Claims
- 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 (II) wherein:R, R1, R2 and R3 are each independently selected from hydrogen, C1-6alkyl, C1-6alkoxy, —(CH2)pOR4, —C(O)OR4, nitro, cyano, halogen, aryl, —S(O)nR4, cycloalkyl, protected —OH, —CONR5R6, —NR5R6, phosphonic acid, sulfonic acid, phosphinic acid and —SO2NR5R6, where p is 0-6; n is 0-2; R4 is hydrogen, alkyl, cycloalkyl, C1-C12aryl, substituted alkyl, substituted cycloalkyl and substituted C1-C12aryl and R5 and R6 are each independently selected from hydrogen, alkyl, C3-6cycloalkyl, aryl or R5 and R6 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; m is 0-6; and AR is 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, aryl, substituted cycloalkyl, substituted aryl, aryloxy, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, —C(O)OR4, —C(O)NR7R8, —S(O)2NR7R8, —S(O)nR4, protected —OH 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)OR4, —C(O)NR7R8, —S(O)2NR7R8, —S(O)nR4, aryloxy, nitro, cyano, halogen, and protected —OH, where R4 is hydrogen, alkyl, cycloalkyl, C1-C12aryl, substituted alkyl, substituted cycloalkyl and substituted C1-C12aryl; and R7 and R8 are independently 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)OR4, —S(O)nR4, —C(O)NR4R4, —S(O)2NR4R4, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C1-C12aryl, substituted C1-C12aryl and protected —OH, or R7 and R8 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, where R4 is as described above and n is 0-2; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
- 2. The method of claim 1 wherein the mammal is a human.
- 3. The method of claim 2 wherein the compound is selected from3-hydroxy-4-{[5-hydroxy-3-methyl-1-(4-methylphenyl)-1H-pyrazol-4-yl]azo}benzoic acid; 3-hydroxy-4-[(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]benzoic acid; 4-{[1-(4-benzyloxyphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 4-{[1-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 4-{[1-(3-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 4-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 3-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-4-hydroxybenzoic acid; 3-hydroxy-4-{[5-hydroxy-3-methyl-1-(3-methylphenyl)-1H-pyrazol-4-yl]azo}benzoic acid; 3-hydroxy-4-{[5-hydroxy-3-methyl-1-(4-trifluoromethylphenyl)-1H-pyrazol-4-yl]azo}benzoic acid; 3-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-2-hydroxybenzoic acid; 2-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 5-chloro-3-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-2-hydroxybenzenesulfonic acid; 3-tert-butyl-4-{[1-(3,4-dimethylphenyl)-5-hydroxy-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 4-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-phenyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; methyl 3-hydroxy-4-{[5-hydroxy-3-methyl-1-(4-methylphenyl)-1H-pyrazol-4-yl]azo}benzoate; and 4-{[1-(4-tert-butylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
- 4. 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 claim 1.
- 5. The method of claim 4 wherein the mammal is a human.
- 6. The method of claim 5 wherein the compound is selected from3-hydroxy-4-{[5-hydroxy-3-methyl-1-(4-methylphenyl)-1H-pyrazol-4-yl]azo}benzoic acid; 3-hydroxy-4-[(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]benzoic acid; 4-{[1-(4-benzyloxyphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 4-{[1-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 4-{[1-(3-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 4-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 3-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-4-hydroxybenzoic acid; 3-hydroxy-4-{[5-hydroxy-3-methyl-1-(3-methylphenyl)-1H-pyrazol-4-yl]azo}benzoic acid; 3-hydroxy-4-{[5-hydroxy-3-methyl-1-(4-trifluoromethylphenyl)-1H-pyrazol-4-yl]azo}benzoic acid; 3-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-2-hydroxybenzoic acid; 2-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 5-chloro-3-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-2-hydroxybenzenesulfonic acid; 3-tert-butyl-4-{[1-(3,4-dimethylphenyl)-5-hydroxy-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 4-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-phenyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; methyl 3-hydroxy-4-{[5-hydroxy-3-methyl-1-(4-methylphenyl)-1H-pyrazol-4-yl]azo}benzoate; and 4-{[1-(4-tert-butylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
- 7. A pharmaceutical composition for use in enhancing platelet production which comprises a compound of Formula (II), as described in claim 1, and a pharmaceutically acceptable carrier.
