Small-molecule modulators of hepatocyte growth factor/scatter factor activities

Abstract

The invention is directed to small organic molecules having the ability to mimic or agonize hepatocyte growth factor/scatter factor (HGF/SF) activity, or inhibit or antagonize HGF/SF activity, the former useful for promoting, for example, vascularization of tissues or organs for promoting wound or tissue healing, or augmenting or restoring blood flow to ischemic tissues such as the heart following myocardial infarction. Inhibition of cellular growth or proliferation is beneficial in the treatment, for example, of inflammatory diseases such as inflammatory joint and skin diseases, and dysproliferative diseases such as cancer.

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         5 . A method for modulating HGF/SF activity in a mammal comprising administering to said mammal an effective HGF/SF activity modulating amount of a compound with the general formula II:  
       
         
           
           
               
               
           
         
       
       wherein 
 R5 is methyl;  
 R3 is an alkyl-, halogen- or alkyloxy-substituted phenyl group;  
 R1 is hydrogen or methyl; and  
 R2 is a substituted pyridyl or arylthiocarbonyl group or a 4-aryl-substituted 5-methylisoxazonecarbonyl group.  
 
     
     
         6 . The method of  claim 5  wherein said pyridyl group is a 2-(6-trifluoromethyl)pyridyl group or said arylthiocarbonyl group is a 2-(nitrophenyl)thiocarbonyl group.  
     
     
         7 . A method for modulating HGF/SF activity in a mammal comprising administering to said mammal an effective HGF/SF activity modulating amount of a compound selected from the group consisting of 
 N′4,5-dimethyl-N′4-(5-nitro-2-pyridyl)-3-(2,6-dichlorophenyl)isoxazole-4-carbohydrazide;    N′4-(2-(((2,4-dichlorobenzylidene)amino)oxy)acetyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide;    N′4-(3-(3,4,5-trimethoxyphenyl)propanoyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide;      2 -nitrophenyl 2-((3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl)carbonyl)hydrazine-1-carbothioate;    N′4-((2-methyl-1,3-thiazol-4-4yl)carbonyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-4carbohydrazide;    N1-((2-((3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl)carbonyl)hydrazino)(methylthio)methylidene)benzene-1-sulfonamide;    N′4-(2,4,6-trichlorophenyl)-3-3(2,6-dichlorophenyl )-5-methylisoxazole-4-carbohydrazide;    N′4,3-di(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide;    N′4-(3,5-dichloro-4-pyridyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide;    N′4-phenyl-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide;    N′4,N′4,5-trimethyl-3-(2,6-dichlorophenyl)isoxazole-4-carbohydrazide;    N4-azepan-1-yl-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxamide; N′4-(6-(trifluoromethyl)-2-pyridyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide; and    N′4-(3,3-diethoxypropanoyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbohydrazide.    
     
     
         8 . The method of  claim 5  or  7  where said compound is an HGF/SF agonist or an HGF/SF antagonist.  
     
     
         9 . A pharmaceutical composition comprising a compound with the general formula II:  
       
         
           
           
               
               
           
         
       
       wherein 
 R5 is methyl;  
 R3 is an alkyl-, halogen- or alkyloxy-substituted phenyl group;  
 R1 is hydrogen or methyl; and  
 R2 is a substituted pyridyl or arylthiocarbonyl group or a 4-aryl-substituted 5-methylisoxazonecarbonyl group;  
 And a pharmaceutically-acceptable carrier.  
 
     
     
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         19 . A method for increasing hepatocyte growth factor/scatter factor (HGF/SF) activities in a mammal comprising administration to said mammal an effective amount of a compound having a molecular weight below about 1,000 Daltons, said compound exhibiting HGF/SF-like activity in at least one HGF/SF activity assay selected from the group consisting of 
 induction of proliferation of endothelial cells in vitro or in vivo;    induction of angiogenesis in vitro or in vivo;    increasing angiogenesis in wounds in vivo;    promoting tumor growth;    inducing gene expression of angiogenic-cascade-related genes such as but not limited to IL-8 and angiopoietin-2;    inducing anti-apoptotic activity; and    inducing scatter activity.    
     
     
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         22 . The method of  claim 19  wherein said compound exhibits HGF/SF-like activity in at least two said HGF/SF activity assays, at least three said HGF/SF activity assays, at least four said HGF/SF activity assays, at least five said HGF/SF activity assays, at least six said HGF/SF activity assays, or in all said HGF/SF activity assays.  
     
     
         23 . The method of  claim 19  wherein said compound has a molecular weight between about 200 and about 1,000 Daltons.  
     
     
         24 . The method of  claim 23  wherein said compound has a molecular weight between 300 Daltons and about 750 Daltons.  
     
     
         25 . The method of  claim 24  wherein said compound has a molecular weight between about 300 Daltons and about 500 Daltons.  
     
