US2023265041A1PendingUtilityA1
Curcumin analogues as zinc chelators and tehir uses
Est. expiryMay 15, 2029(~2.8 yrs left)· nominal 20-yr term from priority
C07C 69/738C07C 49/255C07C 225/22C07C 235/78C07C 235/80C07C 237/20C07D 213/50C12N 9/6491C12Y 304/24A61P 39/04
86
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
This invention provides a compound having the structure wherein α, β, X, Y, and R 1 -R 11 are defined herein. This invention also provides a pharmaceutical composition comprising the above compounds, a method of inhibiting the activity and/or levels of a matrix metalloproteinase (MMP), a method of inhibiting the production of a cytokine in a population of cells, a method of inhibiting the production of a growth factor in a population of cells, and a method of inhibiting NF K -B activation in a population of cells.
Claims
exact text as granted — not AI-modified1 . A compound having the structure
wherein
bond α and β are each, independently, present or absent;
X is CR 5 or N; Y is CR 10 or N;
R 1 is H, CF 3 , halogen, —NO 2 , —OCF 3 , —OR 12 , —NHCOR 12 , —SR 12 , —SO 2 R 13 , —COR 14 , —CSR 14 , —C (═NR 12 ) R 14 , —C (═NH) R 14 , —SOR 12 , —POR 12 , —P (═0) (OR 12 ) (OR 13 ), or —P (OR 12 ) (OR 13 ),
wherein R 12 and R 13 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 14 is C 2-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroaryl,
heterocyclyl, methoxy, —OR 15 , -NR 16 R 17 , or
wherein R 15 is H, C 3-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl;
R 16 and R 17 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 1S , R 19 , R 21 , and R 22 are each independently H, halogen, —NO 2 , —CN, —NR 23 R 24 , —SR 23 , —SO 2 R 23 , —CO 2 R 23 , —OR 25 , CF 3 , —SOR 23 , —POR 23 , —C (═S) R 23 , —C (═NH) R 23 , —C (═NR 24 ) R 23 , —C (═N) R 23 , —P (═O) (OR 23 ) (OR 24 ), —P (OR 23 ) (OR 24 ), —C (═S) R 23 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 23 , R 24 , and R 25 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 20 is halogen, —NO 2 , —CN, -NR 26 R 27 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 26 and R 27 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R e , R 9 , R 10 , and R 11 are each independently, H, halogen, —NO 2 , —CN, —NR 28 R 29 , —NHR 28 R 29 + , —SR 28 , —SO 2 R 28 , —OR 28 , —CO 2 R 28 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 28 and R 29 are each, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl, or -C(=O)-heterocyclyl; and
wherein when R 1 is H, R 3 , R 4 , R 5 , R 8 , R 9 , or R 10 , is halogen, —NO 2 , —CN, —NR 28 R 29 , —NHR 28 R 29 + , —SR 28 , —SO 2 R 28 , —CO 2 R 28 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 28 and R 29 are each, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2 - 10 alkynyl, or heterocyclyl; and
wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
2 . The compound of claim 1 , wherein when R 1 is H, R 3 , R 4 , R 5 , R 8 , R 9 , or R 10 , is —NO 2 , —NR 28 R 29 , —NHR 28 R 29 + , —SR 28 , —SO 2 R 28 , —CO 2 R 28 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl; or a salt thereof, or
wherein when R 1 is H, R 4 or R 9 is —NO 2 , —NR 28 R 29 , —NHR 28 R 29 + ; or a salt thereof,
wherein when R 1 is H, R 4 or R 9 is -NR 28 R 29 or —NHR 28 R 29 + ; or a salt thereof.
3 - 4 . (canceled)
5 . The compound of claim 1 , wherein
R 1 is H or —COR 14 ,
wherein R 14 is methoxy or -NH-phenyl;
R 2 , R 5 , R 6 , R 7 , R 10 and R 11 are each H; R 3 , R 4 , R 8 , and R 9 are each, independently H, —OH, —OCH 3 , -N (CH 3 ) 2 or —NH (CH 3 ) 2 + ; or a salt thereof.
6 . The compound of claim 1 , having the structure
or a salt thereof.
