Inhibitors of collagen prolyl 4-hydroxylase
Biheteroaryl dicarboxylates and esters, and salts thereof which are useful as modulators of CP4H activity and more particularly as inhibitors of CP4H. Compounds of formula: and salts thereof where: X is S, O, NH, or NR, where R is an alkyl group having 1-3 carbon atoms; R 1 and R 2 independently are —OR 7 , or —NHSO 2 R 8 , where R 7 is selected from: hydrogen, alkyl, alkenyl, alkoxyalkyl, —R′—CO—R″, —R′—CO—O—R″, —CO—R″, —R′—O—CO—R″, —R′—CO—NR″, —CO—NR″, or —R′—O—CO—NR″, and R 8 is selected from hydrogen, alkyl, aryl, arylalkyl; R 3 , R 4 and R 6 independently are hydrogen, alkyl, alkoxy, alkenyl, alkenoxy, haloalkyl, haloalkenyl, halogen, hydroxyl, hydroxyalkyl, hydroxyalkenyl, aryl, aryloxy, arylalkyl or arylalkyloxy; R 5 is hydrogen, halogen, alkyl having 1-3 carbon atoms, or alkoxy having 1-3 carbon atoms; —R′— is a divalent straight chain or branched alkylene, and —R″ is an alkyl, alkenyl, arylalkyl, or aryl group. Methods for inhibition of CP4H in vivo and in vitro.
1. A compound of formula:
or salts thereof,
where:
X is S, O, NH, or NR,
where R is an alkyl group having 1-3 carbon atoms;
R 1 and R 2 independently are —OR 7 , or —NHSO 2 R 8 ,
where R 7 is selected from:
hydrogen, alkyl, alkoxyalkyl, —R′—CO—R″, —R′—CO—O—R″, —CO—R″, —R′—O—CO—R″, —R′—CO—NR″, —CO—NR″, —R′—O—CO—NR″, and
R 8 is selected from hydrogen, alkyl, aryl or arylalkyl;
R 3 , R 4 and R 6 independently are hydrogen, alkyl, alkoxy, alkenyl, alkenoxy, haloalkyl, haloalkenyl, halogen, hydroxyl, hydroxyalkyl, hydroxyalkenyl, aryl, aryloxy, arylalkyl or arylalkyoxy;
R 5 is hydrogen, an alkyl having 1-3 carbon atoms or an alkoxy having 1-3 carbon atoms;
—R′— is a divalent straight chain or branched alkylene, and
—R″ is an alkyl, aryl or arylalkyl.
2. The compound of claim 1 , where X is S.
3. The compound of claim 1 , where X is O.
4. The compound of claim 1 , where X is NH.
5. The compound of claim 1 , where X is NCH 3 .
6. The compound of claim 1 , wherein R 3 , R 4 and R 6 are all hydrogens.
7. The compound of claim 1 , wherein R 3 , R 4 and R 6 are selected from hydrogen, alkyl, alkoxy or halogen.
8. The compound of claim 1 , wherein R 3 , R 4 , and R 6 are hydrogen or alkyl groups having 1-3 carbon atoms.
9. The compound of claim 1 , wherein R 3 , R 4 and R 6 independently are hydrogen, alkyl, alkoxy, halogen, hydroxyl, phenyl or benzyl.
10. The compound of claim 1 , wherein R 1 and R 2 are independently —OR 7 groups where R 7 is an alkyl group having 1-8 carbon atoms.
11. The compound of claim 1 , wherein R 1 and R 2 are —OR 7 groups where R 7 is a methyl or an ethyl group.
12. The compound of claim 1 , wherein R 1 and R 2 are —OR 7 groups where R 7 is an alkoxyalkyl group.
13. The compound of claim 1 , wherein at least one of R 1 or R 2 is —NHSO 2 R 8 .
14. A compound of formula:
or salts thereof,
where:
R 1 and R 2 independently are —OR 7 , or —NHSO 2 R 8 ,
where R 7 is selected from:
hydrogen, alkyl, alkoxyalkyl, —R′—CO—R″, —R′—CO—O—R″, —CO—R″, —R′—O—CO—R″, —R′—CO—NR″, —CO—NR″, —R′—O—CO—NR″, and
R 8 is selected from hydrogen, alkyl, aryl or arylalkyl;
R 3 , R 4 and R 6 independently are hydrogen, alkyl, alkoxy, alkenyl, alkenoxy, haloalkyl, haloalkenyl, halogen, hydroxyl, hydroxyalkyl, hydroxyalkenyl, aryl, aryloxy, arylalkyl or arylalkyoxy;
R 5 is hydrogen, an alkyl having 1-3 carbon atoms or an alkoxy having 1-3 carbon atoms;
—R′— is a divalent straight chain or branched alkylene;
—R″ is an alkyl, aryl or arylalkyl; and
HET is selected from:
where R is hydrogen or an alkyl group.
15. The compound of claim 14 , wherein Het is
16. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds or salts of claim 1 and a pharmaceutically acceptable carrier.
17. The compound of claim 14 , wherein R is hydrogen, R 3 -R 6 are each hydrogen, R 1 and R 2 are —OR 7 and R 7 is an alkyl group having 1-8 carbon atoms.
18. The compound of claim 17 , wherein Het is
19. The compound of claim 18 , wherein R 7 is ethyl.
20. The compound of claim 17 , wherein Het is
21. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds or salts of claim 17 and a pharmaceutically acceptable carrier.