Macrocyclic compounds useful as pharmaceuticals

Abstract

The present invention provides compounds, methods for the synthesis thereof and methods for the use thereof in the treatment of various disorders including inflammatory or autoimmune disorders, and disorders involving malignancy or increased angiogenesis.

1 . A compound having the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester or salt of ester thereof; 
         wherein R 1  is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl; 
         R 2  is methyl and R 3  is hydrogen or halogen; 
         R 4  is hydrogen or halogen; 
         R 5  is hydrogen or an oxygen protecting group; 
         R 6  is hydrogen, hydroxyl, or protected hydroxyl; 
         n is 1; 
         R 7  is hydrogen; 
         R 8  is hydrogen, halogen, hydroxyl, protected hydroxy or alkyloxy; 
         R 9  is hydroxyl, protected hydroxyl, OR 12 , SR 12 , NR 12 R 13 , —X 1 (CH 2 ) p X 2 —R 14 , or is C 1-6 alkyl optionally substituted with hydroxyl, protected hydroxyl, halogen, amino, protected amino, or —X 1 (CH 2 ) p X 2 —R 14 ; 
         wherein R 12  and R 13 , taken together, form a saturated or unsaturated cyclic ring containing 1 to 4 carbon atoms and 1 to 3 nitrogen or oxygen atoms, and each of R 12  and R 13  are optionally further substituted with one or more occurrences of hydroxyl, protected hydroxyl, alkyloxy, amino, protected amino, alkylamino, aminoalkyl, or halogen; or 
         wherein R 12  is selected from hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl, heteroaryl and a protecting group, and R 13  and R 8 , taken together, form a cyclic ring containing 1 to 4 carbon atoms and 1 to 3 nitrogen or oxygen atoms and is optionally substituted with hydrogen, alkyloxy, amino, alkylamino, aminoalkyl, and halogen; 
         wherein X 1  and X 2  are each independently absent, or are oxygen, NH, or —N(alkyl), or wherein X 2 —R 14  together are N 3  or are a saturated or unsaturated heterocyclic moiety, 
         p is 2-10, and 
         R 14  is hydrogen, or an aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety, or is —(C═O)NHR 15 —(C═O)OR 15 , or —(C═O)R 15 , wherein each occurrence of R 15  is independently hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl; or R 14  is —SO 2 (R 16 ), wherein R 16  is an aliphatic moiety, wherein one or more of R 14 , R 15 , or R 16  are optionally substituted with one or more occurrences of hydroxyl, protected hydroxyl, alkyloxy, amino, protected amino, alkylamino, aminoalkyl, or halogen; or 
         R 8  and R 9  may, when taken together, form a saturated or unsaturated cyclic ring containing 1 to 4 carbon atoms and 1 to 3 nitrogen or oxygen atoms and is optionally substituted with hydroxyl, protected hydroxyl, alkyloxy, amino, protected amino, alkylamino, aminoalkyl, or halogen; 
         R 10  is hydroxyl, protected hydroxyl, or amino; 
         R 11  is hydrogen, 
         X is O, NH or N-alkyl; 
         Y is CHR 17 , O, CR 17  or NR 17 ; and Z is CHR 18 , C═O or CR 18  wherein each occurrence of R 17  and R 18  is hydrogen, or R 17  and R 18  taken together is —O— or —CH 2 —, and Y and Z are connected by a single or double bond. 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , wherein:
 R 1  is hydrogen, straight or branched C 1-6 alkyl, straight or branched C 1-6 heteroalkyl, or aryl,   wherein the alkyl, heteroalkyl, and aryl groups may optionally be substituted with one or more occurrences of halogen, hydroxyl or protected hydroxyl; and   R 3  is hydrogen.   
     
     
         4 . The compound of  claim 3 , where X is oxygen. 
     
     
         5 . (canceled) 
     
     
         6 . The compound of  claim 3 , where R 4  is hydrogen. 
     
     
         7 . The compound of  claim 3 , where Y and Z together represent —CH═CH—. 
     
     
         8 . The compound of  claim 3 , where Y and Z together represent trans —CH═CH—. 
     
     
         9 . The compound of  claim 3 , wherein R 1  is methyl and R 3  is hydrogen and the compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         10 - 126 . (canceled) 
     
     
         127 . The compound of  claim 9 , wherein X is oxygen, R 4  is hydrogen and Y and Z together represent —CH═CH—. 
     
     
         128 . A compound of  claim 1  having a structure selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters and salts of esters thereof. 
       
