IP Library › Patent Application 13700500

Patent Application

App. No. 13/700,500

OLIGO-BENZAMIDE COMPOUNDS AND THEIR USE

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Patent No.: US None
App. No.: 13/700,500

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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 (56)

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)

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 20, 2013

From: AHN, JUNG-MO; RAJ, GANESH

To: THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM

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