Synthesis of rocaglamide natural products via photochemical generation of oxidopyrylium species

Abstract

The present invention provides new strategies for the synthesis of compounds of the rocaglamide family and related natural products. In particular, the new biomimetic synthetic approach involves photochemical generation of an oxidopyrylium species from a 3-hydroxychromone derivative followed by 1,3-dipolar cycloaddition of the oxidopyrylium species to a dipolarophile. This approach can be used for the formation of adducts containing an aglain core structure. Methods for the conversion of aglain core structures to aglain, rocaglamide and forbaglin ring systems are also provided. The present invention also relates to the use of rocaglamide/aglain/forbaglin derivatives for the manufacture of medicaments for use in the treatment of cancer or cancerous conditions, disorders associated with cellular hyperproliferation, or NF-κB-dependent conditions.

1 - 78 . (canceled) 
     
     
         79 . A rocaglamide derivative having the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R, R a  and R b  are identical or different and selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkyl, thioaryl, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —NO 2 , —CN, —CF 3 , —CH 2 CF 3 , —CHCl 2 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 SO 2 CH 3 , —C(═O)R x , —CO 2 (R x ), —C(═O)N(R x ) 2 , —OC(═O)N(R x ) 2 , —OC(═O)R x , —OCO 2 R x , —S(O)R x , —S(O) 2 R x , —NR x (CO)R x , —N(R x )CO 2 R x , —N(R x )C(═O)N(R x ) 2 , —N(R x )S(O) 2 R x , and —S(O) 2 N(R x ) 2 ,
 wherein each occurrence of R x  is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl. 
 
       
     
     
         80 . A rocaglamide derivative having the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R a  and R b  are identical or different and selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkyl, thioaryl, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —NO 2 , —CN, —CF 3 , —CH 2 CF 3 , —CHCl 2 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 SO 2 CH 3 , —C(═O)R x , —CO 2 (R x ), —C(═O)N(R x ) 2 , —OC(═O)N(R x ) 2 , —OC(═O)R x , —OCO 2 R x , —S(O)R x , —S(O) 2 R x , —NR x (CO)R x , —N(R x )CO 2 R x , —N(R x )C(═O)N(R x ) 2 , —N(R x )S(O) 2 R x , and —S(O) 2 N(R x ) 2 ,
 wherein each occurrence of R x  is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl. 
 
       
     
     
         81 . A rocaglamide derivative having the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R, R′, R a  and R b  are identical or different and selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkyl, thioaryl, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —NO 2 , —CN, —CF 3 , —CH 2 CF 3 , —CHCl 2 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 SO 2 CH 3 , —C(═O)R x , —CO 2 (R x ), —C(═O)N(R x ) 2 , —OC(═O)N(R x ) 2 , —OC(═O)R x , —OCO 2 R x , —S(O)R x , —S(O) 2 R x , —NR x (CO)R x , —N(R x )CO 2 R x , —N(R x )C(═O)N(R x ) 2 , —N(R x )S(O) 2 R x , and —S(O) 2 N(R x ) 2 ;
 wherein R′ is selected from the group consisting of hydrogen, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 SO 2 CH 3 , —C(═O)R x , —CO 2 (R x ), —C(═O)N(R x ) 2 , —S(O)R x , —NR x (CO)R x , —N(R x )CO 2 R x , —N(R x )C(═O)N(R x ) 2 , and —N(R x )S(O) 2 R x ; and 
 wherein each occurrence of R x  is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl. 
 
