US2009137845A1PendingUtilityA1

Novel 4-Dedimethylaminotetracycline derivatives

66
Assignee: GALDERMA LAB INCPriority: Nov 18, 1998Filed: Oct 23, 2008Published: May 28, 2009
Est. expiryNov 18, 2018(expired)· nominal 20-yr term from priority
A61P 7/00A61P 7/04A61P 37/06A61P 3/10A61P 37/02A61P 43/00A61P 9/14A61P 29/00A61P 31/04A61P 35/00A61P 27/02A61P 1/02A61P 11/00A61P 19/10C07C 237/26A61P 1/18A61P 13/12A61P 17/00A61P 19/02C07C 235/82C07C 247/18A61P 17/06C07C 245/20C07D 295/13C07C 329/20C07C 2603/46A61P 1/04A61P 19/00
66
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Claims

Abstract

The present invention provides new chemically modified 4-dedimethylaminotetracycline compounds that can be substituted with aryl, alkenyl, or alkynyl groups. The 7, 8, and/or 9 positions and methods for preparing such compounds. Other tetracycline compounds include the 4-dedimethylaminotetracycline derivatives with an oxime group, NH-Alkyl, or N—NH-Alkyl group substituted at the C4 position as well as C2 Mannich derivatives. The present invention also provides a method of treating a mammal suffering from conditions or diseases by administering to the mammal an effective amount of the new chemically modified tetracycline compounds.

Claims

exact text as granted — not AI-modified
1 . A tetracycline compound of the formulae: 
     
       
         
         
             
             
         
       
       wherein:
 R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl)amino, halogen, di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl; 
 R6-a is selected from the group consisting of hydrogen and methyl; 
 R6 and R5 are selected from the group consisting of hydrogen and hydroxyl; 
 R8 is selected from the group consisting of hydrogen and halogen; 
 R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl)amino, halogen, diazonium, di(lower alkyl)amino and RCH(NH 2 )CO; 
 R is hydrogen or lower alkyl; and 
 
       pharmaceutically acceptable and unacceptable salts thereof; with the following provisos:
 when either R7 and R9 are hydrogen then R8 must be halogen; and 
 when R6-a, R6, R5 and R9 are all hydrogen and R7 is hydrogen, amino, nitro, halogen, dimethylamino or diethylamino, then R8 must be halogen; and 
 when R6-a is methyl, R6 and R9 are both hydrogen, R5 is hydroxyl, and R7 is hydrogen, amino, nitro, halogen or diethylamino, then R8 is halogen; and 
 when R6-a is methyl, R6 is hydroxyl, R5, R7 and R9 are all hydrogen, then R8 must be halogen; and 
 when R6-a, R6 and R5 are all hydrogen, R9 is methylamino and R7 is dimethylamino, then R8 must be halogen; and 
 when R6-a is methyl, R6 is hydrogen, R5 is hydroxyl, R9 is methylamino and R7 is dimethylamino, then R8 must be halogen; and 
 when R6-a is methyl, R6, R5 and R9 are all hydrogen and R7 is cyano, then R8 must be halogen. 
 
     
   
   
       2 . A tetracycline compound of the formulae: 
     
       
         
         
             
             
         
       
       wherein:
 R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl)amino, halogen, and di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl; 
 R6-a is selected from the group consisting of hydrogen and methyl; 
 R6 and R5 are selected from the group consisting of hydrogen and hydroxyl; 
 R4 is selected from the group consisting of NOH, N—NH-A, and NH-A, 
 where A is a lower alkyl group; 
 R8 is selected from the group consisting of hydrogen and halogen; 
 R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl)amino, halogen, di(lower alkyl)amino and RCH(NH 2 )CO; 
 R is hydrogen or lower alkyl; and 
 pharmaceutically acceptable and unacceptable salts thereof, with the following provisos: 
 when R4 is NOH, N—NH-alkyl or NH-alkyl and R7, R6-a, R6, R5, and R9 are all hydrogen, then R8 must be halogen; and 
 when R4 is NOH, R6-a is methyl, R6 is hydrogen or hydroxyl, R7 is halogen, R5 and R9 are both hydrogen, then R8 must be halogen; and 
 when R4 is N—NH-alkyl, R6-a is methyl, R6 is hydroxyl and R7, R5, R9 are all hydrogen, then R8 must be halogen; and 
 when R4 is NH-alkyl, R6-a, R6, R5 and R9 are all hydrogen, R7 is hydrogen, amino, mono(lower alkyl)amino, halogen, di(lower alkyl)amino or hydroxyl, then R8 must be halogen; and 
 when R4 is NH-alkyl, R6-a is methyl, R6 and R9 are both hydrogen, R5 is hydroxyl, and R7 is mono(lower alkyl)amino or di(lower alkyl)amino, then R8 must be halogen; and 
 when R4 is NH-alkyl, R6-a is methyl, R6 is hydroxy or hydrogen and R7, R5, and R9 are all be hydrogen, then R8 must be halogen. 
 
