IP Library › Granted Patent US 9,856,206
Granted Patent B2
US 9,856,206 · App. 14/932,480 · Granted Jan 2, 2018

Oligo-benzamide compounds and their use

Inventors: Jung-Mo Ahn (Plano, TX); Ganesh Raj (Plano, TX)
Assignee: The Board of Regents of the University of Texas System
C07C235/56A61K31/167C07C237/06C07C237/44C07C279/08C07D493/10
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Quick Facts
Patent No.
US 9,856,206
App. No.
14/932,480
Granted
Jan 2, 2018
Kind
B2
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 (74)

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 , —NH 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 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 , —NH 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 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,

R 1 and R 2 are optionally substituted C 1 -C 15 arylalkyl,

R 1 and R 2 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,

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,

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,

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,

R 1 is C 1 -C 10 alkyl, C 1 -C 10 alkenyl, or C 1 -C 10 alkynyl, and R 2 is C-C 15 optionally substituted arylalkyl,

R 1 is —(CH 2 ) n —NRR′ or —(CH 2 ) 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, or

R 1 is —(CH 2 ) n —COOR, —(CH 2 ) n —SO m R, —(CH 2 ) n —PO m R , and R 2 is —(CH 2 ) n —NRR′ or —(CH 2 ) 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.

7. 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,

R 1 , R 2 , and R 3 are optionally substituted C 1 -C 15 arylalkyl,

R 1 , R 2 , and R 3 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,

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,

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,

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,

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,

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,

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,

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,

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,

R 1 and R 2 are —(CH 2 ) n —NRR′ or —(CH 2 ) 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,

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 —(CH 2 ) 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,

R 1 and R 2 are —(CH 2 ) n —NRR′ or —(CH 2 ) 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,

R 1 is C 1 -C 15 optionally substituted arylalkyl, and R 2 and R 3 are —(CH 2 ) n —NRR′ or —(CH 2 ) 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,

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,

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,

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,

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,

R 1 and R 3 are —(CH 2 ) n —NRR′ or —(CH 2 ) 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, or

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.

8. 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.

9. The compound of claim 3 , wherein X′ is —NHC(O)CH 2 NH 2 .

10. The compound of claim 2 , wherein R 1 or R 2 is isopropyl, isobutyl, n-butyl, sec-butyl or n-pentyl.

11. The compound of claim 3 , wherein R 1 , R 2 or R 3 is isopropyl, isobutyl, n-butyl, sec-butyl or n-pentyl.

12. The compound of claim 3 , wherein R 1 , R 2 or R 3 is:

13. The compound of claim 1 , wherein the compound is:

14. A compound of the formula:

15. 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 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 , —NH 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 , —NH 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.

16. The method of claim 15 , wherein the compound is of formula (A).

17. The method of claim 15 , wherein the compound is of formula (B).

18. The method of claim 15 , wherein the compound is:

19. The method of claim 15 , wherein the AR-positive tumor cell is a carcinoma cell, a leukemia cell or a myeloma cell.

20. The method of claim 19 , wherein the carcinoma cell is a prostate or breast carcinoma cell.

Continuity (3)
Continuation 13700500
Provisional Application 61349555 · May 28, 2010
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