Thrombopoietin mimetics
View Patent ↗Invented are non-peptide TPO mimetics. Also invented are novel processes and intermediates used in the preparation of the presently invented compounds. 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 hydroxy-1-azobenzene derivative.
1. A compound selected from the group consisting essentially of:
3-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2-hydroxy-3′-(tetrazol-5-yl)biphenyl, and a pharmaceutically acceptable salt, a hydrate, a solvate, and an ester, thereof.
2. A pharmaceutical composition which comprises a compound of claim 1 and a pharmaceutically acceptable carrier.
3. A method of treating thrombocytopenia in a human in need thereof which comprises administering to such human a therapeutically effective amount of the compound of claim 1 .
4. The method of claim 3 wherein the compound is administered orally.
5. The method of claim 3 wherein the compound is administered parenterally.
6. The method of claim 3 further comprising co-administering a therapeutically effective amount of an agent selected from the group consisting of: a colony stimulating factor, cytokine, chemokine, and an interleukin or cytokine receptor agonist or antagonist.
7. The method of claim 6 wherein the agent is selected from the group consisting of: G-CSF, GM-CSF, TPO, M-CSF, EPO, Gro-beta, IL-11, SCF, FLT3 ligand, LIF, IL-3, IL-6, IL-1, NESP, SD-01, IL-8, and IL-5.
8. The method of claim 3 wherein said thrombocytopenia is due to myelosuppression caused by chemotherapy or radiation therapy.
9. The method of claim 3 wherein said thrombocytopenia is due to an organ transplant.
10. The method of claim 3 wherein said thrombocytopenia is due to bone marrow, stem cell, or liver transplant.
11. The method of claim 3 wherein said thrombocytopenia is due to idiopathic thrombocytopenia purpura (ITP).
12. The method of claim 3 wherein said thrombocytopenia is due to myelodysplastic syndromes (MDS), aplastic anemia or leukemia.
13. The method of claim 3 wherein said thrombocytopenia is due to viral, fungal, microbial or parasitic infection.
14. The method of claim 3 wherein said thrombocytopenia is due to liver dysfunction.
15. The method of claim 3 wherein said thrombocytopenia is due to surgical procedures.
16. The method of claim 3 wherein said thrombocytopenia is due to treatment with antiviral or antibiotic agents.
17. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of the compound of claim 1 , which process comprises bringing said compound into association with the pharmaceutically acceptable carrier or diluent.
18. A compound selected from the group consisting essentially of:
3′-{N′-[1-(4-tert-butylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid, and a pharmaceutically acceptable salt, a hydrate, a solvate, and an ester, thereof.
19. A compound selected from the group consisting essentially of:
3-Aza-3′-{N′-[1-(4-tert-butylpbenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-5-carboxylic acid, and a pharmaceutically acceptable salt, a hydrate, a solvate, and an ester, thereof.
20. The compound 3-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2-hydroxy-3′-(tetrazol-5-yl)biphenyl, or a pharmaceutically acceptable salt thereof.
21. A compound of claim 20 , wherein the compound is in the form of a pharmaceutically acceptable salt.
22. A compound of claim 20 , wherein the compound is 3-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2-hydroxy-3′-(tetrazol-5-yl)biphenyl.
23. The compound 3-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2-hydroxy-3′-(tetrazol-5-yl)biphenyl, or an ester thereof.
24. A compound of claim 23 , wherein the compound is in the form of an ester.
25. A pharmaceutical composition which comprises a compound of claim 20 and a pharmaceutically acceptable carrier.
26. A pharmaceutical composition which comprises a compound of claim 21 and a pharmaceutically acceptable carrier.
27. A pharmaceutical composition which comprises the compound of claim 22 and a pharmaceutically acceptable carrier.
28. A pharmaceutical composition which comprises a compound of claim 23 and a pharmaceutically acceptable carrier.
29. A pharmaceutical composition which comprises a compound of claim 24 and a pharmaceutically acceptable carrier.
30. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of claim 20 , which process comprises bringing said compound into association with the pharmaceutically acceptable carrier or diluent.
31. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of claim 23 , which process comprises bringing said compound into association with the pharmaceutically acceptable carrier or diluent.
32. A method of claim 6 wherein the co-administered agent is selected from the group consisting of: a colony stimulation factor, cytokine and chemokine.
33. A method of claim 7 wherein the agent is selected from the group consisting of G-CSF, GM-CSF, EPO and IL-5.