4-thio coumarins
View Patent ↗4-Thio substituted coumarin derivatives, 4,5-dithio substituted coumarin derivatives, and coumarin dimers are provided, as well as processes for their preparation. The invention also provides a method and composition for the treatment of hepatitis C virus (HCV) by adiministering 4-thio substituted coumarin derivatives, 4,5-dithio substituted coumarin derivatives, and coumarin dimers.
1. A compound of the formula XI:
wherein
R 1 and R 10 are independently selected from
an unsubstituted or substituted aromatic group, wherein the substituted aromatic group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
a substituted aralkyl group, wherein the substituted aralkyl group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
an unsubstituted or substituted alkyl group, wherein the substituted alkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy; and
an unsubstituted or substituted cycloalkyl group, wherein the substituted cycloalkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy;
R 3 is selected from halogen, hydroxy, amino, lower alkyl, lower alkoxy, lower alkenyl, and lower alkynyl, wherein the lower alkyl, lower alkoxy, lower alkenyl and lower alkynyl may be unsubstituted or may be substituted with one or more of halogen, hydroxy, and lower alkoxy; or R 3 is a group of the formula
Z-(CH 2 ) a —Y b —(CH 2 ) c -Q d -(CH 2 ) e —
wherein Y and Q are independently selected from an aromatic group, O, S, —CR═CR—,
each R is independently selected from H or lower alkyl,
Z is selected from H, —CO 2 R, —OR, —SR, —NR 2 ,
a, C and e are independently selected from values from 0 to 10;
b and d are independently selected from 0 and 1, provided that when a=0 then b=0, and when c=0 then d=0;
or R 3 may occupy two adjacent positions to form a fused aromatic ring; and
n is selected from values between 0 and 4.
2. The compound of claim 1 , having the formula XII
wherein
each R 11 is independently selected from halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
each R 12 is independently selected from halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
R 3 is selected from halogen, hydroxy, amino, lower alkyl, lower alkoxy, lower alkenyl, and lower alkynyl, wherein the lower alkyl, lower alkoxy, lower alkenyl and lower alkynyl may be unsubstituted or may be substituted with one or more of halogen, hydroxy, and lower alkoxy; or R3is a group of the formula
Z-(CH 2 ) a —Y b —(CH 2 ) c -Q d -(CH 2 ) e —
wherein Y and Q are independently selected from an aromatic group, O, S, —CR═CR—,
each R is independently selected from H or lower alkyl,
Z is selected from H, —CO 2 R, —OR, —SR, —NR 2 ,
a, c and e are independently selected from values from 0 to 10;
b and d are independently selected from 0 and 1, provided that when a=0 then b=0, and when c=0 then d=0;
or R 3 may occupy two adjacent positions to form a fused aromatic ring;
n is selected from values between 0 and 4;
p is selected from values between 0 and 5; and
q is selected from values between 0 and 5.
3. The compound of claim 2 , having the formula XII a :
wherein
each R 11 is independently selected from halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
each R 12 is independently selected from halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
p is selected from values between 0 and 5; and
q is selected from values between 0 and 5.
4. The compound of claim 3 , having the formula
5. The compound of claim 3 , having the formula
6. The compound of claim 3 , having the formula
7. The compound of claim 3 , having the formula
8. A method of treating HCV infection comprising administering a therapeutically effective amount of a compound of Formula I
wherein
R 1 is selected from
an unsubstituted or substituted aromatic group, wherein the substituted aromatic group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
a substituted or unsubstituted aralkyl group, wherein the substituted aralkyl group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
an unsubstituted or substituted alkyl group, wherein the substituted alkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy; and
an unsubstituted or substituted cycloalkyl group, wherein the substituted cycloalkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy;
R 3 is selected from halogen, hydroxy, amino, lower alkyl, lower alkoxy, lower alkenyl, and lower alkynyl, wherein the lower alkyl, lower alkoxy, lower alkenyl and lower alkynyl may be unsubstituted or may be substituted with one or more of halogen, hydroxy, and lower alkoxy; or R 3 is a group of the formula
Z-(CH 2 ) a —Y b —(CH 2 ) c -Q d -(CH 2 ) e —
wherein Y and Q are independently selected from an aromatic group, O, S, —CR═CR—,
each R is independently selected from H or lower alkyl,
Z is selected from H, —CO 2 R, —OR, —SR, —NR 2 ,
a, c and e are independently selected from values from 0 to 10;
b and d are independently selected from 0 and 1, provided that when a=0 then b=0, and when c=0 then d=0;
or R 3 may occupy two adjacent positions to form a fused aromatic ring,
n is selected from values between 0 and 4;
R 5 is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aralkyl, aryl, thioalkyl, thioaryl, and thioaralkyl,
each of which may be unsubstituted or substituted with one or more substituents selected from halogen, lower alkyl, and lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide; or R 5 may be a group of the formula
