Methods of Preparing Substituted Tetracyclines with Transition Metal-Based Chemistries

Abstract

The present invention relates to novel chemistries which allow for heretofore unobtainable substituted tetracycline compounds which exhibit significant activity in tetracycline responsive states. The methods disclosed herein utilize reactive tetracycline-based precursor compounds, reactive organic substituent precursors and transition metal catalysts under conditions such that a tetracycline compound substituted with the desired organic substituent is formed. In one embodiment of the invention, a substituted tetracycline compound may be prepared by combining a reactive tetracycline-based precursor compound such as an arene tetracycline diazonium salt, and a reactive organic substituent precursor, e.g., alkenes, substituted alkenes, vinyl monomers, aromatics and heteroaromatics, in the presence of a transition metal catalyst, such as palladium chloride, under conditions such that a tetracycline compound substituted with the organic substituent is formed. Such compounds may optionally act as intermediates for making other compounds, e.g., hydrogenation of unsaturated groups on the substituent.

1 . A compound selected from the group consisting of:
 [4S-(4α,12aα)]-9-[3′-(E)-propenoic acid]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,1′-dioxo-2-naphthacenecarboxamide,   [4S-(4α,12aα)]-9-[3′-(E)-butylpropenoate]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,1′-dioxo-2-naphthacenecarboxamide,   [4S-(4α,12aα)]-9-[3′-(E)-butylpropenoate]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,1′-dioxo-2-naphthacenecarboxamide,   [4S-(4α,12aα)]-9-[1′-(E)-(2′-phenyl)ethenyl]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,1′-dioxo-2-naphthacenecarboxamide,   [4S-(4α,12aα)]-9-carboxy-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,1′-dioxo-2-naphthacenecarboxamide,   9-phenyl minocycline,   7,9-diphenyl sancycline,   7-ethylenyl sancycline,   [4S-(4α,12aα)]-7-[3′-(E)-butylpropenoate]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,1′-dioxo-2-naphthacenecarboxamide,   [4S-(4α,12aα)]-13-(4′-methylphenyl)-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methylene-1,1′-dioxo-2-naphthacenecarboxamide,   [4S-(4α,12aα)]-13-(3′-carboxyphenyl)-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methylene-1,1′-dioxo-2-naphthacenecarboxamide, and   [4S-(4α,12aα)]-13-(4′-ethoxyphenyl)-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methylene-1,1′-dioxo-2-naphthacenecarboxamide,   
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A compound selected from the group consisting of:
 9-iodo-minocycline,   9-iodo-sancycline,   9-iodo-doxycycline,   7,9-diiodosancycline, and   7-iododoxycycline,   
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . A 7-substituted tetracycline analog, wherein the substituent at the 7 position is connected with a —C—C— linkage, and wherein the substituent comprises a —C═C— bond adjacent to the —C—C— linkage. 
     
     
         4 . The 7-substituted tetracycline analog of  claim 3 , wherein the substituent is of the formula 
       
         
           
           
               
               
           
         
       
       wherein R 2  and R 3  are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxyl, cyano, alkoxy, aryloxy, or carboxyl; or R 2  and R 3 , taken together, form a substituted or unsubstituted carbocyclic or heterocyclic ring having 5 to 15 atoms in the ring. 
     
     
         5 . The 7-substituted tetracycline analog of  claim 4 , wherein R 2  is hydrogen; R 3  is 
       
         
           
           
               
               
           
         
       
       and R 4  is hydrogen, cyano, or C 1 -C 5  alkoxy. 
     
     
         6 . The 7-substituted tetracycline analog of  claim 4 , wherein R 2  and R 3 , taken together, form a substituted or unsubstituted carbocyclic or heterocyclic ring having 5 to 15 atoms in the ring. 
     
     
         7 . The 7-substituted tetracycline analog of  claim 5 , wherein the substituted or unsubstituted carbocyclic or heterocyclic ring is selected from the group consisting of conjugated and unconjugated aromatic ring systems. 
     
     
         8 . A pharmaceutical composition comprising the compound of any one of  claims 1 - 7  and a pharmaceutically acceptable carrier.