Method for reducing or preventing the establishment, growth or metastasis of cancer by administering PAR-1 and optionally PAR-2 antagonists

Abstract

We have discovered a method of modifying the tumor cell microenvironment to reduce or prevent the establishment, growth or metastasis of malignant cells comprising administering to a patient having malignant cells a pharmaceutically effective amount of a PAR-1 inhibitor and optionally a PAR-2 inhibitor to prevent or reduce activation of normal cells within the tumor microenviroment. This method also has the effect in some patients of modulating the immune system to facilitate a more efficient immune response to malignant cells and maybe coupled with cytokine therapy and T-cell therapy to enhance the patient's immune response to the malignant cells.

We Claim:  
     
         1 . A method of modifying the tumor cell microenviromnent to reduce or prevent the establishment, growth or metastasis of malignant cells that directly or indirectly activate the PAR-i receptor of normal cells comprising providing a pharmaceutically effective amount of a PAR-1 inhibitor and optionally a PAR-2 inhibitor to a patient with malignant cells that directly or indirectly activate PAR-1 and/or PAR-2.  
     
     
         2 . The method of  claim 1  wherein the PAR-1 inhibitor is a compounds of the general formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is selected from amino, C 1 -C 8  alkylamino, C 1 -C 8  dialkylamino, arylarnino, arC 1 -C 8  alkylamino, C 3 -C 8  cycloalkylamino, heteroalkylC 1 -C 8  alkylamino, heteroalkylC 1 -C 8  alkyl-N-methylamino, C 1 -C 8  dialkylamino C 1 -C 8  alkylamino, -N(C 1 -C 8 alkyl)-C 1 -C 8 alkyl-N(C 1 -C 8 alkyl) 2 , -N(C 1 -C 8  alkyl)(C 1 C- 8  alkenyl), -N(C 1 -C 8 alkyl)(C 3 -C 8 cycloalkyl), heteroalkyl or substituted heteroalkyl, wherein the substituent on the heteroalkyl is selected from oxo, amino, C 1 -C 8  alkoxy, C 1 -C 8  alkyl, C 1 -C 8  alkylamino or C 1 -C 8  dialkylamino;  
 R 2  is selected from unsubstituted or substituted aryl, arC 1 -C 8  alkyl, C 3 -C 8 cycloalkyl or heteroaryl, wherein the substituents on the aryl, aralkyl, cycloalkyl or heteroaryl group are independently selected from one or more of halogen, nitro, amino, cyano, hydroxyalkyl, C 1 -C 8  alkyl, C 1 -C 8  alkoxy, C 1 -C 8 alkoxycarbonyl, acetyl, fluorinated C 1 -C 4  alkyl, fluorinated C 1 -C 4  alkoxy or C 1 -C 4  alkylsulfonyl;  
 R 3  is selected from H or C 1 -C 8  alkyl;  
 R 4  and R 5  are each selected from H, C 1 -C 8  alkyl, amino C 1 -C 8  alkyl, amidino C 1 -C 8  alkyl, guanidino C 1 -C 8  alkyl, aryl, aryl C 1 -C 8  alkyl, substituted aryl, substituted arylC 1 -C 8  alkyl, heteroaryl, heteroaryl C 1 -C 8  alkyl, substituted heteroaryl, substituted heteroaryl C 1 -C 8  alkyl, cyclo C 3 -C 6  alkyl or substituted cycloC 3 -C 6 alkyl, wherein the substituents on the aryl, aralkyl, cycloalkyl or heteroaryl group are independently selected from one or more of halogen, nitro, amino, amidino, guanidino, cyano, hydroxyalkyl, C 1 -C 8  alkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkoxycarbonyl, acetyl, fluorinated C 1 -C 4  alkyl, fluorinated C 1 -C 4  alkoxy or C 1 -C 4  alkylsulfonyl;  
 R 6  and R 7  are each selected from H, C 1 -C 8  alkyl, amino-C 1 -C 8  alkyl, amino-C 3 -C 8  cycloalkyl, amidino C 1 -C 8  alkyl, guanidino C 1 -C 8  alkyl, aryl, substituted aryl, aryl C 1 -C 8  alkyl, substituted aryl C 1 -C 8  alkyl, heteroaryl C 1 -C 8  alkyl or substituted heteroaryl C 1 -C 8  alkyl, wherein the substituents on the aryl, aralkyl, cycloalkyl or heteroaryl group are independently selected from one or more of halogen, nitro, amino, amidino, guanidino, cyano, hydroxyalkyl, C 1 -C 8  alkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkoxycarbonyl, acetyl, fluorinated C 1 -C 4  alkyl, fluorinated C 1 -C 4  alkoxy or C 1 -C 4  alkylsulfonyl;  
 Either R 5  or R 7  must be H when m is 1; in addition, when R 5  is H, then R 4  cannot be H; and, when R 7  is H, then R 6  cannot be H;  
 R 8  is selected from H, C 1 -C 8  alkyl, amino C 1 -C 8  alkyl, allyl, C 3 -C 8  cycloalkyl, substituted C 3 -C 8  cycloalkyl, aryl, substituted aryl, ar C 1 -C 8  alkyl, substituted ar C 1 -C 8  alkyl, heteroaryl, substituted heteroaryl, heteroaryl C 1 -C 8  alkyl or substituted heteroaryl C 1 -C 8  alkyl, wherein the substituents on the aryl, aralkyl, cycloalkyl or heteroaryl group are independently selected from one or more of halogen, nitro, amino, amidino, guanidino, cyano, hydroxyalkyl, C 1 -C 8  alkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkoxycarbonyl, acetyl, fluorinated C 1 -C 4  alkyl, fluorinated C 1 -C 4  alkoxy or C 1 -C 4  alkylsulfonyl;  
 X is CH or N;  
 n is an integer selected from 0, 1, 2 or 3;  
 m is an integer selected from 0 or 1;  
 p is an integer selected from 1 or 2;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         3 . The method of  claim 1  wherein the PAR-1 inhibitor is administered with a therapeutically effective amount of at least one PAR-2 inhibitor.  
     