7 . The compound of claim 1 having the structure
wherein
bond α and β are each, independently, present or absent;
R 1 is CF 3 , halogen, —NO 2 , —OCF 3 , —OR 12 , —NHCOR 12 , —SR 12 , —SO 2 R 13 , —COR 14 , —CSR 14 , or —CNR 14 ,
wherein R 12 and R 13 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 14 is C 2-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroaryl,
heterocyclyl, methoxy, —OR 15 , —NR 16 R 17 , or
wherein R 15 is H, C 3-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl;
R 16 and R 17 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 1S , R 19 , R 21 , and R 22 are each independently H, halogen, —NO 2 , —CN, —NR 23 R 24 , —SR 23 , —SO 2 R 23 , —CO 2 R 23 , —OR 25 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 23 , R 24 , and R 25 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 20 is halogen, —NO 2 , —CN, —NR 26 R 27 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 26 and R 27 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently, H, halogen, —NO 2 , —CN, —NR 28 R 29 , —SR 28 , —SO 2 R 28 , —OR 28 , —CO 2 R 28 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 28 and R 29 are each, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and
wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; and
wherein at least one of R 2 , R 3 , R 4 , R 5 , and R 6 and at least one of R 7 , R 8 , R 9 , R 10 , and R 11 , are each, independently, —OR 28 ;
or a salt thereof.
8 . The compound of claim 7 having the structure
wherein R 1 is CF 3 , halogen, —NO 2 , —OCF 3 , —OR 12 , —NHCOR 12 , —SR 12 , —SO 2 R 13 , —COR 14 , —CSR 14 , or —CNR 14 ,
wherein R 12 and R 13 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 14 is C 2-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroaryl,
heterocyclyl, methoxy, —OR 15 , —NR 16 R 17 , or
wherein R 15 is H, C 3-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl;
R 16 and R 17 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 1S , R 19 , R 21 , and R 22 are each independently H, halogen, —NO 2 , —CN, —NR 23 R 24 , —SR 23 , —SO 2 R 23 , —CO 2 R 23 , —OR 25 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 23 , R 24 , and R 25 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 20 is halogen, —NO 2 , —CN, —NR 26 R 27 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 26 and R 27 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently, H, halogen, —NO 2 , —CN, —NR 28 R 29 , —SR 28 , —SO 2 R 28 , —OR 28 , —CO 2 R 28 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 28 and R 29 are each, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and
wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; and
wherein at least one of R 2 , R 3 , R 4 , R 5 , and R 6 and at least one of R 7 , R 8 , R 9 , R 10 , and R 11 , are each, independently, —OR 28 ;
or a salt thereof.
9 . The compound of claim 8 having the structure
wherein R 14 is C 2-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroaryl,
heterocyclyl, methoxy, —OR 15 , —NR 16 R 17 , or
wherein R 15 is H, C 3-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl;
R 16 and R 17 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 1S , R 19 , R 21 , and R 22 are each independently H, halogen, —NO 2 , —CN, —NR 23 R 24 , —SR 23 , —SO 2 R 23 , —CO 2 R 23 , —OR 25 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 23 , R 24 , and R 25 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 20 is halogen, —NO 2 , —CN, —NR 26 R 27 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 26 and R 27 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently, H, halogen, —NO 2 , —CN, —NR 28 R 29 , —SR 28 , —SO 2 R 28 , —OR 28 , —CO 2 R 28 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 28 and R 29 are each, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and
wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; and
wherein at least one of R 2 , R 3 , R 4 , R 5 , and R 6 and at least one of R 7 , R 8 , R 9 , R 10 , and R 11 , are each, independently, —OR 28 ;
or a salt thereof.
