3'-[(2Z)-[1-(3,4-DIMETHYLPHENYL)-1,5-DIHYDRO-3-METHYL-5-OXO-4H-PYRAZOL-4-YLIDENE]HYDRAZINO]-2'-HYDROXY-[1,1'-BIPHENYL]-3-CARBOXYLIC ACID bis-(MONOETHANOLAMINE)

Abstract

An improved thrombopoietin mimetic, the bis-(monoethanolamine) salt of 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid.

1 . A method of enhancing platelet production in a human in need thereof which comprises administering to such human an effective amount of the compound 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine). 
     
     
         2 . The method of  claim 1  wherein the compound is administered orally. 
     
     
         3 . The method of  claim 1  wherein the compound is administered parenterally. 
     
     
         4 . A method for enhancing platelet production obtained from a human donor which comprises administering to such donor an effective therefore amount of the compound 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine) prior to platelet pheresis, blood donation or platelet donation. 
     
     
         5 . A method for enhancing the number of peripheral blood stem cells obtained from a human donor which comprises administering to such donor an effective amount of the compound 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine) prior to leukapheresis. 
     
     
         6 . A method of  claim 5  further comprising co-administering a therapeutically effective amount of a hematopoietic-cell mobilizing agent selected from the group consisting of: a colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist, adhesion molecule antagonists or antibodies. 
     
     
         7 . The method of  claim 6  wherein the mobilizing agent is selected from the group consisting of: G-CSF, GM-CSF, TPO, EPO, Gro-beta, IL-8, cytoxan, VLA-4 inhibitors, SCF, FLT3 ligand or a biologically active derivative of G-CSF, GM-CSF, TPO, EPO, Gro-beta or IL-8. 
     
     
         8 . An in vitro or ex vivo method for enhancing stimulation of megakaryocyte maturation and/or platelet production which comprises adding an effective therefore amount of the compound described in  claim 1  to a culture medium of cells that express the TPO receptor. 
     
     
         9 . An in vitro or ex vivo method for enhancing stimulation of megakaryocyte maturation and/or platelet production which comprises adding an effective amount of the compound described in  claim 1  to a culture medium of stem cells, bone marrow cells, cord-blood cells or peripheral blood cells. 
     
     
         10 . A method of  claim 9 , wherein the megakaryocytes or platelets are returned to the mammal following chemotherapy or radiation therapy. 
     
     
         11 . An in vitro or ex vivo method for enhancing the survival and/or proliferation of stem cells, bone marrow cells, cord-blood cells, peripheral blood cells or other types of cells expressing the TPO receptor in culture which comprises culturing said cell in a medium containing an effective therefore amount of the compound described in  claim 1 . 
     
     
         12 . A method of  claim 11  further comprising co-administration of a therapeutically effective amount of a colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist. 
     
     
         13 . A method of  claim 11  wherein the stem cells are returned to the subject following chemotherapy or radiation therapy. 
     
     
         14 . A method of treating of neutropenia in a mammal, including a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of the compound described in  claim 1 . 
     
     
         15 . An in vitro or ex vivo method for enhancing stimulation of neutrophil production which comprises adding an effective amount of the compound described in  claim 1  to a culture medium of stem cells, bone marrow cells, cord-blood cells, peripheral blood cells or other types of cells expressing the TPO receptor. 
     
     
         16 . A method of  claim 15 , wherein the neutrophils are returned to the subject following chemotherapy or radiation therapy.