     
         26 . A method for the prophylaxis or treatment in a mammal of hepatic disease, renal disease, bone regeneration, hair growth, promoting wound or tissue healing, promoting vascularization of a tissue, promoting wound healing, promoting vascularization of an ischemic tissue, promoting vascularization of a tissue susceptible to ischemia, or augmenting or restoring blood flow to ischemic tissues such as the heart following myocardial infarction comprising administered systemically or locally to particular tissues or organ in need thereof a an effective amount of a compound having a molecular weight below about 1,000 Daltons, said compound exhibiting HGF/SF-like activity in at least one HGF/SF activity assay selected from the group consisting of 
 induction of proliferation of endothelial cells in vitro or in vivo;    induction of angiogenesis in vitro or in vivo;    increasing angiogenesis in wounds in vivo;    promoting tumor growth;    inducing gene expression of angiogenic-cascade-related genes such as but not limited to IL-8 and angiopoietin-2;    inducing anti-apoptotic activity; and    inducing scatter activity.    
     
     
         27 . The method of  claim 26  wherein said HGF/SF activity of said compound is inhibited in the presence of c-Met.  
     
     
         28 . The method of  claim 26  wherein said compounds binds c-Met.  
     
     
         29 . The method of  claim 26  wherein said compound exhibits HGF/SF-like activity in at least two said HGF/SF activity assays, at least three said HGF/SF activity assays, at least four said HGF/SF activity assays, at least five said HGF/SF activity assays, at least six said HGF/SF activity assays, or in all said HGF/SF activity assays.  
     
     
         30 . The method of  claim 26  wherein said compound has a molecular weight between about 200 and about 1,000 Daltons.  
     
     
         31 . The method of  claim 30  wherein said compound has a molecular weight between 300 Daltons and about 750 Daltons.  
     
     
         32 . The method of  claim 31  wherein said compound has a molecular weight between about 300 Daltons and about 500 Daltons.  
     
     
         33 . A method for inhibiting the activity of hepatocyte growth factor/scatter factor (HGF/SF) in a mammal comprising administering to said mammal an effective amount of a compound having a molecular weight below about 1,000 Daltons, said compound exhibiting HGF/SF inhibitory or antagonistic activity in at least one HGF/SF activity assay selected from the group consisting of 
 inhibiting proliferation of endothelial cells in vitro or in vivo;    inhibiting the growth of tumor cells in vitro or in vivo;    inhibiting scatter of normal or tumor cells in vitro or in vivo; and    inhibiting anti-apoptotic activity.    
     
     
         34 . The method of  claim 33  wherein said activities are exhibitable in the presence of exogenously-added HGF/SF.  
     
     
         35 . The method of  claim 33  wherein said compound exhibits HGF/SF inhibitory activity in at least two said HGF/SF activity assays, in at least three said HGF/SF activity assays, or in all said HGF/SF activity assays.  
     
     
         36 . The method of  claim 33  wherein said compound has a molecular weight between about 200 Daltons and about 1,000 Daltons.  
     
     
         37 . The method of  claim 36  wherein said compound has a molecular weight between about 300 Daltons and about 750 Daltons.  
     
     
         38 . The method of  claim 22  wherein said compound has a molecular weight between about 300 Daltons and about 500 Daltons.  
     
     
         39 . A method for the prophylaxis or treatment in a mammal of a condition of disease selected from the group consisting of excessive cellular proliferation, angiogenesis, a dysproliferative disease, cancer, metastasis, inflammatory disease, diabetic retinopathy, inflammatory joint disease, and inflammatory skin disease comprising administering to said mammal an effective amount of a compound having a molecular weight below about 1,000 Daltons, said compound exhibiting HGF/SF inhibitory or antagonistic activity in at least one HGF/SF activity assay selected from the group consisting of 
 inhibiting proliferation of endothelial cells in vitro or in vivo;    inhibiting the growth of tumor cells in vitro or in vivo;    inhibiting scatter of normal or tumor cells in vitro or in vivo; and    inhibiting anti-apoptotic activity.    
     
     
         40 . The method of  claim 39  wherein said activities are exhibitable in the presence of exogenously-added HGF/SF.  
     
     
         41 . The method of  claim 39  wherein said compound exhibits HGF/SF inhibitory activity in at least two said HGF/SF activity assays, in at least three said HGF/SF activity assays, or in all said HGF/SF activity assays.  
     
     
         42 . The method of  claim 39  wherein said compound has a molecular weight between about 200 Daltons and about 1,000 Daltons.  
     
     
         43 . The method of  claim 42  wherein said compound has a molecular weight between about 300 Daltons and about 750 Daltons.  
     
     
         44 . The method of  claim 43  wherein said compound has a molecular weight between about 300 Daltons and about 500 Daltons.