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.

What is claimed is: 
     
         1 . 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 . A pharmaceutical composition comprising 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) and a pharmaceutically acceptable carrier or diluent. 
     
     
         3 . A method of treating thrombocytopenia in a mammal, including a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound as described in  claim 1 . 
     
     
         4 . A method as claimed in  claim 3 , wherein the mammal is a human. 
     
     
         5 . A method of enhancing platelet production in a mammal, including a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound as described in  claim 1 . 
     
     
         6 . A method as claimed in  claim 5 , wherein the mammal is a human. 
     
     
         7 . A method of agonizing the TPO receptor in a subject which comprises administering an effective amount of a compound as described in  claim 1 . 
     
     
         8 . A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound as described in  claim 1 , which process comprises bringing the compound described in  claim 1  into association with the pharmaceutically acceptable carrier or diluent. 
     
     
         9 . 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, interleukin or cytokine receptor agonist or antagonists, soluble receptors, receptor agonists or antagonist antibodies, or small molecules or peptides that act by the same mechanisms of one or more of said agents. 
     
     
         10 . A method for enhancing platelet production obtained from a donor which comprises administering to such donor a therapeutically effective amount of a compound as described in  claim 1  prior to platelet pheresis, blood donation or platelet donation. 
     
     
         11 . A method for enhancing the number of peripheral blood stem cells obtained from a donor which comprises administering to such donor a therapeutically effective amount of a compound as described in  claim 1  prior to leukapheresis. 
     
     
         12 . An in vitro or ex vivo method for enhancing stimulation of megakaryocyte maturation and/or platelet production which comprises adding an effective amount of a compound as described in  claim 1  to the culture medium of cells that express the TPO receptor. 
     
     
         13 . An in vitro or ex vivo method for enhancing stimulation of megakaryocyte maturation and/or platelet production which comprises adding an effective amount of a compound as described in  claim 1  to the culture medium of stem cells, bone marrow cells, cord-blood cells or peripheral blood cells. 
     
     
         14 . A method of  claim 13 , wherein the megakaryocytes or platelets are returned to the mammal following chemotherapy or radiation therapy. 
     
     
         15 . 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 amount of a compound as described in  claim 1 . 
     
     
         16 . A method of  claim 15  wherein the stem cells are returned to the mammal following chemotherapy or radiation therapy. 
     
     
         17 . 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 a compound as described in  claim 1 . 
     
     
         18 . An in vitro or ex vivo method for enhancing stimulation of neutrophil production which comprises adding an effective amount of a compound as described in  claim 1  to the culture medium of stem cells, bone marrow cells, cord-blood cells, peripheral blood cells or other types of cells expressing the TPO receptor. 
     
     
         19 . A method of  claim 18 , wherein the neutrophils are returned to the mammal following chemotherapy or radiation therapy. 
     
     
         20 . A process for preparing the compound of  claim 1 , which process comprises:
 i) dissolving 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 in an appropriate organic solvent, to form a solution;   ii) adding two or more equivalents of ethanolamine to the solution; and   iii) isolating the prepared compound.