Natural product analogs including an anti-inflammatory cyanoenone pharmacore and methods of use

Abstract

wherein X, R1 and R2 are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds, methods and intermediates useful for making the compounds, and methods of using the compounds and compositions.

1 . A compound comprising:
 a) the basic skeleton of an organic compound having two to eight five and/or six-membered rings provided that the basic skeleton is not the basic skeleton of argentatin, betulinic acid, lanostane, oleanic acid, boswellic acid, glycyrrhetinic acid, ursolic acid, or tricyclic-bis-enone;   b) a structural unit of the formula:   
       
         
           
           
               
               
           
         
         
           wherein:
 the carbon atoms labeled 1, 2 and 3 are part of a five or six-membered ring; 
 X is cyano or —C(O)R a , wherein R a  is:
 hydrogen, hydroxy, halo, amino, hydroxyamino, azido or mercapto; or 
 alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , alkoxy (C≤12) , alkenyl-oxy (C≤12) , alkynyloxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , heteroaralkoxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , alkoxyamino (C≤12) , alkenylamino (C≤12) , alkynylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , heteroaralkyl-amino (C≤12) , alkylsulfonylamino (C≤12) , amido (C≤12) , alkyl-silyloxy (C≤12) , or substituted versions of any of these groups; and 
 
 R 1  and R 2  are each independently:
 hydrogen; or 
 alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤8) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , hetero-aralkoxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkyl-amino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , hetero-arylamino (C≤12) , heteroaralkylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or 
 
 R 1  and R 2  are taken together and are alkanediyl (C≤12) , alkenediyl (C≤12) , alkanediyl (C≤12)  or alkenediyl (C≤12) ; and 
 
         
         c) from 0 to 8 chemical groups attached to a carbon atom of the basic skeleton other than carbon atoms 1, 2, 3 or 4, wherein each chemical group is independently:
 hydroxy, halo, oxo, amino, hydroxyamino, nitro, imino, cyano, azido, mercapto, or thio; or 
 alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , acyl (C≤12) , alkylidene (C≤12) , alkoxy (C≤12) , alkenyloxy (C≤12) , alkynyloxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , heteroaralkoxy (C≤12) , acyl-oxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , alkoxyamino (C≤12) , alkenylamino (C≤12) , alkynylamino (C≤12) , arylamino (C≤12) , aralkyl-amino (C≤12) , heteroarylamino (C≤12) , heteroaralkylamino (C≤12) , alkylsulfonylamino (C≤12) , amido (C≤12) , alkylimino (C≤12) , alkenyl-imino (C≤12) , alkynylimino (C≤12) , arylimino (C≤12) , aralkylimino (C≤12) , heteroarylimino (C≤12) , heteroaralkylimino (C≤12) , acylimino (C≤12) , alkylthio (C≤12) , alkenylthio (C≤12) , alkynylthio (C≤12) , arylthio (C≤12) , aralkylthio (C≤12) , heteroarylthio (C≤12) , heteroaralkylthio (C≤12) , acyl-thio (C≤12) , thioacyl (C≤12) , alkylsulfonyl (C≤12) , alkenylsulfonyl (C≤8) , alkynylsulfonyl (C≤12) , arylsulfonyl (C≤12) , aralkylsulfonyl (C≤12) , heteroarylsulfonyl (C≤12) , heteroaralkylsulfonyl (C≤12) , alkyl-ammonium (C≤12) , alkylsulfonium (C≤12) , alkylsilyl (C≤12) , alkylsilyl-oxy (C≤12) , or a substituted version of any of these groups; 
 
       
       or pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, acetals, ketals, prodrugs, or optical isomers thereof. 
     
     
         2 . The compound of  claim 1 , wherein R 1  and R 2  are each independently hydrogen, alkyl (C≤8)  or substituted alkyl (C≤8) . 
     
