Benzo lipoxin analogues

Abstract

Benzolipoxin analogs, methods of their preparation and pharmaceutical compositions containing the compounds are provided. The compounds and compositions are useful in methods for treatment of various diseases, including, inflammation, autoimmune disease and abnormal cell proliferation.

1 . A compound of general formula 1:  
       
         
           
           
               
               
           
         
         wherein: 
 A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or —OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, and the cations of sodium, potassium, magnesium and zinc;  
 W is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, or sulfonamide;  
 R a -R c  are independently selected from a group consisting of hydrogen, alkyl, aryl, acyl or alkoxyacyl;  
 the integer n is zero, one or two;  
 the integer m is one or two;  
 
         the two substituents on ring x are ortho-, meta- or para-:  
       
     
     
         2 . A compound selected from a group consisting of general structures 2-7:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein: 
 A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or —OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, and the cations of sodium, potassium, magnesium and zinc;  
 W is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, or sulfonamide;  
 R a -R c  are independently selected from a group costing of hydrogen, alkyl, aryl, acyl or alkoxyacyl;  
 the integer n is zero, one or two;  
 the integer m is one or two.  
 
       
     
     
         3 . A compound selected from a group consisting of general structures 8-13:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein: 
 A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or —OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, and the cations of sodium, potassium, magnesium and zinc;  
 W is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, or sulfonamide;  
 R a -R c  are independently selected from a group costing of hydrogen, alkyl, aryl, acyl or alkoxyacyl;  
 the integer n is zero, one or two;  
 the integer m is one or two.  
 
       
     
     
         4 . A compound selected from a group consisting of general structures 14-19:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein: 
 A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or —OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, and the cations of sodium, potassium, magnesium and zinc;  
 W is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, or sulfonamide;  
 R a -R c  are independently selected from a group costing of hydrogen, alkyl, aryl, acyl or alkoxyacyl;  
 the integer n is zero, one or two;  
 the integer m is one or two.  
 
       
     
     
         5 . A compound selected from a group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or —OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, and the cations of sodium, potassium, magnesium and zinc.  
 
     
     
         6 . The compound of  claim 1 , wherein W is alkyl or aryloxy.  
     
     
         7 . The compound of  claim 1 , wherein W is butyl.  
     
     
         8 . The compound of  claim 1 , wherein W is aryloxy.  
     
     
         9 . The compound of  claim 1 , wherein A is hydroxy or alkoxy.  
     
     
         10 . A method for preparation of a compound of the general formula 1:  
       
         
           
           
               
               
           
         
         by 
 providing a compound of formula 20, a compound of formula 21, and a compound of formula 22 
                     
 wherein: 
 G, Q, X and Y are independently selected from a group consisting of bromo, chloro, iodo, triflyl, diazonium, iodonium, boronic acid, boronate, borinate, borate, trifluoroborate, stannyl, perfluorostannyl, silyl, zinc, magnesium or copper.  
 A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or —OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, and the cations of sodium, potassium, magnesium and zinc;  
 W is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, or sulfonamide;  
 R a -R c  are independently selected from a group costing of hydrogen, alkyl, aryl, acyl or alkoxyacyl;  
 the integer n is zero, one or two;  
 the integer m is one or two;  
 
 the two substituents on ring X are either ortho-, meta- or para- and by: 
 reacting a compound of formula 20, with a compound of formula 21 in the presence of a metal catalyst, followed by reaction with a compound of formula 22 in the presence of a metal catalyst selected from a group consisting of palladium, nickel and copper;  
 or reacting a compound of formula 20, with a compound of formula 22 in the presence of a metal catalyst, followed by reaction with a compound of formula 21 in the presence of a metal catalyst selected from a group consisting of palladium, nickel and copper.  
 
 
       
     
     
         11 . The method of  claim 10 , where the two coupling steps are carried out in sequence or in one pot.  
     
     
         12 . The method of  claim 10 , wherein 20, 21 or 22 is connected to a polymeric chain or other solid phase material.  
     
     
         13 . A pharmaceutical composition, comprising: a compound according to  claim 1;  and a pharmaceutically acceptable carrier.  
     
     
         14 . A method of ameliorating or treating a disease or condition associated with inflammation, autoimmune diseases and abnormal cell proliferation, the method comprising administering to a subject an effective amount of a compound according to  claim 1 .  
     
     
         15 . The method of  claim 14 , wherein the disease is selected from rheumatoid arthritis and other forms of arthritis, asthma, psoriasis, inflammatory bowel disease, systemic lupus erythematosus, systemic dermatomyositis, inflammatory ophthalmic diseases, autoimmune hematologic disorders, multiple sclerosis, vasculitis, idiopathic nephrotic syndrome, transplant rejection and graft versus host disease.  
     
     
         16 . The method of  claim 14 , wherein the abnormal cell proliferation is a non-small cell lung cancer, head and neck squamous cancers, colorectal cancer, prostate cancer, breast cancer, acute lymphocytic leukemia, adult acute myeloid leukemia, adult non-Hodgkin's lymphoma, brain tumors, cervical cancers, childhood cancers, childhood sarcoma, chronic lymphocytic leukemia, chronic myeloid leukemia, esophageal cancer, hairy cell leukemia, kidney cancer, liver cancer, multiple myeloma, neuroblastoma, oral cancer, pancreatic cancer, primary central nervous system lymphoma, skin cancer, and small-cell lung cancer.  
     
     
         17 . An article of manufacture, comprising packaging material, the compound of  claim 1 , or a pharmaceutically acceptable derivative thereof, contained within packaging material, which is used for treatment, prevention or amelioration of one or more symptoms associated with inflammation, autoimmune disease or abnormal cell proliferation, and a label that indicates that the compound or pharmaceutically acceptable derivative thereof is used for treatment, prevention or amelioration of one or more symptoms associated with inflammation, autoimmune disease or abnormal cell proliferation.