US2013231385A1PendingUtilityA1

Oligo-benzamide compounds and their use

48
Assignee: AHN JUNG-MOPriority: May 28, 2010Filed: May 27, 2011Published: Sep 5, 2013
Est. expiryMay 28, 2030(~3.9 yrs left)· nominal 20-yr term from priority
Inventors:Jung-Mo AhnGanesh Raj
A61P 35/00A61P 43/00A61P 35/02C07D 493/10A61K 31/167C07C 237/44C07C 235/56C07C 237/06A61P 15/00C07C 279/08A61P 13/08C07C 205/06A61K 31/16C07C 217/66
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Claims

Abstract

The present invention includes bis- and tris-benzamide compounds that block AR signaling and have anticancer activity. Uses for these compounds, and pharmaceutical compositions containing the same, also are provided.

Claims

exact text as granted — not AI-modified
1 . A compound of formulas (A) or (B): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are each independently C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, C 1 -C 15  optionally substituted arylalkyl, —(CH 2 ) n —COOR, —(CH 2 ) n —CONRR′, —(CH 2 ) n —NRR′, —(CH 2 ) n —NH(C═NH)NRR′, —(CH 2 ) n —NRCOR′, —(CH 2 ) n —NRCOOR′, —(CH 2 ) n —OR, —(CH 2 ) n —SR, —(CH 2 ) n —SO m R, —(CH 2 ) n —PO m R, wherein n and m may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl group; 
 X is —NO 2  or —NHC(O)CH 2 R 3 , wherein R 3  is —NO 2 , —Z, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  arylalkyl, each of which is optionally substituted with —COOR, —CONRR′, —NRR′, —NH(C═NH)NRR′, —NRCOR′, —NRCOOR′, —OR, —SR, —SO n R, or —PO n R, wherein n may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl group, and wherein Z is: 
 
       
         
           
           
               
               
           
         
       
       and
 Y is —(CH 2 ) n COOR 4 , —(CH 2 ) n CONR 4 R 5 , —(CH 2 ) n NR 4 R 5 , —(CH 2 ) n —NR 4 R 5 , —(CH 2 ) n —NH(C═NH)NR 4 R 5 , —(CH 2 ) n —NR 4 COR 5 , —(CH 2 ) n —NR 4 COOR 5 , —(CH 2 ) n —OR 4 , —(CH 2 ) n —SR 4 , —(CH 2 ) n —SO m R 4 , —(CH 2 ) n —PO m R 4 , wherein n and m may be any number between 0 and 6, 
 R 4  and R 5  are independently selected from —H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl group; or 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2  and R 3  are each independently C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, C 1 -C 15  optionally substituted arylalkyl, —(CH 2 ) n —COOR, —(CH 2 ) n —CONRR′, —(CH 2 ) n —NRR′, —(CH 2 ) n —NH(C═NH)NRR′, —(CH 2 ) n —NRCOR′, —(CH 2 ) n —NRCOOR′, —(CH 2 ) n —OR, —(CH 2 ) n —SR, —(CH 2 ) n —SO m R, —(CH 2 ) n —PO m R, wherein n and m may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl group or 
 
       
         
           
           
               
               
           
         
         X′ is —NO 2  or —NHC(O)CH 2 R 3 , wherein R 3  is —NO 2 , —Z′, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  arylalkyl, each of which is optionally substituted with —COOR, —CONRR′, —NRR′, —NH(C═NH)NRR′, —NRCOR′, —NRCOOR′, —OR, —SR, —SO n R, or —PO n R, wherein n may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl group, and wherein Z′ is: 
       
       
         
           
           
               
               
           
         
       
       and
 Y′ is —(CH 2 ) n COOR 4 , —(CH 2 ) n CONR 4 R 5 , —(CH 2 ) n NR 4 R 5 , —(CH 2 ) n —NR 4 R 5 , —(CH 2 ) n —NH(C═NH)NR 4 R 5 , —(CH 2 ) n —NR 4 COR 5 , —(CH 2 ) n —NR 4 COOR 5 , —(CH 2 ) n —OR 4 , —(CH 2 ) n —SR 4 , —(CH 2 ) n —SO m R 4 , —(CH 2 ) n —PO m R 4 , wherein n and m may be any number between 0 and 6, 
 R 4  and R 5  are independently selected from —H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl group. 
 
     
     
         2 . The compound of  claim 1 , further defined as a compound of formula (A). 
     
     
         3 . The compound of  claim 1 , further defined as a compound of formula (B). 
     
     
         4 . The compound of  claim 2 , wherein X is —NO 2 . 
     
     
         5 . The compound of  claim 3 , wherein X′ is —NO 2 . 
     
     
         6 . The compound of  claim 4 , wherein R 1  and R 2  are C 1 -C 10  alkyl, C 1 -C 10  alkenyl, or C 1 -C 10  alkynyl. 
     
     
         7 . The compound of  claim 4 , wherein R 1  and R 2  are optionally substituted C 1 -C 15  arylalkyl. 
     
