Non-peptide inhibition of T-lymphocyte activation and therapies related thereto

Abstract

Compounds, preparations and methods for immunosuppressive treatment of autoimmune disorders, graft rejection and/or graft/host disease. Therapeutically effective amounts of certain substituted triarylmethane compounds, such as 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole, are administered to mammalian patients to selectively inhibit the calcium-activated K + channel (IKCa1) in lymphocytes, monocytes, macrophages, platelets or endothelial cells without concomitant inhibition of P450-dependent enzyme systems, resulting in reduction of antigen-, cytokine-, or mitogen-induced calcium entry through store operated calcium channels in these cells, suppression of cytokine production by these cells, and inhibition of activation of these cells. Such inhibition of the Ca ++ activated K + channel (IKCa1) prevents the pre-Ca ++ stage of cell activation and thus causes immunosuppression and an anti-inflammatory response.

1 - 18 . (canceled)  
   
   
       19 . A method for suppressing antigen- or cytokine- or mitogen-stimulated calcium entry via store-operated calcium channels in lymphocytes, monocytes, macrophages, platelets and endothelial cells and/or cytokine production by these cells and/or activation of these cells of a mammalian patient, without concomitant cytochrome P450 inhibition, said method comprising the step of administering to the patient a therapeutically effective amount of a compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein; 
 X, Y and Z are the same or different and are independently selected from CH2, O, S, NR 1 , N═CH, CH═N and R 2 —C═C—R 3 , where R 2  and R 3  are H or may combine to form a saturated or unsaturated carbocyclic or heterocyclic ring, optionally substituted with one or more R groups;  
 R 1  is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl and aroyl, optionally substituted with hydroxy, amino, substituted amino, cyano, alkoxy, halogen, trihaloalkyl, nitro, thio, alkylthio, carboxy and alkoxycarbonyl groups;  
 R is selected from H, halogen, trihaloalkyl, hydroxy, acyloxy, alkoxy, alkenyloxy, thio, alkylthio, nitro, cyano, ureido, acyl, carboxy, alkoxycarbonyl, N—(R 4 )(R 5 ) and saturated or unsaturated, chiral or achiral, cyclic or acyclic, straight or branched hydrocarbyl group with from 1 to 20 carbon atoms, optionally substituted with hydroxy, halogen, trihaloalkyl, alkylthio, alkoxy, carboxy, alkoxycarbonyl, oxoalkyl, cyano and N—(R 4 )(R 5 ) group,  
 R 4  and R 5  are selected from H, alkyl, alkenyl, alkynyl, cycloalkyl and acyl or R 4  and R 5  may combine to form a ring, wherein a carbon may be optionally substituted by a heteroatom selected from O, S or N—R 6 ,  
 R 6  is H, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl or carboxyalkyl,  
 n is 0-5; m is 1 or 2; with the proviso that when m is 1, Q is selected from OH, CN, carboxyalkyl, N—(R 7 )(R 8 ), where R 7  and R 8  are selected from H, lower alkyl (1-4C), cycloalkyl, aryl, acyl, amido, or R 7  and R 8  may combine to form a saturated or unsaturated heterocylic ring and optionally substituted with up to 3 additional heteroatoms selected from N, O, and S; or  
 —NH-heterocycle, where the heterocycle is represented by thiazole, oxazole,  
                     
 isoxazole, pyridine, pyrimidine, and purine and  
 where U and V are selected from H and O; and  
 when m is 2, Q is a spacer of from 2-10 carbons either as a straight or branched, chiral or achiral, cyclic or acyclic, saturated or unsaturated, hydrocarbon group such as phenyl.  
 
   
   
       20 . A method according to  claim 19  wherein the compound is 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole.  
   
   
       21 . A method according to  claim 19  wherein the compound is 1-[(2-fluorophenyl)diphenylmethyl]-1H-pyrazole.  
   
   
       22 . A method according to  claim 19  wherein the compound is 1-[(4-chlorophenyl)diphenylmethyl]-1H-pyrazole.  
   
   
       23 . A method according to  claim 19  wherein the compound is 1-[(2-fluorophenyl)diphenylmethyl]-1H-pyrazole.  
   
   
       24 . A method according to  claim 19  wherein the compound is 1-[(2-chlorophenyl)diphenylmethyl]-1H-1,2,3,4-tetrazole.  
   
   
       25 . A method according to  claim 19  wherein the compound is 2-(2-chlorophenyl)-2,2-diphenylacetonitrile.  
   
   
       26 . A method according to  claim 19  wherein the compound is 2-(2-fluorophenyl)-2,2-diphenylacetonitrile.  
   
   
       27 . A method according to  claim 19  wherein the method is carried out for the purpose of treating or preventing an autoimmune disorder, transplant rejection or graft-versus-host disease in a mammalian patient.  
   
   
       28 . A method according to  claim 19  wherein the method is carried out for the purpose of causing immunomodulation.  
   
   
       29 . A method according to  claim 28  wherein the method is carried out for the purpose of causing immunomodulation as a treatment for an autoimmune disorder, to prevent transplant rejection or to treat graft-versus-host disease.