     
   
   
       3 . A 4-dedimethylamino tetracycline compound selected from: 
     
       
         
         
             
             
         
       
       wherein: R7, R8, and R9 taken together in each case, have the following meanings: 
     
     
       
         
               
               
               
               
             
                   
                   
               
                   
                 R7 
                 R8 
                 R9 
               
                   
                   
               
                   
                 azido 
                 hydrogen 
                 hydrogen 
               
                   
                 dimethylamino 
                 hydrogen 
                 azido 
               
                   
                 hydrogen 
                 hydrogen 
                 amino 
               
                   
                 hydrogen 
                 hydrogen 
                 azido 
               
                   
                 hydrogen 
                 hydrogen 
                 nitro 
               
                   
                 dimethylamino 
                 hydrogen 
                 amino 
               
                   
                 acylamino 
                 hydrogen 
                 hydrogen 
               
                   
                 hydrogen 
                 hydrogen 
                 acylamino 
               
                   
                 amino 
                 hydrogen 
                 nitro 
               
                   
                 hydrogen 
                 hydrogen 
                 (N,N-dimethyl)glycylamino 
               
                   
                 amino 
                 hydrogen 
                 amino 
               
                   
                 hydrogen 
                 hydrogen 
                 ethoxythiocarbonylthio 
               
                   
                 dimethylamino 
                 hydrogen 
                 acylamino 
               
                   
                 dimethylamino 
                 hydrogen 
                 diazonium 
               
                   
                 dimethylamino 
                 chloro 
                 amino 
               
                   
                 hydrogen 
                 chloro 
                 amino 
               
                   
                 amino 
                 chloro 
                 amino 
               
                   
                 acylamino 
                 chloro 
                 acylamino 
               
                   
                 amino 
                 chloro 
                 hydrogen 
               
                   
                 acylamino 
                 chloro 
                 hydrogen 
               
                   
                 monoalkylamino 
                 chloro 
                 amino 
               
                   
                 nitro 
                 chloro 
                 amino 
               
                   
                 dimethylamino 
                 chloro 
                 acylamino 
               
                   
                 dimethylamino 
                 chloro 
                 dimethylamino 
               
                   
                 hydrogen 
                 hydrogen 
                 dimethylamino 
               
                   
                 dimethylamino 
                 hydrogen 
                 hydrogen 
               
                   
                   
               
           
              
              
              
             
             
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
             
          
         
       
       and 
     
     
       
         
         
             
             
         
       
       wherein: R7, R8, and R9 taken together in each case, have the following meanings: 
     
     
       
         
               
               
               
               
             
                   
                   
               
                   
                 R7 
                 R8 
                 R9 
               
                   
                   
