# US 6,720,345 B1 · Semicarbazone derivatives and their use as thrombopoietin mimetics

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- Number: US 6,720,345 B1
- Document ID: US6720345B1
- Status: Granted
- Kind: B1
- Application number: 10/129,211
- Filed: 2002-05-03
- Granted: 2004-04-13
- Earliest claimed: 1999-11-05
- Assignees: SmithKline Beecham Corporation
- Inventors: Juan I. Luengo; Kevin J. Duffy; Antony N. Shaw
- Web page: https://patentgrep.com/patent/US6720345B1

## CPC

- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 277/36: Sulfur atoms
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds of formula (I), particularly a compound of formula (Ia), are non-peptide TPO mimetics, useful in the treatment of thrombocytopenia.

## Claims

### Claim 1

A method of treating of thrombocytopenia in a mammal in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I):
wherein:
R1 and R2 are each independently selected from hydrogen, C1-12alkyl, aryl, substituted aryl, and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryl, substituted aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, —C(O)OR7, —S(O)2NR7R8, —S(O)nR6, aryloxy, nitro, cyano, halogen, and protected —OH,
where
R6 is selected from hydrogen, alkyl, cycloalkyl, C1-C12aryl, substituted alkyl, substituted cycloalkyl and substituted C1-C12aryl, and
R7 and R8 are independently selected from hydrogen, cycloalkyl, aryl, substituted cycloalkyl, substituted aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, —C(O)OR6, —S(O)nR6, —C(O)NR6R6, —S(O)2NR6R6, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C1-C12aryl, substituted C1-C12aryl and protected —OH where R6 is as described above; and
n is 0-3; or R1 and R2 taken together with the group to which they are attached represent a ring of formula (A):
where
R4 and R10 are each independently selected from two hydrogens, ═NR5, ═O, ═S, and ═CHR5, where R5 is C1-C12aryl or substituted C1-C12aryl; and m is 0 to 2;
Z is a bond or selected from S or NR5, where R5 is C1-C12aryl or substituted C1-C12aryl;
R3 is selected from hydrogen, C1-C10alkyl, phenyl, substituted phenyl, carboxyl or C1-C10alkoxycarbonyl;
L is a group of formula (L):
where
A, B, D and E independently represent CR11 or N; where R11 is selected from hydrogen, halogen, —CF3, —CN, —SO3H, —SO3Na, —SO2R14, —NO2, phenyl, substituted phenyl, C1-C10alkyl, C1-C10alkoxy, C1-C10acyloxy, arylalkoxy, —COR14, —NR12R13, hydroxy or cycloalkyl;
where R14 is selected from hydroxy, C1-C10alkyl, phenyl, amino, mono- or dialkylamino;
R12 and R13 are independently selected from hydrogen, C1-10alkyl, C1-C12aryl, substituted C1-C12aryl, C1-10acyl or cycloalkyl;
or either A═B or D═E alternatively represent O, S or NR12; where R12 is as defined above;
Y is selected from S, O and NR15, where R15 is selected from hydrogen, C1-C10alkyl, substituted C1-C10alkyl, C1-C6alkylphenyl, substituted C1-C6alkylphenyl, C1-C10acyl, substituted C1-C10acyl, or SO2R9, where R9 is C1-C10alkyl, substituted C1-C10alkyl, C1-C12aryl or substituted C1-C12aryl; and
X is selected from SR16, OR16 or NHR17; where R16 is hydrogen, C1-C10alkyl or substituted C1-C10alkyl;
R17 is hydrogen, C1-C10alkyl, substituted C1-C10alkyl, C1-C6alkylphenyl, C1-C10acyl, substituted C1-C10acyl or SO2R9; where R9 is C1-C10alkyl, substituted C1-C10alkyl, C1-C12aryl or substituted C1-C12aryl; or a
pharmaceutically acceptable salt, hydrate, solvate or ester thereof,
provided that;
when R1 and R2 do not form a ring and X is not —NHSO2R9, R5 is not a substituted or unsubstituted pyridyl or a substituted or unsubstituted phenyl.