     
     
         129 . A pharmaceutical composition comprising a compound having the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester or salt of ester thereof; 
         wherein R 1  is hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl; 
         R 2  is methyl and R 3  is hydrogen or halogen; 
         R 4  is hydrogen or halogen; 
         R 5  is hydrogen or an oxygen protecting group; 
         R 6  is hydrogen, hydroxyl, or protected hydroxyl; 
         n is 1; 
         R 7  is hydrogen; 
         R 8  is hydrogen, halogen, hydroxyl, protected hydroxyl or alkyloxy; 
         R 9  is hydroxyl, protected hydroxyl, OR 12 , SR 12 , NR 12 R 13 , —X 1 (CH 2 ) p X 2 —R 14 , or is C 1-6 alkyl optionally substituted with hydroxyl, protected hydroxyl, halogen, amino, protected amino, or —X 1 (CH 2 ) p X 2 —R 14 ; 
         wherein R 12  and R 13 , taken together, form a saturated or unsaturated cyclic ring containing 1 to 4 carbon atoms and 1 to 3 nitrogen or oxygen atoms, and each of R 12  and R 13  are optionally further substituted with one or more occurrences of hydroxyl, protected hydroxyl, alkyloxy, amino, protected amino, alkylamino, aminoalkyl, or halogen; or 
         wherein R 12  is selected from hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl, heteroaryl and a protecting group, and R 13  and R 8 , taken together, form a cyclic ring containing 1 to 4 carbon atoms and 1 to 3 nitrogen or oxygen atoms and is optionally substituted with hydrogen, alkyloxy, amino, alkylamino, aminoalkyl, and halogen; 
         wherein X 1  and X 2  are each independently absent, or are oxygen, NH, or —N(alkyl), or wherein X 2 —R 14  together are N 3  or are a saturated or unsaturated heterocyclic moiety, 
         p is 2-10, and 
         R 14  is hydrogen, or an aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety, or is —(C═O)NHR 15 —(C═O)OR 15 , or —(C═O)R 15 , wherein each occurrence of R 15  is independently hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl; or R 14  is —SO 2 (R 16 ), wherein R 16  is an aliphatic moiety, wherein one or more of R 14 , R 15 , or R 16  are optionally substituted with one or more occurrences of hydroxyl, protected hydroxyl, alkyloxy, amino, protected amino, alkylamino, aminoalkyl, or halogen; or 
         R 8  and R 9  may, when taken together, form a saturated or unsaturated cyclic ring containing 1 to 4 carbon atoms and 1 to 3 nitrogen or oxygen atoms and is optionally substituted with hydroxyl, protected hydroxyl, alkyloxy, amino, protected amino, alkylamino, aminoalkyl, or halogen; 
         R 10  is hydroxyl, protected hydroxyl, or amino; 
         R 11  is hydrogen; 
         X is O, NH or N-alkyl; 
         Y is CHR 17 , O, CR 17  or NR 17 ; and Z is CHR 18 , C═O or CR 18 , wherein each occurrence of R 17  and R 18  is hydrogen, or R 17  and R 18  taken together is —O— or —CH 2 —, and Y and Z are connected by a single or double bond. 
       
     
     
         130 . The pharmaceutical composition of  claim 129 , wherein:
 R 1  is hydrogen, straight or branched C 1-6 alkyl, straight or branched C 1-6 heteroalkyl, or aryl; wherein the alkyl, heteroalkyl, and aryl groups may optionally be substituted with one or more occurrences of halogen, hydroxyl or protected hydroxyl; and   R 3  is hydrogen.   
     
     
         131 . The pharmaceutical composition of  claim 129 , wherein X is oxygen. 
     
     
         132 . The pharmaceutical composition of  claim 129 , wherein X is oxygen, R 4  is hydrogen and Y and Z together represent —CH═CH—. 
     
     
         133 . The pharmaceutical composition of  claim 129  wherein the compound has a structure selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters and salts of esters thereof. 
       
     
     
         134 . The pharmaceutical composition of  claim 129 , wherein the composition is formulated for topical administration. 
     
     
         135 . A method for treating an inflammatory and/or autoimmune disorder or a disorder resulting from increased angiogenesis and/or cell proliferation comprising:
 administering to a subject in need thereof a therapeutically effective amount of a compound according to  claim 1 .   
     
     
         136 . The method of  claim 135 , wherein the method is for treating a disorder selected from the group consisting of rheumatoid arthritis, psoriasis, asthma, cancer, sepsis, inflammatory bowel disease, atopic dermatitis, Crohn's disease, and autoimmune disorders. 
     
     
         137 . The method of  claim 135 , wherein the method is for treating rheumatoid arthritis. 
     
     
         138 . The method of  claim 135 , wherein the method is for treating psoriasis. 
     
     
         139 . The method of  claim 135 , wherein the method is for treating cancer.