     
         8 . The compound of  claim 4 , wherein R 1  and R 2  are —(CH 2 ) n —NRR′ or —(CH 2 ) n —NH(C═NH)NRR′ groups, wherein n may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl. 
     
     
         9 . The compound of  claim 4 , wherein R 1  and R 2  are —(CH 2 ) n —COOR, —(CH 2 ) n —CONRR′, —(CH 2 ) n —NRCOR′, —(CH 2 ) n —NRCOOR′, —(CH 2 ) n —SO m R, —(CH 2 ) n —PO m R, wherein n and m may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl. 
     
     
         10 . The compound of  claim 4 , wherein R 1  and R 2  are —(CH 2 ) n —OR, —(CH 2 ) n —SR, wherein R may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl. 
     
     
         11 . The compound of  claim 4 , wherein R 1  is C 1 -C 15  optionally substituted arylalkyl, and R 2  is C 1 -C 10  alkyl, C 1 -C 10  alkenyl, or C 1 -C 10  alkynyl. 
     
     
         12 . The compound of  claim 4 , wherein R 1  is C 1 -C 10  alkyl, C 1 -C 10  alkenyl, or C 1 -C 10  alkynyl, and R 2  is C 1 -C 15  optionally substituted arylalkyl. 
     
     
         13 . The compound of  claim 4 , wherein R 1  is —(CH 2 ) n —NRR′ or —(CH2) n -NH(C═NH)NRR′, and R 2  is —(CH 2 ) n —COOR, —(CH 2 ) n —SO m R, —(CH 2 ) n —PO m R, wherein n and m may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl group. 
     
     
         14 . The compound of  claim 4 , wherein R 1  is —(CH 2 ) n —COOR, —(CH 2 ) n —SO m R, —(CH 2 )—PO m R 1  and R 2  is —(CH 2 ) n —NRR′ or —(CH2) n -NH(C═NH)NRR′, wherein n and m may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl group. 
     
     
         15 . The compound of  claim 5 , wherein R 1 , R 2 , and R 3  are C 1 -C 10  alkyl, C 1 -C 10  alkenyl, or C 1 -C 10  alkynyl. 
     
     
         16 . The compound of  claim 5 , wherein R 1 , R 2 , and R 3  are optionally substituted C 1 -C 15  arylalkyl. 
     
     
         17 . The compound of  claim 5 , wherein R 1 , R 2 , and R 3  are —(CH 2 ) n —NRR′ or —(CH2) n -NH(C═NH)NRR′ groups, wherein n may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl. 
     
     
         18 . The compound of  claim 5 , wherein R 1 , R 2 , and R 3  are —(CH 2 ) n —COOR, —(CH 2 ) n —CONRR′, —(CH 2 ) n —NRCOR′, —(CH 2 ) n —NRCOOR′, —(CH 2 ) n —SO m R, —(CH 2 ) n —PO m R, wherein n and m may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl. 
     
     
         19 . The compound of  claim 5 , wherein R 1 , R 2 , and R 3  are —(CH 2 ) n —OR, —(CH 2 ) n —SR, wherein R may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl. 
     
     
         20 . The compound of  claim 5 , wherein R 1  is C 1 -C 15  optionally substituted arylalkyl, and R 2  and R 3  are C 1 -C 10  alkyl, C 1 -C 10  alkenyl, or C 1 -C 10  alkynyl. 
     
     
         21 . The compound of  claim 5 , wherein R 1  and R 2  are C 1 -C 10  alkyl, C 1 -C 10  alkenyl, or C 1 -C 10  alkynyl, and R 3  is C 1 -C 15  optionally substituted arylalkyl. 
     
     
         22 . The compound of  claim 5 , wherein R 1  is C 1 -C 10  alkyl, C 1 -C 10  alkenyl, or C 1 -C 10  alkynyl, and R 2  and R 3  are C 1 -C 15  optionally substituted arylalkyl. 
     
     
         23 . The compound of  claim 5 , wherein R 1  and R 2  are C 1 -C 15  optionally substituted arylalkyl, and R 3  is C 1 -C 10  alkyl, C 1 -C 10  alkenyl, or C 1 -C 10  alkynyl. 
     
     
         24 . The compound of  claim 5 , wherein R 1  and R 3  are C 1 -C 10  alkyl, C 1 -C 10  alkenyl, or C 1 -C 10  alkynyl, and R 2  is C 1 -C 15  optionally substituted arylalkyl. 
     
     
         25 . The compound of  claim 5 , wherein R 1  and R 3  are C 1 -C 15  optionally substituted arylalkyl, and R 2  is C 1 -C 10  alkyl, C 1 -C 10  alkenyl, or C 1 -C 10  alkynyl. 
     
     
         26 . The compound of  claim 5 , wherein R 1  and R 2  are —(CH 2 ) n —NRR′ or —(CH2) n -NH(C═NH)NRR′, and R 3  is C 1 -C 10  alkyl, C 1 -C 10  alkenyl, or C 1 -C 10  alkynyl, wherein n may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl. 
     