               
                   
                 azido 
                 hydrogen 
                 hydrogen 
               
                   
                 dimethylamino 
                 hydrogen 
                 azido 
               
                   
                 hydrogen 
                 hydrogen 
                 amino 
               
                   
                 hydrogen 
                 hydrogen 
                 azido 
               
                   
                 hydrogen 
                 hydrogen 
                 nitro 
               
                   
                 dimethylamino 
                 hydrogen 
                 amino 
               
                   
                 acylamino 
                 hydrogen 
                 hydrogen 
               
                   
                 hydrogen 
                 hydrogen 
                 acylamino 
               
                   
                 amino 
                 hydrogen 
                 nitro 
               
                   
                 hydrogen 
                 hydrogen 
                 (N,N-dimethyl)glycylamino 
               
                   
                 amino 
                 hydrogen 
                 amino 
               
                   
                 hydrogen 
                 hydrogen 
                 ethoxythiocarbonylthio 
               
                   
                 dimethylamino 
                 hydrogen 
                 acylamino 
               
                   
                 hydrogen 
                 hydrogen 
                 diazonium 
               
                   
                 hydrogen 
                 hydrogen 
                 dimethylamino 
               
                   
                 diazonium 
                 hydrogen 
                 hydrogen 
               
                   
                 ethoxythiocarbonylthio 
                 hydrogen 
                 hydrogen 
               
                   
                 dimethylamino 
                 chloro 
                 amino 
               
                   
                 amino 
                 chloro 
                 amino 
               
                   
                 acylamino 
                 chloro 
                 acylamino 
               
                   
                 hydrogen 
                 chloro 
                 amino 
               
                   
                 amino 
                 chloro 
                 hydrogen 
               
                   
                 acylamino 
                 chloro 
                 hydrogen 
               
                   
                 monoalkylamino 
                 chloro 
                 amino 
               
                   
                 nitro 
                 chloro 
                 amino 
               
                   
                   
               
           
              
              
              
             
             
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
             
          
         
       
       and 
     
     
       
         
         
             
             
         
       
       wherein: R8 is hydrogen or halogen and R9 is selected from the group consi051205650512sting of nitro, (N,N-dimethyl)glycylamino, and ethoxythiocarbonylthio; and 
     
     
       
         
         
             
             
         
       
       wherein: R7, R8, and R9 taken together in each case, have the following meanings: 
     
     
       
         
               
               
               
               
             
                   
                   
               
                   
                 R7 
                 R8 
                 R9 
               
                   
                   
               
                   
                 amino 
                 hydrogen 
                 hydrogen 
               
                   
                 nitro 
                 hydrogen 
                 hydrogen 
               
                   
                 azido 
                 hydrogen 
                 hydrogen 
               
                   
                 dimethylamino 
                 hydrogen 
                 azido 
               
                   
                 hydrogen 
                 hydrogen 
                 amino 
               
                   
                 hydrogen 
                 hydrogen 
                 azido 
               
                   
                 hydrogen 
                 hydrogen 
                 nitro 
               
                   
                 bromo 
                 hydrogen 
                 hydrogen 
               
                   
                 dimethylamino 
                 hydrogen 
                 amino 
               
                   
                 acylamino 
                 hydrogen 
                 hydrogen 
               
                   
                 hydrogen 
                 hydrogen 
                 acylamino 
               
                   
                 amino 
                 hydrogen 
                 nitro 
               
                   
                 hydrogen 
                 hydrogen 
                 (N,N-dimethyl)glycylamino 
               
                   
                 amino 
                 hydrogen 
                 amino 
               
                   
                 diethylamino 
                 hydrogen 
                 hydrogen 
               
                   
                 hydrogen 
                 hydrogen 
                 ethoxythiocarbonylthio 
               
                   
                 dimethylamino 
                 hydrogen 
                 methylamino 
               
                   
                 dimethylamino 
                 hydrogen 
                 acylamino 
               
                   
                 dimethylamino 
                 chloro 
                 amino 
               
                   
                 amino 
                 chloro 
                 amino 
               
                   
                 acylamino 
                 chloro 
                 acylamino 
               
                   
                 hydrogen 
                 chloro 
                 amino 
               
                   
                 amino 
                 chloro 
                 hydrogen 
               
                   
                 acylamino 
                 chloro 
                 hydrogen 
               
                   
                 monoalkylamino 
                 chloro 
                 amino 
               
                   
                 nitro 
                 chloro 
                 amino 
               
                   
                   
               
           
              
              
              
             
             
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
             
          
         
       
       
         and pharmaceutically acceptable and unacceptable salts thereof. 
       
     
   
   
       4 - 21 . (canceled)

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