Curcumin analogues as zinc chelators and their uses

Patent metadata

Field	Value
Publication number	US-10669227-B2
Application number	US-201615383735-A
Country	US
Kind code	B2
Filing date	Dec 19, 2016
Priority date	May 15, 2009
Publication date	Jun 2, 2020
Grant date	Jun 2, 2020

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 NFκ-B activation in a population of cells.

First claim

What is claimed is:

1. 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 , —COR 14 , —CSR 14 , —C(═NR 12 )R 14 , —C(═NH) R 14 , —SOR 12 , —POR 12 , —P(═O)(OR 12 )(OR 13 ), or —P (OR 12 )(OR 13 ),
wherein
R 12 is H;
R 13 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 14 is

R 18 , 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 16 R 17 , CF 3 , C 3-18 , alkyl, C 1-10 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 , —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, then R 3 , R 5 , R 8 , 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, or

when R 1 is H, then R 4 and R 9 are —NHR 28 R 29 + ,
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
R 1 is H;
R 2 , R 5 , R 6 , R 7 , R 10 and R 11 are each H;
R 3 , and R 8 are each, independently H, —OH, —OCH 3 , —N(CH 3 ) 2 or —NH (CH 3 ) 2 + ; and
when R 1 is H, then R 4 and R 9 are —NH(CH 3 ) 2 + ,
or a salt thereof.

3. The compound of claim 1 having the structure

or a salt thereof.

4. 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 , —COR 14 or —CSR 14 , wherein R 12 is H;
R 13 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 14 is

wherein R 18 , 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 3-10 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 L-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and

wherein when R 1 is H, then R 3 , R 5 , R 8 , 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, or

when R 1 is H, then R 4 and R 9 are —NHR 28 R 29 + ,
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 ;
wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted;
or a salt thereof.

5. The compound of claim 4 having the structure

wherein R 1 is CF 3 , halogen, —NO 2 , —OCF 3 , —OR 12 , —NHCOR 12 , —SR 12 , —COR 14 or —CSR 14 ,
wherein R 12 is H;
R 13 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 14 is

wherein R 18 , 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 26 R 29 , —SR 28 , —SO 2 R 26 , —OR 2 , —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 1-10 alkenyl, or C 2-10 alkynyl; and

wherein when R 1 is H, then R 3 , R 5 , R 8 , 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, or

when R 1 is H, then R 4 and R 9 are —NHR 28 R 29 + ,
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 ;
wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted;
or a salt thereof.

6. The compound of claim 5 havi

Assignees

• Johnson Francis
• Golub Lorne
• Univ New York State Res Found

Inventors

• Johnson Francis
• Golub Lorne

Classifications

• C12N9/6491

  Matrix metalloproteases [MMP's], e.g. interstitial collagenase (3.4.24.7); Stromelysins (3.4.24.17; 3.2.1.22); Matrilysin (3.4.24.23) · CPC title

• C07D213/50

  Ketonic radicals · CPC title

• C07C49/255

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title

• C07C235/78

  the carbon skeleton containing rings · CPC title

• C12Y304/24

  Metalloendopeptidases (3.4.24) · CPC title