       
     
     
         82 . A rocaglamide derivative having the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R a  and R b  are identical or different and selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkyl, thioaryl, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —NO 2 , —CN, —CF 3 , —CH 2 CF 3 , —CHCl 2 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 SO 2 CH 3 , —C(═O)R x , —CO 2 (R x ), —C(═O)N(R x ) 2 , —OC(═O)N(R x ) 2 , —OC(═O)R x , —OCO 2 R x , —S(O)R x , —S(O) 2 R x , —NR x (CO)R x , —N(R x )CO 2 R x , —N(R x )C(═O)N(R x ) 2 , —N(R x )S(O) 2 R x , and —S(O) 2 N(R x ) 2 ,
 wherein R′ is selected from the group consisting of hydrogen, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 SO 2 CH 3 , —C(═O)R x , —CO 2 (R x ), —C(═O)N(R x ) 2 , —S(O)R x , —NR x (CO)R x , —N(R x )CO 2 R x , —N(R x )C(═O)N(R x ) 2 , and —N(R x )S(O) 2 R x ; and 
 wherein each occurrence of R x  is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl. 
 
       
     
     
         83 . A method of treating a cancer or a cancerous condition comprising administering a therapeutically effective amount of a rocaglamide derivative as defined in any one of  claims 79 - 82  to a patient in need thereof. 
     
     
         84 . The method of  claim 83 , wherein the cancer or cancerous condition is selected from the group consisting of leukemia, sarcoma, breast, colon, bladder, pancreatic, endometrial, head and neck, mesothelioma, myeloma, oesophagal/oral, testicular, thyroid, cervical, bone, renal, uterine, prostate, brain, lung, ovarian, skin, liver, bowel and stomach cancers, tumors and melanomas. 
     
     
         85 . A method of treating a condition associated with cellular proliferation comprising administering a therapeutically effective amount of a rocaglamide derivative as defined in any one of  claims 79 - 82  to a patient in need thereof. 
     
     
         86 . The method of  claim 85 , wherein the condition associated with cellular proliferation is selected from the group consisting of atherosclerosis, restinosis, rheumatoid arthritis, osteoarthritis, inflammatory arthritis, psoriasis, periodontal disease and virally induced cellular hyperproliferation. 
     
     
         87 . A method of treating a NF-κB-dependent condition comprising administering a therapeutically effective amount of a rocaglamide derivative as defined in any one of  claims 79 - 82  to a patient in need thereof. 
     
     
         88 . The method of  claim 87 , wherein the NF-κB-dependent condition is selected from the group consisting of inflammatory diseases, immunological disorders, septic shock, transplant rejection, radiation damage reperfusion injuries after ischemia, stroke, cerebral trauma, thromboses, cirrhosis of the liver, asthma, complex, chronic inflammatory disorders, arteriosclerosis, and multiple sclerosis. 
     
     
         89 . The rocaglamide derivative of  claim 80  wherein the rocaglamide derivative has one of the following chemical structures: 
       
         
           
           
               
               
           
         
       
     
     
         90 . The rocaglamide derivative of  claim 82  wherein the rocaglamide derivative has one of the following chemical structures: 
       
         
           
           
               
               
           
         
       
     
     
         91 . The rocaglamide derivative of any one of  claims 79 - 82  and  89 - 90 , wherein:
 R a  is 
 
       
         
           
           
               
               
           
         
         R b  is 
       
       
         
           
           
               
               
           
         
         R 10  is selected from the group consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, and a protecting group; and 
         R 11 , R 12 , R 13 , R 14 , and R 15  are identical or different and selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, thioalkyl, thioaryl, acyl, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylamino, amino alkyl, arylamino, amino aryl, a protecting group, —NO 2 , —CN, —CF 3 , —CH 2 CF 3 , —CHCl 2 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 SO 2 CH 3 , —C(═O)R x , —CO 2 (R x ), —C(═O)N(R x ) 2 , —OC(═O)N(R x ) 2 , —OC(═O)R x , —OCO 2 R x , —S(O)R x , —S(O) 2 R x , —NR x (CO)R x , —N(R x )CO 2 R x , —N(R x )C(═O)N(R x ) 2 , —N(R x )S(O) 2 R x , and —S(O) 2 N(R x ) 2 ,
 wherein each occurrence of R x  is independently selected from the group consisting of hydrogen, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, and heteroaryl.