- 8. A method of activating the TPO receptor which comprises administrating a compound of Formula (II), as described in claim 1.
- 9. The method of claim 1 wherein the compound is administered orally.
- 10. The method of claim 1 wherein the compound is administered parenterally.
- 11. A method of agonizing the TPO receptor in a subject which comprises administering an effective amount of a compound of Formula (II), as described in claim 1.
- 12. A method of agonizing the TPO receptor in a subject which comprises administering an effective amount of a compound of as described in claim 3.
- 13. A compound represented by the following Formula (I) wherein:R, R1, R2, R3 and R9 are each independently selected from hydrogen, C1-6alkyl, C1-6alkoxy, —(CH2)pOR4, —C(O)OR4, nitro, cyano, halogen, aryl, —S(O)nR4, cycloalkyl, protected —OH, —CONR5R6, phosphonic acid, sulfonic acid, phosphinic acid and —SO2NR5R6, where p is 0-6; n is 0-2; R4 is hydrogen, alkyl, cycloalkyl, C1-C12aryl, substituted alkyl, substituted cycloalkyl and substituted C1-C12aryl, and R5 and R6 are each independently selected from hydrogen, alkyl, C3-6cycloalkyl, aryl or R5 and R6 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; m is 0-6; and R10 is 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, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, aryloxy, alkoxy, acyloxy, amino, nitro, cyano, halogen, hydroxy, protected —OH, and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, aryloxy, amino, nitro, cyano, halogen, hydroxy, and protected —OH; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof; provided that:at least one of R, R1, R2 and R3 is: sulfonic acid, —C(O)OR4, tetrazole, —CONR5R6, phosphonic acid or phosphinic acid; where R4, R5 and R6 are as described above; and provided that:when R1 is carboxylic acid; R, R2 and R3 are hydrogen; and R9 is methyl; R10 is not unsubstituted phenyl.
- 14. A compound of claim 13 selected from3-hydroxy-4-{[5-hydroxy-3-methyl-1-(4-methylphenyl)-1H-pyrazol-4-yl]azo}benzoic acid; 4-{[1-(4-benzyloxyphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 4-{[1-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 4-{[1-(3-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 4-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 3-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-4-hydroxybenzoic acid; 3-hydroxy-4-{[5-hydroxy-3-methyl-1-(3-methylphenyl)-1H-pyrazol-4-yl]azo}benzoic acid; 3-hydroxy-4-{[5-hydroxy-3-methyl-1-(4-trifluoromethylphenyl)-1H-pyrazol-4-yl]azo}benzoic acid; 3-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-2-hydroxybenzoic acid; 2-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 5-chloro-3-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-2-hydroxybenzenesulfonic acid; 3-tert-butyl-4-{[1-(3,4-dimethylphenyl)-5-hydroxy-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; 4-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-phenyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; methyl 3-hydroxy-4-{[5-hydroxy-3-methyl-1-(4-methylphenyl)-1H-pyrazol-4-yl]azo}benzoate; and 4-{[1-(4-tert-butylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
- 15. A process for the preparation of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R, R1, R2, R3 R9, R10 and m are as described in claim 13, which comprises:reacting a compound of the following formula (i), wherein R, R1, R2, R3 and m are as described in claim 13 with a nitrite and an acid to form a diazonium compound of formula (ii), wherein R, R1, R2, R3 and m are as described in claim 13; followed by a coupling reaction with an appropriate pyrazole reactant, to form a compound of Formula (I),and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.
- 16. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of the Formula (II) as described in claim 1 and pharmaceutically acceptable salts, hydrates, solvates and esters thereof which process comprises bringing the compound of the Formula (II) into association with the pharmaceutically acceptable carrier or diluent.
Parent Case Info
This application is a 371 of PCT/US00/24665, filed on Sep. 8, 2000.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/US00/24665 |
|
WO |
00 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO01/17349 |
3/15/2001 |
WO |
A |
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
5482546 |
Eida |
Jan 1996 |
A |