claim 3 wherein X is cyclopropyl, Y is methyl, R3 is hydrogen, R4 is methyl and R5 is hydrogen, and wherein said compound is 1-cyclopropyl-3-hydroxy-6-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide.

### Claim 5

A pharmaceutical composition comprising 1-cyclopropyl-3-hydroxy-6-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide and a pharmaceutically acceptable carrier.

### Claim 6 (depends on 5)

The pharmaceutical composition of claim 5, which is adopted for oral administration.

### Claim 7 (depends on 2)

A compound of claim 2 wherein X is C3-C6 cycloalkyl, Y is C3-C6 cycloalkyl and R5 is hydrogen.

### Claim 8 (depends on 7)

A compound of claim 7 wherein X is cyclopropyl, Y is cyclopropyl, R3 is hydrogen, R4 is methyl, and wherein said compound is N,1-dicyclopropyl-3-hydroxy-6-methyl-4-oxo-1,4-dihydropyridine-2-carboxamide.

### Claim 9 (depends on 3)

A compound of claim 3 wherein X is cyclopropyl, Y is methyl, R3 is hydrogen, R4 is methyl and R5 is methyl, and wherein said compound is 1-cyclopropyl-3-hydroxy-N,N,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide.

### Claim 10 (depends on 1)

A compound according to claim 1 wherein R1 is T with the proviso that R2 is W.

### Claim 11 (depends on 10)

A compound of claim 10 wherein T is C1-C6 alkyl and W is C3-C6 cycloalkyl.

### Claim 12 (depends on 11)

A compound of claim 11 wherein T is methyl, W is cyclopropyl, R3 is hydrogen, R4 is methyl and R5 is hydrogen, and wherein said compound is 3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid cyclopropylamide.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and a physiologically acceptable carrier.

### Claim 14 (depends on 13)

A pharmaceutical composition according to claim 13, which is adopted for oral administration.

### Claim 15 (depends on 4)

A method of treating at least one medical condition related to a toxic concentration of iron comprising administering to an animal suffering from said condition a therapeutically effective amount of the compound of claim 4, wherein said at least one medical condition is selected from the group consisting of thalassaemia, sickle cell disease and haemochromatosis.