Lipoxins and aspirin-triggered lipoxins and their stable analogs in the treatment of asthma and inflammatory airway diseases

Abstract

The use of lipoxin analogs for the treatment or prevention of asthma and asthma related diseases is described. In particular, acetylenic lipoxin analogs are effective for the treatment and prevention of eosinophil recruitment involved with the inflammation processes associated with asthma, asthma like conditions, and lung injuries associated from airway inflammation or infection as brought about by leukocyte-mediated injury from within.

What is claimed is:  
     
         1 . A method for treating or preventing disorders of the respiratory tract or lung comprising the step of administering to a subject in need thereof, a therapeutically effective amount of a lipoxin analog having the formula  
       
         
           
           
               
               
           
         
         wherein X is R 1 , OR 1 , or SR 1 ;  
         wherein R 1  is 
 (i) a hydrogen atom;  
 (ii) an alkyl of 1 to 8 carbon atoms, inclusive, which may be straight chain or branched;  
 (iii) a cycloalkyl of 3 to 10 carbon atoms;  
 (iv) an aralkyl of 7 to 12 carbon atoms;  
 (v) phenyl;  
 (vi) substituted phenyl  
                     
 
         wherein Z 1 , Z ii , Z iii , Z iv  and Z v  are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x  is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl; 
 (vii) a detectable label molecule; or  
 (viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;  
 
         wherein Q 1  is (C═O), SO 2  or (CN), provided when Q 1  is CN, then X is absent;  
         wherein Q 3  and Q 4  are each independently O, S or NH;  
         wherein one of R 2  and R 3  is a hydrogen atom and the other is 
 (a) H;  
 (b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched;  
 (c) a cycloalkyl of 3 to 6 carbon atoms, inclusive;  
 (d) an alkenyl of 2 to 8 carbon atoms, inclusive, which may be straight chain or branched; or  
 (e) R a Q 2 R b  wherein Q 2  is —O— or —S—; wherein R a  is alkylene of 0 to 6 carbon atoms, inclusive, which may be straight chain or branched and wherein R b  is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when R b  is 0, then R b  is a hydrogen atom;  
 
         wherein R 4  is 
 (a) H;  
 (b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;  
 
         wherein R 5  is  
         
           
             
             
                 
                 
             
           
         
         wherein Z i , Z ii , Z iii , Z iv  and Z v  are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x  is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;  
         wherein Y 1  is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CH a Z b  where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;  
         wherein R 6  is 
 (a) H;  
 (b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;  
 
         wherein T is O or S, and pharmaceutically acceptable salts thereof, thereby treating or preventing disorders of the respiratory tract or lung in the subject.  
       
     
     
         2 . The method of  claim 1 , wherein the disorder of the respiratory tract is chronic bronchitis.  
     
     
         3 . The method of  claim 1 , wherein the disorder of the respiratory tract is bronchiectasis.  
     
     
         4 . The method of  claim 1 , wherein the disorder of the respiratory tract is eosinophilic lung diseases.  
     
     
         5 . The method of  claim 1 , wherein the disorder of the respiratory tract is allergic bronchopulmonary aspergillosis.  
     
     
         6 . The method of  claim 1 , wherein the disorder of the respiratory tract is allergic inflammation of the respiratory tract.  
     
     
         7 . The method of  claim 1 , wherein the disorder of the respiratory tract is bronchiolitis.  
     
     
         8 . The method of  claim 1 , wherein the disorder of the respiratory tract is bronchiolitis obliterans.  
     
     
         9 . The method of  claim 1 , wherein the disorder of the respiratory tract is bronchiolitis obliterans with organizing pneumonia.  
     
     
         10 . The method of  claim 1 , wherein the disorder of the respiratory tract is eosinophilic granuloma.  
     
     
         11 . The method of  claim 1 , wherein the disorder of the respiratory tract is Wegener's granulomatosis.  
     
     
         12 . The method of  claim 1 , wherein the disorder of the respiratory tract is sarcoidosis.  
     
     
         13 . The method of  claim 1 , wherein the disorder of the respiratory tract is hypersensitivity pneumonitis.  
     
     
         14 . The method of  claim 1 , wherein the disorder of the respiratory tract is idiopathic pulmonary fibrosis.  
     
     
         15 . The method of  claim 1 , wherein the disorder of the respiratory tract is pulmonary manifestations of connective tissue disease.  
     
