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 method of therapeutic therapy of thrombocytopenia in a human in need thereof which comprises administering to such human a therapeutically effective amount of a compound of the following formula:
wherein AR is a polycyclic aromatic ring containing 3 to 16 carbon atoms and 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 the AR is optionally substituted with one or more substituents selected from the group consisting of: alkyl, trifluoromethyl and hydroxy; and
R 1 and R 2 are independently selected from hydrogen and alkyl, provided that R 1 and R 2 are not both hydrogen;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 wherein in the administered compound:
the AR contains one or two heteroatoms and is substituted with one or more substituents selected from the group consisting of: alkyl, trifluoromethyl and hydroxy; and
R 1 and R 2 are independently selected from hydrogen and alkyl, provided that R 1 and R 2 are not both hydrogen;
or a pharmaceutically acceptable salt thereof.
3. The method of claim 2 wherein in the administered compound:
the AR is substituted with one or two substituents selected from the group consisting of: alkyl, trifluoromethyl and hydroxy; and
R 1 and R 2 are independently selected from hydrogen and alkyl, provided that R 1 and R 2 are not both hydrogen;
or a pharmaceutically acceptable salt thereof.
4. The method of claim 3 wherein in the administered compound:
R 1 and R 2 are both methyl;
or a pharmaceutically acceptable salt thereof.
5. The method of claim 3 wherein in the administered compound:
one of R 1 and R 2 is hydrogen and the other is propyl;
or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 wherein the compound is administered orally.
7. The method of claim 1 wherein the compound is administered parenterally.
8. The method of claim 1 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.
9. The method of claim 8 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.
10. The method of claim 1 wherein said thrombocytopenia is due to myelosuppression caused by chemotherapy or radiation therapy.
11. The method of claim 1 wherein said thrombocytopenia is due to an organ transplant.
12. The method of claim 1 wherein said thrombocytopenia is due to bone marrow, stem cell, or liver transplant.
13. The method of claim 1 wherein said thrombocytopenia is due to idiopathic thrombocytopenia purpura (ITP).
14. The method of claim 1 wherein said thrombocytopenia is due to myelodysplastic syndromes (MDS), aplastic anemia or leukemia.
15. The method of claim 1 wherein said thrombocytopenia is due to viral, fungal, microbial or parasitic infection.
16. The method of claim 1 wherein said thrombocytopenia is due to liver dysfunction.
17. The method of claim 1 wherein said thrombocytopenia is due to surgical procedures.
18. The method of claim 1 wherein said thrombocytopenia is due to treatment with antiviral or antibiotic agents.