Use of triaryl methane compounds for inhibiting unwanted cellular proliferation associated with inflammatory disease

Abstract

The present invention provides a class of chemical compounds useful as efficacious drugs in the treatment of sickle cell disease and diseases characterized by unwanted or abnormal cell proliferation, and in particular inflammatory diseases associated with unwanted cellular proliferation. The active compounds are substituted triaryl methane compounds or analogues thereof where one or more of the aryl groups is replaced with a heteroaryl, cycloalkyl or heterocycloalkyl group and/or the tertiary carbon atom is replaced with a different atom such as Si, Ge, N or P. the compounds inhibit mammalian cell proliferation, inhibit the Gardos channel of erythrocytes, reduce sickle erythrocyte dehydration and/or delay the occurrence of erythrocyte sickling or deformation.

What is claimed is:  
     
         1 . A method for inhibiting unwanted cellular proliferation associated with an inflammatory disease, said method comprising the step of contacting a cell the proliferation of which contributes to inflammation in situ with an effective amount of a compound having the formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof, wherein:  
         n is 0, 1, 2, 3 or 4;  
         X is absent, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkenyl, or (C 1 -C 3 ) alkynyl;  
         Y is C, N, P, Si or Ge;  
         R 1  is absent, -halo, —R, —OR, —SR, —NR 2 , —ONR 2 , —NO 2 , —CN, —C(O)R, —C(S)R, —C(O)OR, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NR 2 , —C(S)NR 2 , —C(O)NR(OR), —C(S)NR(OR), —C(O)NR(SR), C(S)NR(SR), —CH(CN) 2 , —CH[C(O)R] 2 , —CH[C(S)R] 2 , —CH[C(O)OR] 2 , —CH[C(S)OR] 2 , —CH[C(O)SR] 2 , —CH[C(S)SR] 2  or aryl;  
         Ar 1  is aryl, substituted aryl, heteroaryl other than imidazole, nitroimidazole and triazole, heteroarylium other than imidazolium, nitroimidazolium and triazolium, (C 5 -C 8 ) cycloalkyl or (C 5 -C 8 ) heterocycloalkyl;  
         Ar 2  is aryl or substituted aryl;  
         Ar 3  is aryl, substituted aryl, biaryl or heteroaryl other than imidazole, nitroimidazole and triazole;  
         each R is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, substituted (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, substituted (C 1 -C 6 ) alkenyl (C 1 -C 6 ) alkynyl, substituted (C 1 -C 6 ) alkynyl, and (C 1 -C 6 ) alkoxy;  
         the aryl substituents are each independently selected from the group consisting of -halo, trihalomethyl, —R, —R′, —OR′, —SR′, NR′ 2 , —NO 2 , —CN, —C(O)R′, —C(S)R′, —C(O)OR′, —C(S)OR′, —C(O)SR′ and —C(S)SR′;  
         the alkyl, alkenyl and alkynyl substituents are each independently selected from the group consisting of -halo, —R′, —OR′, —SR′, NR′ 2 , —NO 2 , —CN, —C(O)R′, —C(S)R′, —C(O)OR′, —C(S)OR′, —C(O)SR′, —C(S)SR′, aryl, γ-butyrolactonyl, pyrrolidinyl and succinic anhydridyl; and  
         each R′ is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl and (C 1 -C 6 ) alkynyl.  
       
     
     
         2 . The method of  claim 1 , wherein said compound is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 1 , wherein said administration is selected from the group consisting of oral, parenteral, intravenous, subcutaneous, transdermal and transmucosal for a living human.  
     
     
         4 . The method of  claim 1 , wherein said mammalian cell is a fibrotic cell.  
     
     
         5 . The method of  claim 1 , wherein said mammalian cell is a lymphocyte.  
     
     
         6 . A method of treating an inflammatory disease, said method comprising the step of administering to a subject suffering from an inflammatory disease a therapeutically effective amount of a compound having the formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof, wherein:  
         n is 0, 1, 2, 3 or 4;  
         X is absent, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkenyl, or (C 1 -C 3 ) alkynyl;  
         Y is C, N, P, Si or Ge;  
         R 1  is absent, -halo, —R, —OR, —SR, —NR 2 , —ONR 2 , —NO 2 , —CN, —C(O)R, —C(S)R, —C(O)OR, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NR 2 , —C(S)NR 2 , —C(O)NR(OR), —C(S)NR(OR), —C(O)NR(SR), C(S)NR(SR), —CH(CN) 2 , —CH[C(O)R] 2 , —CH[C(S)R] 2 , —CH[C(O)OR] 2 , —CH[C(S)OR] 2 , —CH[C(O)SR] 2 , —CH[C(S)SR] 2  or aryl;  
         Ar 1  is aryl, substituted aryl, heteroaryl other than imidazole, nitroimidazole and triazole, heteroarylium other than imidazolium, nitroimidazolium and triazolium, (C 5 -C 8 ) cycloalkyl or (C 5 -C 8 ) heterocycloalkyl;  
         Ar 2  is aryl or substituted aryl;  
         Ar 3  is aryl, substituted aryl, biaryl or heteroaryl other than imidazole, nitroimidazole and triazole;  
         each R is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, substituted (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, substituted (C 1 -C 6 ) alkenyl (C 1 -C 6 ) alkynyl, substituted (C 1 -C 6 ) alkynyl, and (C 1 -C 6 ) alkoxy;  
         the aryl substituents are each independently selected from the group consisting of -halo, trihalomethyl, —R, —R′, —OR′, —SR′, NR′ 2 , —NO 2 , —CN, —C(O)R′, —C(S)R′, —C(O)OR′, —C(S)OR′, —C(O)SR′ and —C(S)SR′;  
         the alkyl, alkenyl and alkynyl substituents are each independently selected from the group consisting of -halo, —R′, —OR′, —SR′, NR′ 2 , —NO 2 , —CN, —C(O)R′, —C(S)R′, —C(O)OR′, —C(S)OR′, —C(O)SR′, —C(S)SR′, aryl, γ-butyrolactonyl, pyrrolidinyl and succinic anhydridyl; and  
         each R′ is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl and (C 1 -C 6 ) alkynyl.  
       
     
     
         7 . The method of  claim 6 , wherein said compound is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 6 , wherein said inflammatory disease is diarrhea.  
     
     
         9 . The method of  claim 8 , wherein said diarrhea is caused by inflammatory bowel disease.  
     
     
         10 . The method of  claim 6 , wherein said inflammatory disease is an autoimmune disease.  
     
     
         11 . The method of  claim 10 , wherein said autoimmune disease is lupus.  
     
     
         12 . The method of  claim 6 , wherein said inflammatory disease is glomerulonephritis.  
     
     
         13 . The method of  claim 6 , wherein said administration is parenteral.  
     
     
         14 . The method of  claim 6 , wherein said administration is per oral.  
     
     
         15 . The method of  claim 6 , wherein the inflammatory disease is selected from the group consisting of proliferative glomerulonephritis; lupus erythematosus; scleroderma; temporal arteritis; thromboangiitis obliterans; mucocutaneous lymph node syndrome; asthma; host versus graft; inflammatory bowel disease; multiple sclerosis; rheumatoid arthritis; thyroiditis; Grave's disease; antigen-induced airway hyperactivity; pulmonary eosinophilia; Guillain-Barre syndrome; allergic rhinitis; myasthenia gravis; human T-lymphotrophic virus type 1-associated myelopathy; herpes simplex encephalitis; inflammatory myopathies; atherosclerosis; and Goodpasture's syndrome.