     
         16 . The method of  claim 1 , wherein the disorder of the respiratory tract is acute or chronic lung injury.  
     
     
         17 . The method of  claim 1 , wherein the disorder of the respiratory tract is adult respiratory distress syndrome.  
     
     
         18 . The method of  claim 1 , wherein the disorder of the respiratory tract is lung injury associated with parasite infection.  
     
     
         19 . The method of  claim 1 , wherein the disorder of the respiratory tract is chronic obstructive pulmonary disease (COPD).  
     
     
         20 . The method of  claim 1 , wherein the disorder of the respiratory tract is aspirin-intolerant asthma.  
     
     
         21 . The method of  claim 1 , wherein eosinophil-mediated inflammation of the lung or tissues is inhibited or prevented.  
     
     
         22 . A packaged pharmaceutical composition for treating or preventing disorders of the respiratory tract or lung in a subject, comprising a container holding a therapeutically effective amount of at least one lipoxin analog having the formula  
       
         
           
           
               
               
           
         
         wherein X is R 1 , OR 1 , or SR 1 ;  
         wherein R 1  is 
 (i) a hydrogen atom;  
 (ii) an alkyl of 1 to 8 carbon atoms, inclusive, which may be straight chain or branched;  
 (iii) a cycloalkyl of 3 to 10 carbon atoms;  
 (iv) an aralkyl of 7 to 12 carbon atoms;  
 (v) phenyl;  
 (vi) substituted phenyl  
                     
 
         wherein Z i , Z ii , Z iii , Z iv  and Z v  are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x  is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl; 
 (vii) a detectable label molecule; or  
 (viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;  
 
         wherein Q 1  is (C═O), SO 2  or (CN), provided when Q 1  is CN, then X is absent;  
         wherein Q 3  and Q 4  are each independently O, S or NH;  
         wherein one of R 2  and R 3  is a hydrogen atom and the other is 
 (a) H;  
 (b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched;  
 (c) a cycloalkyl of 3 to 6 carbon atoms, inclusive;  
 (d) an alkenyl of 2 to 8 carbon atoms, inclusive, which may be straight chain or branched; or  
 (e) R a Q 2 R b  wherein Q 2  is —O— or —S—; wherein R a  is alkylene of 0 to 6 carbon atoms, inclusive, which may be straight chain or branched and wherein R b  is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when R b  is 0, then R b  is a hydrogen atom;  
 
         wherein R 4  is 
 (a) H;  
 (b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;  
 
         wherein R 5  is  
         
           
             
             
                 
                 
             
           
         
         wherein Z i , Z ii , Z iii , Z iv  and Z v  are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x  is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;  
         wherein Y 1  is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CH a Z b  where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;  
         wherein R 6  is 
 (a) H;  
 (b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;  
 
         wherein T is O or S, and pharmaceutically acceptable salts thereof; and instruction for treating or preventing disorders of the respiratory tract or lung in the subject.  
       
     
     
         23 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is chronic bronchitis.  
     
     
         24 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is bronchiectasis.  
     
     
         25 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is eosinophilic lung diseases.  
     
     
         26 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is allergic bronchopulmonary aspergillosis.  
     
     
         27 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is allergic inflammation of the respiratory tract.  
     
     
         28 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is bronchiolitis.  
     
     
         29 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is bronchiolitis obliterans.  
     
     
         30 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is bronchiolitis obliterans with organizing pneumonia.  
     
     
         31 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is eosinophilic granuloma.  
     
     
         32 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is Wegener's granulomatosis.  
     
     
         33 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is sarcoidosis.  
     
     
         34 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is hypersensitivity pneumonitis.  
     
     
         35 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is idiopathic pulmonary fibrosis.  
     
     
         36 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is pulmonary manifestations of connective tissue disease.  
     
     
         37 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is acute or chronic lung injury.  
     
     
         38 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is adult respiratory distress syndrome.  
     
     
         39 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is lung injury associated with parasite infection.  
     
     
         40 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is chronic obstructive pulmonary disease (COPD).  
     
     
         41 . The packaged pharmaceutical of  claim 22 , wherein the disorder of the respiratory tract is aspirin-intolerant asthma.  
     
     
         42 . The packaged pharmaceutical of  claim 22 , wherein eosinophil-mediated inflammation of the lung or tissues is inhibited or prevented.