Methods for suppressing an immune response or treating a proliferative disorder

Abstract

Disclosed herein are methods for suppressing an immune response in a subject, treating a neoplasm in a subject, or treating a fibroproliferative vascular disease in a subject, that includes administering to the subject a therapeutically effective amount of a 2-(4-piperazinyl)-substituted 4H-1-benzopyran-4-one compound, or a pharmaceutically acceptable salt thereof, having the structure of wherein the presence of each of R 1 and R 2 is optional and R 1 and R 2 are each independently selected from alkyl, substituted alkyl, heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, halogen, hydroxy, or amino.

What is claimed is: 
     
         1 . A method of suppressing an immune response in a subject, comprising administering to the subject a therapeutically effective amount of a 2-(4-piperazinyl)-substituted 4H-1-benzopyran-4-one compound, or a pharmaceutically acceptable salt thereof, having the structure of 
       
         
           
           
               
               
           
         
         wherein the presence of each of R 1  and R 2  is optional and R 1  and R 2  are each independently selected from alkyl; substituted alkyl; heteroalkyl; cycloalkyl; substituted cycloalkyl; heterocycloalkyl; substituted heterocycloalkyl selected from piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolindinyl, or oxazolinyl, in which one or more hydrogen or carbon atom is replaced by another group selected from a halogen, aryl, substituted aryl, alkoxy, aryloxy, amino or a combination thereof; aryl selected from phenyl, naphthyl, biphenyl, diphenylether, diphenylamine or benzophenone; substituted aryl selected from phenyl, naphthyl, biphenyl, diphenylether, diphenylamine or benzophenone in which one or more hydrogen or carbon atom is replaced by one or more functional groups selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, halogen, alkylhalos, hydroxy, amino, alkoxy, or thio; heteroaryl selected from thiophene, pyridine, isoxazole, phthalidimide, pyrazole, indole, or furan; substituted heteroaryl selected from thiophene, pyridine, isoxazole, phthalidimide, pyrazole, indole, or furan in which one or more hydrogen or carbon atom is replaced by one or more functional groups selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, halogen, alkylhalo, hydroxy, amino, alkoxy, or thio; alkoxy; halogen; hydroxy; or amino; and 
         wherein the 2-(4-piperazinyl)-substituted 4H-1-benzopyran-4-one compound inhibits mammalian Target of Rapamycin or casein kinase 2, but does not significantly inhibit phosphatidylinositol 3-kinase, 
         thereby suppressing the immune response in the subject. 
       
     
     
         2 . The method of  claim 1 , wherein the 2-(4-piperazinyl)-substituted 4H-1-benzopyran-4-one compound comprises a 2-(4-piperazinyl)-8-phenyl-4H-1-benzopyran-4-one compound having the structure of 
       
         
           
           
               
               
           
         
         wherein the presence of each of R 1  and R 2  is optional and R 1  and R 2  are each independently selected from alkyl, aryl, alkoxy, halogen, hydroxy or amino, and wherein R 3  is not present. 
       
     
     
         3 . The method of  claim 1 , wherein the 2-(4-piperazinyl)-substituted 4H-1-benzopyran-4-one compound comprises 2-(4-piperazinyl)-8-phenyl-4H-1-benzopyran-4-one. 
     
     
         4 . The method of  claim 1 , wherein the subject has an autoimmune disorder. 
     
     
         5 . The method of  claim 1 , wherein the subject has an inflammatory response. 
     
     
         6 . The method of  claim 1 , wherein the subject has graft versus host disease. 
     
     
         7 . The method of  claim 1 , wherein the subject is a transplant recipient, and wherein the immune response is a rejection of the transplant. 
     
     
         8 . The method of  claim 1 , further comprising administering a therapeutically effective amount of an additional immunosuppressive agent to the subject. 
     
     
         9 . The method of  claim 8 , wherein the immunosuppressive agent is Cyclosporine A, FK506 or an analog thereof. 
     
     
         10 . The method of  claim 8 , wherein the immunosuppressive agent is a monoclonal antibody that specifically binds CD3, CD4, or CD8. 
     
     
         11 . The method of  claim 1 , wherein the immune response comprises cytokine secretion. 
     
     
         12 . The method of  claim 1 , comprising administering the 2-(4-piperazinyl)-substituted 4H-1-benzopyran-4-one compound, or a pharmaceutically acceptable salt thereof systemically.