Methods relating to the treatment of fibrosis

Abstract

The invention provides α-helix mimetic structures of formula (I) with the definitions of A, B, D, E, G, W, R 1 and R 2 as set out in the description and a chemical library relating thereto. The compounds, pharmaceutical compositions comprising the compounds, and methods of the invention using the compounds, relate to the treatment of fibrotic diseases, such as pulmonary fibrosis.

1 . A method of treating a fibrotic disease, said method comprising administering to a mammal in need of said treatment at least one compound having the following general formula (I) or a stereoisomer thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 A is —(CHR 3 )—(C═O)—; 
 B is —(NR 4 )—; 
 D is —(CHR 5 )— or —(C═O)—; 
 E is -(ZR 6 )— or —(C═O)—, where Z is nitrogen or CH; 
 G is —(XR 7 ) n —, —(CHR 7 )—(NR 8 )—, —(C═O)—(XR 9 )—, or —(C═O)—, where X is nitrogen or CH and n=0 or 1; 
 W is —(Y)—(C═O)—, —(C═O)—(NR 8 )—, —(SO 2 )—, or nothing, where Y is oxygen or sulfur; and 
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are the same or different and independently selected from an amino acid side chain, a derivative of an amino acid side chain, a linker facilitating linkage of the compound to another moiety or compound, a linker joining the compound to a solid support, and a solid support; 
 
       under conditions effective to treat a fibrotic disease in the mammal. 
     
     
         2 . The method according to  claim 1 , wherein the fibrotic disease is at least one selected from the group consisting of radiation-induced pulmonary fibrosis, chemotherapy-induced pulmonary fibrosis, obliterative bronchiolitis, and silicosis lesions. 
     
     
         3 . The method according to  claim 1 , wherein the fibrotic disease is at least one of kidney disease, polycystic kidney disease, renal fibrotic disease, glomerular nephritis, liver cirrhosis, nephritis associated with systemic lupus, peritoneal fibrosis, liver fibrosis, polycystic ovarian syndrome, myocardial fibrosis, Grave's opthalmopathy, glaucoma, scarring, skin lesions, diabetic retinopathy, scleroderma, and Alzheimer's disease. 
     
     
         4 . The method according to  claim 1 , wherein the fibrotic disease is at least one selected from the group consisting of interstitial lung disease, fibrotic lung disease, and pulmonary fibrosis. 
     
     
         5 . The method of  claim 1 , wherein the compound is administered orally, transdermally, intravenously, by inhalation, or rectally. 
     
     
         6 . The method of  claim 5 , wherein the compound is administered orally. 
     
     
         7 . The method of  claim 4 , wherein the compound is administered in a form selected from the group consisting of capsules, tablets, powders, granules, syrups, injectable fluids, creams, ointments, hydrophilic ointments, inhalable fluids, eye drops, and suppositories. 
     
     
         8 . The method according to  claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are independently selected from the group consisting of aminoC 2-5 alkyl, guanidinoC 2-5 alkyl, C 1-4 alkylguanidinoC 2-5 alkyl, diC 1-4 alkylguanidino-C 2-5 alkyl, amidinoC 2-5 alkyl, C 1-4 alkylamidinoC 2-5 alkyl, diC 1-4 alkylamidinoC 2-5 alkyl, C 1-3 alkoxy, Phenyl, substituted phenyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl), benzyl, substituted benzyl (where the substituents on the benzyl are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C 1-4 alkylamino, C 1-4 -dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl), naphthyl, substituted naphthyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl), bis-phenyl methyl, substituted bis-phenyl methyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl), pyridyl, substituted pyridyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl), pyridylC 1-4 alkyl, substituted pyridylC 1-4 alkyl (where the pyridine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl), pyrimidylC 1-4 alkyl, substituted pyrimidylC 1-4 alkyl (where the pyrimidine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl), triazin-2-yl-C 1-4 alkyl, substituted triazin-2-yl-C 1-4 alkyl (where the triazine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl), imidazoC 1-4 alkyl, substituted imidazol C 1-4 alkyl (where the imidazole substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl), imidazolinylC 1-4 alkyl, N-amidinopiperazinyl-N—C 0-4 alkyl, hydroxyC 2-5 alkyl, C 1-5 alkylaminoC 2-5 alkyl, hydroxyC 2-5 alkyl, C 1-5 alkylaminoC 2-5 alkyl, C 1-5 dialkylaminoC 2-5 alkyl, N-amidinopiperidinylC 1-4 alkyl, and 4-aminocyclohexylC 0-2 alkyl. 
     
     
         9 . The method according to  claim 1 , wherein the compound has the following general formula (III): 
       
         
           
           
               
               
           
         
       
       with the proviso that when Z is CH, X is nitrogen. 
     
     
         10 . The method according to  claim 8 , wherein the compound has the formula (IV): 
       
         
           
           
               
               
           
         
       
       wherein when Z is nitrogen, n is zero; and when Z is CH, X is nitrogen and n is 1, or X( n ) is zero. 
     
     
         11 . A method of treating a fibrotic disease, said method comprising administering to a mammal in need of said treatment at least one compound having the following general formula (V) or a stereoisomer thereof: 
       
         
           
           
               
               
           
         
       
       under conditions effective to treat a fibrotic disease in the mammal.