### Claim 2 (depends on 1)

The method of claim 1 wherein the compound is selected form:
3-[(2-hydroxy-3,5-dibromophen-1-yl)methyleneamino]-2-thioxothiazolidin-4-one;
3-(3-carboxyphenyl)-1-[(1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-ylmethylene)amino]-2-thioxoimidazolidin-4-one;
3-(4-carboxyphenyl)-1-[(1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-ylmethylene)amino]-2-thioxoimidazolidin-4-one;
5-(4-carboxybenzylidene)-3-[(1-{3,4-dimethylphenyl}-4-hydroxy-3-methyl-1H -pyrazol-4-ylmethylene)amino]-2-thioxothiazolidin-4-one; and
5-(3-carboxybenzylidene)-3-[(1-{3,4-dimethylphenyl}-4-hydroxy-3-methyl-1H -pyrazol-4-ylmethylene)amino]-2-thioxothiazolidin-4-one;
or a pharmaceutically acceptable salt, hydrate, solvate or ester thereof.

### Claim 3 (depends on 1)

A method of enhancing platelet production in a mammal, including a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I) as defined in claim 1.

### Claim 4 (depends on 3)

The method of claim 3 wherein the compound is selected from:
3-[(2-hydroxy-3,5-dibromophen-1-yl)methyleneamino]-2-thioxothiazolidin-4-one;
3-(3-carboxyphenyl)-1-[(1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-ylmethylene)amino]-2-thioxoimidazolidin-4-one;
3-(4-carboxyphenyl)-1-[(1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H -pyrazol-4-ylmethylene)amino]-2-thioxoimidazolidin-4-one;
5-(4-carboxybenzylidene)-3-[(1-{3,4-dimethylphenyl}-4-hydroxy-3-methyl-1H -pyrazol-4-ylmethylene)amino]-2-thioxothiazolidin-4-one; and
5-(3-carboxybenzylidene)-3-[(1-{3,4-dimethylphenyl}-4-hydroxy-3-methyl-1H -pyrazol-4-ylmethylene)amino]-2-thioxothiazolidin-4-one;
or a pharmaceutically acceptable salt, hydrate, solvate or ester thereof.

### Claim 5 (depends on 1)

The method of claim 1 wherein the compound is administered orally.

### Claim 6 (depends on 1)

The method of claim 1 wherein the compound is administered parenterally.

### Claim 7 (depends on 1)

A method of agonizing the thrombopoietin receptor in a subject which comprises administering an effective amount of a compound of Formula (I), as defined in claim 1.

### Claim 8 (depends on 1)

The method of claim 1 wherein the compound is
3-[(2-hydroxy-3,5-dibromophen-1-yl)methyleneamino]-2-thioxothiazolidin-4-one;
or a pharmaceutically acceptable salt, hydrate, solvate or ester thereof.

### Claim 9

A compound selected from:
3-[(2-hydroxy-3,5-dibromophen-1-yl)methyleneamino]-2-thioxothiazolidin-4-one;
3-(3-carboxyphenyl)-1-[(1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-ylmethylene)amino]-2-thioxoimidazolidin-4-one;
3-(4-carboxyphenyl)-1-[(1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-ylmethylene)amino]-2-thioxoimidazolidin-4-one;
5-(4-carboxybenzylidene)-3-[(1-{3,4-dimethylphenyl}-4-hydroxy-3-methyl-1H-pyrazol -4-ylmethylene)amino]-2-thioxothiazolidin-4-one; and
5-(3-carboxybenzylidene)-3-[(1-{3,4-dimethylphenyl}-4-hydroxy-3-methyl-1H-pyrazol-4-ylmethylene)amino]-2-thioxothiazolidin-4-one;
or a pharmaceutically acceptable salt, hydrate, solvate or ester thereof.

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 1)

The method of claim 1 in which the mammal is a human.