Quinazoline derivatives as medicaments

Abstract

Quinazoline derivatives and their pharmaceutically acceptable salts are inhibitors of TGFβ activity and are used to treat conditions characterized by enhanced TGFβ activity.

1 . A compound of the formula:  
       
         
           
           
               
               
           
         
         or the pharmaceutically acceptable salts thereof;  
         wherein each of Z 5 , Z 6 , Z 7  and Z 8  is N or CH and wherein one of Z 5 , Z 6 , Z 7  and Z 8  is N and the rest are CH;  
         wherein m and n are each independently 0-3;  
         wherein each R 1  is independently OH, SH, NH 2 , OR, SR, NHR, halo or R-halide;  
         wherein two adjacent R 1  groups may be joined to form an aliphatic heterocyclic ring of 5-6 members;  
         wherein each R 2  is independently R, halo, R-halide, OR-halide, NH 2 , CONH 2  or CONHR;  
         wherein R is optionally substituted C 1 -C 12  alkyl, C 1 -C 12  alkenyl, C 1 -C 12  alkynyl, or aryl C 1 -C 12  alkyl, containing 0-4 heteroatoms in place of a carbon in the carbon backbone, where the optional substituents are ═O, ═N, or OH; and  
         wherein R 3  is H or CH 3 ;  
         with the following provisos:  
         when Z 5 -Z 7  are CH and Z 8  is N, R 3  is H, and the pyridyl is unsubstituted, then m is 1-3, and m is 1, then R 1  is not 2-fluoro or 2-chloro; and  
         when Z 5  is N and Z 6 -Z 8  are CH, R 3  is H, and the pyridyl is unsubstituted, then the phenyl is substituted.  
       
     
     
         2 . The compound of  claim 1  wherein 
 R 1  is selected from the group consisting of H, fluoro, chloro, bromo, iodo, methoxy, ethoxy, isopropoxy, and the trifluoro methyl or    wherein two R 1  form a fused 1,3, dioxolane ring.    
     
     
         3 . The compound of  claim 1  wherein R 1  is one or more halos.  
     
     
         4 . The compound of  claim 1  wherein R 1  is independently one or more alkyls, alkyl halides, alkoxys or O-alkyl phenyls.  
     
     
         5 . The compound of  claim 1  wherein m is 0, n is 1, and R 2  is positioned at the 3′ position of the pyridyl.  
     
     
         6 . The compound of  claim 1  wherein m is 1 or 2 and R 1  is positioned at the 2′ or 5′ position of the phenyl moiety.  
     
     
         7 . The compound of  claim 1  wherein each R 2  is independently a hydrocarbyl residue (1-6C) containing 0-2 heteroatoms selected from O, S and N.  
     
     
         8 . The compound of  claim 7  wherein each R 2  is independently alkyl, CONH 2 , CONHR, or halo.  
     
     
         9 . The compound of  claim 1  where R 2  is selected from the group consisting of methyl, ethyl, CONH 2  and bromo.  
     
     
         10 . The compound of  claim 1  wherein m and n are each independently 0-2.  
     
     
         11 . The compound of  claim 1  where n is 0.  
     
     
         12 . The compound of  claim 1  having the formula:  
       
         
           
           
               
               
           
         
         or the pharmaceutically acceptable salts thereof;  
         wherein each of Z 5 , Z 6  and Z 7  is N or CH and one of Z 5 , Z 6  and Z 7  is N and and the rest are CH;  
         wherein R 1  is F, Cl, Br, I or CH 3 ;  
         wherein R 1′  is Br, F or Cl; and  
         wherein R 2  is not present, is CH 3  or is an electron-withdrawing group.  
       
     
     
         13 . The compound of  claim 12  or the pharmaceutically acceptable salts thereof, wherein R 2  is not present or is CH 3 , F, Cl, OCF 2 H, OCF 3 , CF 3 , CONHR or CONH 2 ; wherein R is optionally substituted C 1 -C 12  alkyl, C 1 -C 12  alkenyl, C 1 -C 12  alkynyl, or aryl C 1 -C 12  alkyl, containing 0-4 heteroatoms in place of a carbon in the carbon backbone, where the optional substituents are ═O, ═N, or OH.  
     
     
         14 . The compound of  claim 13  or the pharmaceutically acceptable salts thereof, wherein R 1  is Cl and R 1′  is F.  
     
     
         15 . A pharmaceutical composition for treating conditions characterized by enhanced TGF-β activity which composition comprises 
 a therapeutically effective amount of a compound of  claim 1 .                          or the pharmaceutically acceptable salts thereof and    at least one pharmaceutically acceptable carrier.    
     
     
         16 . The composition of  claim 10  which further contains an additional therapeutic agent.  
     
     
         17 . (canceled)  
     
     
         18 . A method of treating a condition characterized by enhanced TGFβ activity, said method comprising administering to a subject in need thereof, the compound of  claim 1  or a pharmaceutically acceptable salt thereof.  
     
     
         19 . The method of  claim 18  wherein said condition comprises a fibroproliferative response.  
     
     
         20 . The method of  claim 19  wherein said fibroproliferative response is associated with a renal disorder, a vascular disorder, a fibrosis, an autoimmune disorder, an eye disease, excessive scarring, a neurological condition, myelofibrosis, tissue thickening, nasal polyposis, a polyp, liver cirrhosis, or osteoporosis.  
     
     
         21 . The method of  claim 20  wherein said renal disorder is selected from the group consisting of glomerulonephritis, diabetic nephropathy, renal interstitial fibrosis, renal fibrosis in transplant patients receiving cyclosporin, and HIV-associated nephropathy; and 
 wherein said vascular disorder is selected from the group consisting of progressive systemic sclerosis, polymyositis, scleroderma, dermatomyositis, eosinophilic fascitis, morphea, and Raynaud's syndrome; and    wherein said fibrosis is associated with adult respiratory distress syndrome, idiopathic pulmonary fibrosis, interstitial pulmonary fibrosis, cardiac fibrosis, keloid formation, or hypertrophic scarring; and    wherein said autoimmune disorder is selected from the group consisting of systemic lupus erythematosus, scleroderma, and rheumatoid arthritis; and    wherein said eye disease is retinal detachment, cataracts, or glaucoma; and    wherein said neurological condition is CNS injury, Alzheimer's disease, or Parkinson's disease.    
     
     
         22 . The method of  claim 18  wherein the condition is not characterized by overactivity of p38 or epidermal growth factor (EGF).