     
         3 - 6 . (canceled) 
     
     
         7 . A compound comprising:
 a) the basic skeleton of a natural product having two to eight rings, provided that the natural product is not argentatin, betulinic acid, lanostane, oleanic acid, or ursolic acid;   b) a structural unit of the formula:   
       
         
           
           
               
               
           
         
         
           wherein:
 the carbon atoms labeled 1, 2 and 3 are part of a six-membered ring; 
 X is cyano, fluoroalkyl (C≤8) , substituted, fluoroalkyl (C≤8) , or —C(O)R a , wherein R a  is:
 hydrogen, hydroxy, halo, amino, hydroxyamino, azido or mercapto; or 
 alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , alkoxy (C≤12) , alkenyl-oxy (C≤12) , alkynyloxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , heteroaralkoxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , alkoxyamino (C≤12) , alkenylamino (C≤12) , alkynylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , heteroaralkyl-amino (C≤12) , alkylsulfonylamino (C≤12) , amido (C≤12) , alkyl-silyloxy (C≤12) , or substituted versions of any of these groups; and 
 
 R 1  and R 2  are each independently:
 hydrogen; or 
 alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , hetero-aralkoxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkyl-amino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , hetero-arylamino (C≤12) , heteroaralkylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or 
 
 R 1  and R 2  are taken together and are alkanediyl (C≤12) , alkenediyl (C≤12) , alkanediyl (C≤12)  or alkenediyl (C≤12) ; and 
 
         
         c) from 0 to 8 chemical groups attached to a carbon atom of the basic skeleton other than carbon atoms 1, 2, 3 or 4, wherein each chemical group is independently:
 hydroxy, halo, oxo, amino, hydroxyamino, nitro, imino, cyano, azido, mercapto, or thio; or 
 alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , acyl (C≤12) , alkylidene (C≤12) , alkoxy (C≤12) , alkenyloxy (C≤12) , alkynyloxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , heteroaralkoxy (C≤12) , acyl-oxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , alkoxyamino (C≤12) , alkenylamino (C≤12) , alkynylamino (C≤12) , arylamino (C≤12) , aralkyl-amino (C≤12) , heteroarylamino (C≤12) , heteroaralkylamino (C≤12) , alkylsulfonylamino (C≤12) , amido (C≤12) , alkylimino (C≤12) , alkenyl-imino (C≤12) , alkynylimino (C≤12) , arylimino (C≤12) , aralkylimino (C≤12) , heteroarylimino (C≤12) , heteroaralkylimino (C≤12) , acylimino (C≤12) , alkylthio (C≤12) , alkenylthio (C≤12) , alkynylthio (C≤12) , arylthio (C≤12) , aralkylthio (C≤12) , heteroarylthio (C≤12) , heteroaralkylthio (C≤12) , acyl-thio (C≤12) , thioacyl (C≤8) , alkylsulfonyl (C≤12) , alkenylsulfonyl (C≤12) , alkynylsulfonyl (C≤12) , arylsulfonyl (C≤12) , aralkylsulfonyl (C≤12) , heteroarylsulfonyl (C≤12) , heteroaralkylsulfonyl (C≤12) , alkyl-ammonium (C≤12) , alkylsulfonium (C≤12) , alkylsilyl (C≤12) , alkylsilyl-oxy (C≤12) , or a substituted version of any of these groups; 
 
       
       or pharmaceutically acceptable salts, esters, hydrates, solvates, tautomers, acetals, ketals, prodrugs, or optical isomers thereof. 
     
     
         8 . The compound of  claim 7 , wherein R 1  and R 2  are each independently hydrogen, alkyl (C≤8)  or substituted alkyl (C≤8) . 
     
     
         9 - 15 . (canceled) 
     
     
         16 . The compound of  claim 7 , wherein X is —CN. 
     
     
         17 - 18 . (canceled) 
     
     
         19 . The compound of  claim 16 , wherein the structural unit is further defined as: 
       
         
           
           
               
               
           
         
       
     
     
         20 - 173 . (canceled) 
     
     
         174 . A method of making a compound of  claim 1 , comprising:
 (a) obtaining an organic compound having two to eight five and/or six-membered rings, provided that the organic compounds is not argentatin, betulinic acid, lanostane, oleanic acid, boswellic acid, glycyrrhetinic acid, ursolic acid, or tricyclic-bis-enone;   (b) reacting the organic compound in a series of one of more steps to obtain a compound according to  claim 1 .   
     
     
         175 . The method of  claim 174 , wherein the compound's induction of Nrf2 activity is at least ten times higher than the organic compound's induction of Nrf2 activity. 
     
     
         176 . The method of  claim 174 , wherein the compound's inhibition of NF-κB activity is at least ten times higher than the organic compound's inhibition of NF-κB activity. 
     
     
         177 . The method of  claim 174 , wherein the compound's inhibition of IFNγ induced NO activity is at least ten times higher than the organic compound's inhibition of IFNγ induced NO activity.