US 6,552,008 B1Granted

Thrombopoietin mimetics

AssigneeSmithKline Beecham Corporation

InventorsKevin J. Duffy, Nannan Liu, Juan I. Luengo

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Abstract

Invented are non-peptide TPO mimetics. Also invented is a method of treating thrombocytopenia, in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a selected azo-pyrazole derivative.

Claims14

Dependent claims

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:
X and Y are independently selected from sulfur, oxygen, an amino group which is optionally substituted by C1-C10alkyl, benzyl or phenyl;
R and R20 is selected from hydrogen, alkyl, cycloalkyl, C1-C12aryl, substituted alkyl, substituted cycloalkyl and substituted C1-C12aryl;
R1 and R2 are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, substituted alkyl, substituted cycloalkyl, substituted aryl, alkoxy, substituted alkoxy, —(CH2)mOR5, sulfonic acid, —COOR5, nitro, amino, —NR6R7, —N-acylamino, —N(R10)C(O)R11, —N(R10)C(O)NR6R7, —N(R10)SO2R11, cyano, halogen, —S(O)nR5, protected —OH, —CONR6R7, phosphonic acid, phosphinic acid and —SO2NR6R7, where
m is 0-6;
R5 is selected from hydrogen, alkyl, cycloalkyl, C1-C12aryl, substituted alkyl, substituted cycloalkyl and substituted C1-C12aryl,
R6 and R7 are each independently selected from hydrogen, alkyl, C3-C6cycloalkyl, phenyl, C1-C12aryl or R6 and R7 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen,
R10 and R11 are each independently selected from hydrogen, alkyl, C3-C6cycloalkyl, phenyl, C1-C12aryl and
n is 0-2;
R3 and R4 are independently selected from alkyl, cycloalkyl, substituted alkyl, substituted cycloalkyl, —(CH2)mCOOR5 and a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and optionally containing one or more heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of:
alkyl, C1-C12aryl, substituted cycloalkyl, substituted C1-C12aryl, aryloxy, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, —C(O)OR12, —C(O)NR8R9, —S(O)2NR8R9, —S(O)nR5, protected —OH and alkyl substituted with one or more substituents selected from the group consisting of:
alkoxy, acyloxy, C1-C12aryl, substituted C1-C12aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, —C(O)OR12, —S(O)2NR8R9, —S(O)nR5, aryloxy, nitro, cyano, halogen, and protected —OH, where
m is 0-6,
R5 is as described above,
R8 and R9 are independently selected form hydrogen, cycloalkyl, C1-C12aryl, substituted cycloalkyl, substituted C1-C12aryl, 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)OR5, —S(O)nR5, C(O)NR5R5, S(O)2NR5R5, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C1-C12aryl, substituted C1-C12aryl and protected —OH where R5 and n are as described above, or R8 and R9 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen,
R12 is selected form hydrogen, cycloalkyl, C1-C12aryl, substituted cycloalkyl, substituted C1-C12aryl, 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)OR5, —S(O)nR5, C(O)NR5R5, S(O)2NR5R5, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C1-C12aryl, substituted C1-C12aryl and protected —OH where R5 and n are as described above, and
n is 0-2;
and
pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

18 more elements

A method of enhancing platelet production in a mammal in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I),

wherein:
X and Y are independently selected from sulfur, oxygen, an amino group which is optionally substituted by C1-C10alkyl, benzyl or phenyl;
R and R20 is selected from hydrogen, alkyl cycloalkyl, C1-C12aryl, substituted alkyl substituted cycloalkyl and substituted C1-C12aryl;
R1 and R2 are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, substituted alkyl, substituted cycloalkyl, substituted aryl, alkoxy, substituted alkoxy, (CH2)mOR5, sulfonic acid, —COOR5, nitro, amino, —NR6R7, N-acylamino, —N(R10)C(O)R11, —N(R10)C(O)NR6R7, —N(R10)SO2R11, cyano, halogen, S(O)nR5, protected —OH, —CONR6R7, phosphonic acid, phosphinic acid and —SO2NR6R7, where
m is 0-6;
R5 is selected from hydrogen, alkyl, cycloalkyl, C1-C12aryl, substituted alkyl substituted cycloalkyl and substituted C1-C12aryl,
R6 and R7 are each independently selected from hydrogen, alkyl, C3-C6cycloalkyl, phenyl, C1-C12aryl or R6 and R7 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen,
R10 and R11 are each independently selected from hydrogen, alkyl, C3-C6cycloalkyl, phenyl, C1-C12aryl and
n is 0-2;
R3 and R4 are independently selected from alkyl, cycloalkyl, substituted alkyl, substituted cycloalkyl, —(CH2)mCOOR5 and a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and optionally containing one or more heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of:
alkyl, C1-C12aryl, substituted cycloalkyl, substituted C1-C12aryl, aryloxy, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, —C(O)OR12, —C(O)NR8R9, —S(O)2NR8R9, —S(O)nR5, protected —OH and alkyl substituted with one or more substituents selected from the group consisting of:
alkoxy, acyloxy, C1-C12aryl, substituted C1-C12aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, —C(O)OR12, —S(O)2NR8R9, —S(O)nR5, aryloxy, nitro, cyano, halogen, and protected —OH, where
m is 0-6,
R5 is as described above,
R8 and R9 are independently selected form hydrogen, cycloalkyl, C1-C12aryl, substituted cycloalkyl, substituted C1-12aryl, 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)OR5, —S(O)nR5, C(O)NR5R5, S(O)2NR5R5, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C1-C12aryl, substituted C1-C12aryl and protected —OH where R5 and n are as described above, or R8 and R9 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen,
R12 is selected form hydrogen, cycloalkyl, C1-C12aryl, substituted cycloalkyl, substituted C1-C12aryl, 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)OR5, —S(O)nR5, C(O)NR5R5, S(O)2NR5R5, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C1-C12aryl, substituted C1-C12aryl and protected —OH where R5 and n are as described above, and
n is 0-2;
and
pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