10 . The compound of claim 9 having the structure
wherein R 14 is C 2-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroaryl,
heterocyclyl, methoxy, —OR 15 , —NR 16 R 17 , or
wherein R 15 is H, C 3-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl;
R 16 and R 17 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 1S , R 19 , R 21 , and R 22 are each independently H, halogen, —NO 2 , —CN, -NR 23 R 24 , —SR 23 , —SO 2 R 23 , —CO 2 R 23 , —OR 25 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 23 , R 24 , and R 25 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 20 is halogen, —NO 2 , —CN, —NR 26 R 27 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 26 and R 27 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently, H, halogen, —NO 2 , —CN, —NR 28 R 29 , —SR 28 , —SO 2 R 28 , —OR 28 , —CO 2 R 28 , CF 3 ;
wherein R 28 and R 29 are each, H, CF 3 , C 1-5 alkyl, C 2-5 alkenyl, or C 2-5 alkynyl; and
wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; and
wherein at least one of R 2 , R 3 , R 4 , R 5 , and R 6 and at least one of R 7 , R 8 , R 9 , R 10 , and R 11 , are each, independently, —OR 28 ;
or a salt thereof.
11 . The compound of claim 8 wherein R 14 is methoxy,
—OR 15 or —NR 16 R 17 ,
wherein R 15 is H, C 3-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl;
R 16 and R 17 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
or a salt thereof, or
wherein R 14 is methoxy or -NR 16 R 17 ,
wherein R 16 and R 17 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
or a salt thereof, or
wherein R 14 is —OR 15 , wherein R 15 is H, C 3-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; or a salt thereof, or
wherein R 14 is -NR 16 R 17 ,
wherein R 16 and R 17 are each, independently, H or aryl;
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently, H, -NR 28 R 29 , or —OR 28 ,
wherein R 28 and R 29 are each, H or C 1-10 alkyl;
or a salt thereof, or
wherein R 14 is —NH—phenyl;
R 2 , R 5 , R 6 , R 7 , R 10 , and R 11 are each H;
R 3 , R 4 , R 8 , and R 9 are each, independently, H, —OH, or —OCH 3 ; or a salt thereof.
12 - 15 . (canceled)
16 . The compound of claim 15 having the structure:
or a salt thereof.
17 . The compound of claim 11 having the structure
wherein R 3 , R 4 , R 8 , and R 9 are H, —OCH 3 , or —OH; R 14 is methoxy or —N(CH 3 ) 2 ; or a salt thereof.
18 . The compound of claim 17 having the structure
or a salt thereof.
19 . The compound of claim 11 wherein R 14 is methoxy;
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each, independently, H, —OH, —OCH 3 , —NO 2 , or —CO 2 CH 3 ; or a salt thereof.
20 . The compound of claim 19 having the structure
or a salt thereof.
21 . The compound of claim 1 , wherein X is N and/or α and β are both present; or a salt thereof.
22 . (canceled)
23 . The compound of claim 19 having the structure:
or a salt thereof.
24 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 .
25 . A method of inhibiting the activity and/or levels of a matrix metalloproteinase (MMP) or inhibiting the production of a cytokine in a population of mammalian cells or inhibiting the production of a growth factor in a population of mammalian cells or inhibiting NF K -B activation in a population of cells comprising contacting the matrix metalloproteinase or a cell producing an MMP or MMPs or the population of cells with the compound of claim 1 so as to inhibit the activity of a matrix metalloproteinase.
26 - 34 . (canceled)
35 . A method of increasing water solubility, metal binding ability, MMP inhibition activity, cytokine inhibition activity, growth factor inhibition activity, or NF K B activation inhibition activity of curcumin comprising synthesizing a compound having the structure
wherein
bond α and β are each, independently, present or absent;
X is CR 5 or N; Y is CR 10 or N;
R 1 is H or an electron-withdrawing group;
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently, H, halogen, —NO 2 , —CN, —NR 28 R 29 , —NHR 28 R 29 + , —SR 28 , —SO 2 R 28 , —OR 28 , —CO 2 R 28 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 28 and R 29 are each, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl, or -C(=O)-heterocyclyl; and
wherein when R 1 is H, R 3 , R 4 , R 5 , R 8 , R 9 , or R 10 , is halogen, —NO 2 , —CN, -NR 28 R 29 , —NHR 28 R 29 +, —SR 28 , —SO 2 R 28 , —CO 2 R 28 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 28 and R 29 are each, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl, or -C(=O)-heterocyclyl; and
wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted;
or a salt thereof.
36 - 37 . (canceled)
38 . The method of claim 35 , wherein the compound synthesized has the structure
wherein R 1 is an electron-withdrawing group, or a salt thereof.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.