     
         27 . The compound of  claim 5 , wherein R 1  is C 1 -C 10  alkyl, C 1 -C 10  alkenyl, or C 1 -C 10  alkynyl, and R 2  and R 3  are —(CH 2 ) n —NRR′ or —(CH2) n -NH(C═NH)NRR′, wherein n may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl. 
     
     
         28 . The compound of  claim 5 , wherein R 1  and R 2  are —(CH 2 ) n —NRR′ or —(CH2) n -NH(C═NH)NRR′, and R 3  is C 1 -C 15  optionally substituted arylalkyl, wherein n may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl. 
     
     
         29 . The compound of  claim 5 , wherein R 1  is C 1 -C 15  optionally substituted arylalkyl, and R 2  and R 3  are —(CH 2 ) n —NRR′ or —(CH2) n -NH(C═NH)NRR′, wherein n may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl. 
     
     
         30 . The compound of  claim 5 , wherein R 1  and R 2  are —(CH 2 ) n —COOR, —(CH 2 ) n —CONRR′, —(CH 2 ) n —NRCOR′, —(CH 2 ) n —NRCOOR′, —(CH 2 ) n —SO m R, —(CH 2 ) n —PO m R, and R 3  is C 1 -C 10  alkyl, C 1 -C 10  alkenyl, or C 1 -C 10  alkynyl, wherein n and m may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl. 
     
     
         31 . The compound of  claim 5 , wherein R 1  is C 1 -C 10  alkyl, C 1 -C 10  alkenyl, or C 1 -C 10  alkynyl, and R 2  and R 3  are —(CH 2 ) n —COOR, —(CH 2 ) n —CONRR′, —(CH 2 ) n —NRCOR′, —(CH 2 ) n —NRCOOR′, —(CH 2 ) n —SO m R, —(CH 2 ) n —PO m R, wherein n and m may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl. 
     
     
         32 . The compound of  claim 5 , wherein R 1  and R 2  are —(CH 2 ) n —COOR, —(CH 2 ) n —CONRR′, —(CH 2 ) n —NRCOR′, —(CH 2 ) n —NRCOOR′, —(CH 2 ) n —SO m R, —(CH 2 ) n —PO m R, and R 3  is C 1 -C 15  optionally substituted arylalkyl, wherein n and m may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl. 
     
     
         33 . The compound of  claim 5 , wherein R 1  is C 1 -C 15  optionally substituted arylalkyl, and R 2  and R 3  are —(CH 2 ) n —COOR, —(CH 2 ) n —CONRR′, —(CH 2 ) n —NRCOR′, —(CH 2 ) n —NRCOOR′, —(CH 2 ) n —SO m R, —(CH 2 ) n —PO m R, wherein n and m may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl. 
     
     
         34 . The compound of  claim 5 , wherein R 1  and R 3  are —(CH 2 ) n —NRR′ or —(CH2) n -NH(C═NH)NRR′, and R 2  is —(CH 2 ) n —COOR, —(CH 2 ) n —CONRR′, —(CH 2 ) n —NRCOR′, —(CH 2 ) n —NRCOOR′, —(CH 2 ) n —SO m R, —(CH 2 ) n —PO m R, wherein n and m may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl. 
     
     
         35 . The compound of  claim 5 , wherein R 1  and R 3  are —(CH 2 ) n —COOR, —(CH 2 ) n —CONRR′, —(CH 2 ) n —NRCOR′, —(CH 2 ) n —NRCOOR′, —(CH 2 ) n —SO m R, —(CH 2 ) n —PO m R, and R 2  is —(CH 2 ) n —NRR′ or —(CH2) n -NH(C═NH)NRR′, wherein n and m may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, or C 1 -C 15  optionally substituted arylalkyl. 
     
     
         36 . The compound of  claim 2 , wherein X is —NHC(O)CH 2 R 3  and R 3  is —NH 2  or C 1 -C 10  alkyl, optionally substituted with —COOH. 
     
     
         37 . The compound of  claim 3 , wherein X′ is —NHC(O)CH 2 NH 2 . 
     
     
         38 . The compound of  claim 2 , wherein R 1  or R 2  are independently selected from isopropyl, isobutyl, n-butyl, sec-butyl or n-pentyl. 
     
     
         39 . The compound of  claim 3 , wherein R 1 , R 2  or R 3  are independently selected from isopropyl, isobutyl, n-butyl, sec-butyl or n-pentyl. 
     
     
         40 . The compound of  claim 3 , wherein R 1 , R 2  or R 3  is: 
       
         
           
           
               
               
           
         
       
     
     
         41 . The compound of  claim 1 , wherein Y or Y′ is —NH 2 . 
     
     
         42 . (canceled) 
     
     
         43 . A method of inhibiting a androgen receptor (AR)-positive tumor cell in a subject comprising administering to said subject a therapeutically sufficient amount of an oligo-benzamide peptidomimetic compound as shown in  claim 1 . 
     
     
         44 - 67 . (canceled)

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