18 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/110,287Filed 22 Mar 2002 · us provisional application
Priority: 24 Sep 1999
Granted: 22 Apr 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61P 7/00
Drugs for disorders of the blood or the extracellular fluid
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00

Family

Application60/155,958Us provisional application · filed 24 Sep 1999
US 6,552,008 B1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

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:
X and Y are independently selected from sulfur, oxygen, an amino group which is optionally substituted by C1-C10alkyl, benzyl or phenyl;
R and R20 is selected from hydrogen, alkyl, cycloalkyl, C1-C12aryl, substituted alkyl, substituted cycloalkyl and substituted C1-C12aryl;
R1 and R2 are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, substituted alkyl, substituted cycloalkyl, substituted aryl, alkoxy, substituted alkoxy, —(CH2)mOR5, sulfonic acid, —COOR5, nitro, amino, —NR6R7, —N-acylamino, —N(R10)C(O)R11, —N(R10)C(O)NR6R7, —N(R10)SO2R11, cyano, halogen, —S(O)nR5, protected —OH, —CONR6R7, phosphonic acid, phosphinic acid and —SO2NR6R7, where
m is 0-6;
R5 is selected from hydrogen, alkyl, cycloalkyl, C1-C12aryl, substituted alkyl, substituted cycloalkyl and substituted C1-C12aryl,
R6 and R7 are each independently selected from hydrogen, alkyl, C3-C6cycloalkyl, phenyl, C1-C12aryl or R6 and R7 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen,
R10 and R11 are each independently selected from hydrogen, alkyl, C3-C6cycloalkyl, phenyl, C1-C12aryl and
n is 0-2;
R3 and R4 are independently selected from alkyl, cycloalkyl, substituted alkyl, substituted cycloalkyl, —(CH2)mCOOR5 and a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and optionally containing one or more heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of:
alkyl, C1-C12aryl, substituted cycloalkyl, substituted C1-C12aryl, aryloxy, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, —C(O)OR12, —C(O)NR8R9, —S(O)2NR8R9, —S(O)nR5, protected —OH and alkyl substituted with one or more substituents selected from the group consisting of:
alkoxy, acyloxy, C1-C12aryl, substituted C1-C12aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, —C(O)OR12, —S(O)2NR8R9, —S(O)nR5, aryloxy, nitro, cyano, halogen, and protected —OH, where
m is 0-6,
R5 is as described above,
R8 and R9 are independently selected form hydrogen, cycloalkyl, C1-C12aryl, substituted cycloalkyl, substituted C1-C12aryl, 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)OR5, —S(O)nR5, C(O)NR5R5, S(O)2NR5R5, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C1-C12aryl, substituted C1-C12aryl and protected —OH where R5 and n are as described above, or R8 and R9 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen,
R12 is selected form hydrogen, cycloalkyl, C1-C12aryl, substituted cycloalkyl, substituted C1-C12aryl, 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)OR5, —S(O)nR5, C(O)NR5R5, S(O)2NR5R5, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C1-C12aryl, substituted C1-C12aryl and protected —OH where R5 and n are as described above, and
n is 0-2;
and
pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

18 more elements

Facts

Application

10/110,287Filed 22 Mar 2002 · us provisional application

Priority

24 Sep 1999

Granted

22 Apr 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61P 7/00
Drugs for disorders of the blood or the extracellular fluid
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00