     
         4 . The method of  claim 2  wherein the PAR-1 inhibitor is administered with a therapeutically effective amount of a cytokine selected from the group consisting of IL-2, IL-12, IL-18, G-CSF, M-CSF, GM-CSF, INF-α, INF-β, INF-γ, TNF and combinations thereof.  
     
     
         5 . The method of  claim 4  wherein additionally administered in a pharmaceutical effective amount is at least one conventional chemotherapy agent.  
     
     
         6 . The method of  claim 5  wherein the chemotherapy agent is selected from the group consisting of antiangiogenic compounds, alkylating compounds, antimetabolites, hormonal agonist /antagonists, monoclonal antibodies for cancer treatment, antiproliferative compounds and combinations thereof.  
     
     
         7 . The method of  claim 2  wherein additional administered are T cells selected from the group consisting of activated T cells, activated NK cells and combinations thereof.  
     
     
         8 . The method of  claim 1  wherein the PAR-1 inhibitor is administered before surgery.  
     
     
         9 . The method of  claim 1  wherein the PAR-1 inhibitor is administered after surgery.  
     
     
         10 . A method for the modulation of the immune system to enhance a patient's immune response to malignant cells that directly or indirectly activate the PAR-1 receptor of normal cells comprising administer a pharmaceutically effective dose of a PAR-1 inhibitor and optionally a PAR-2 inhibitor to the patient to enhance the patient's immune response to the malignant cells.  
     
     
         11 . The method of  claim 10  wherein additionally administered are cytokines to facilitate the development of a Th1 response.  
     
     
         12 . The method of  claim 11  wherein the cytokines are selected from the group consisting of IL-2, IL 12, IL-I18, INF-α, INF-β, INF-γ, TNF and combinations thereof.  
     
     
         13 . The method of  claim 10  wherein additionally administered are T cells selected from the group consisting of activated CTL cells, activated NK cells and combinations thereof.  
     
     
         14 . The method of  claim 10  wherein additionally administered are activated NK cells.  
     
     
         15 . The method of  claim 10  wherein additionally administered are activated CTL cells.  
     
     
         16 . The method of  claim 10  wherein the PAR-1 inhibitor is administered before surgery.  
     
     
         17 . The method of  claim 10  wherein the PAR-1 inhibitor is administered after surgery.