wherein
R 2 is selected from
an unsubstituted or substituted aromatic group, wherein the substituted aromatic group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
a substituted or unsubstituted aralkyl group, wherein the substituted aralkyl group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
an unsubstituted or substituted alkyl group, wherein the substituted alkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy; and
an unsubstituted or substituted cycloalkyl group, wherein the substituted cycloalkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy;
R 4 is selected from halogen, hydroxy, amino, lower alkyl, lower alkoxy, lower alkenyl, and lower alkynyl, wherein the lower alkyl, lower alkoxy, lower alkenyl and lower alkynyl may be unsubstituted or may be substituted with one or more of halogen, hydroxy, and lower alkoxy; or R 4 is a group of the formula
Z-(CH 2 ) a —Y b —(CH 2 ) c -Q d -(CH 2 ) e —
wherein Y and Q are independently selected from an aromatic group, O, S, —CR═CR—,
each R is independently selected from H or lower alkyl,
Z is selected from H, —CO 2 R, —OR, —SR, —NR 2 ,
a, c and e are independently selected from values from 0 to 10;
b and d are independently selected from 0 and 1, provided that when a=0 then b=0, and when c=0 then d=0;
or R 4 may occupy two adjacent positions to form a fused aromatic ring,
and, m is selected from values between 0 and 4,
in a pharmaceutically acceptable carrier.
9. The method of claim 8 , comprising administering a compound of the formula II,
wherein
R 1 and R 2 are independently selected from
an unsubstituted or substituted aromatic group, wherein the substituted aromatic group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
a substituted or unsubstituted aralkyl group, wherein the substituted aralkyl group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
an unsubstituted or substituted alkyl group, wherein the substituted alkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy; and
an unsubstituted or substituted cycloalkyl group, wherein the substituted cycloalkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy; and
each R 3 and R 4 is independently selected from halogen, hydroxy, amino, lower alkyl, lower alkoxy, lower alkenyl, and lower alkynyl, wherein the lower alkyl, lower alkoxy, lower alkenyl and lower alkynyl may be unsubstituted or may be substituted with one or more of halogen, hydroxy, and lower alkoxy; or is a group of the formula
Z-(CH 2 ) a —Y b —(CH 2 ) c -Q d -(CH 2 ) e —
wherein Y and Q are independently selected from an aromatic group, O, S, —CR═CR—,
each R is independently selected from H or lower alkyl,
Z is selected from H, —CO 2 R, —OR, —SR, —NR 2 ,
a, c and e are independently selected from values from 0 to 10;
b and d are independently selected from 0 and 1, provided that when a=0 then b=0, and when c=0 then d=0;
or R 3 or R 4 may occupy two adjacent positions to form a fused aromatic ring, and
n and m are independently selected from values between 0 and 4.
10. The method of claim 8 , comprising administering a compound of the Formula III
wherein R 1 , R 3 and n are as described for the compound of Formula I.
11. The method of claim 10 , wherein
R 1 is selected from an unsubstituted or substituted aromatic group, wherein the substituted aromatic group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide.
12. The method of claim 11 , wherein the unsubstituted or substituted aromatic group is an unsubstituted or substituted phenyl group.
13. The method of claim 12 , comprising administering a compound having the formula
14. The method of claim 12 , comprising administering a compound having the formula
15. A method of treating HCV infection comprising administering a therapeutically effective amount of a compound according to claim 1 .
16. A method of treating HCV infection comprising administering a therapeutically effective amount of a compound according to claim 2 .
17. The method of claim 16 , comprising administering a compound having the formula
18. The method of claim 16 , comprising administering a compound having the formula
19. The method of claim 16 , comprising administering a compound having the formula
20. A pharmaceutical composition for the treatment of HCV infection comprising a therapeutically effective amount of a compound of Formula I
wherein
R 1 is selected from
an unsubstituted or substituted aromatic group, wherein the substituted aromatic group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
a substituted or unsubstituted aralkyl group, wherein the substituted aralkyl group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
an unsubstituted or substituted alkyl group, wherein the substituted alkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy; and
an unsubstituted or substituted cycloalkyl group, wherein the substituted cycloalkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy;
R 3 is selected from halogen, hydroxy, amino, lower alkyl, lower alkoxy, lower alkenyl, and lower alkynyl, wherein the lower alkyl, lower alkoxy, lower alkenyl and lower alkynyl may be unsubstituted or may be substituted with one or more of halogen, hydroxy, and lower alkoxy; or R 3 is a group of the formula
Z-(CH 2 ) a —Y b —(CH 2 ) c -Q d -(CH 2 ) e —
wherein Y and Q are independently selected from an aromatic group, O, S, —CR═CR—,
each R is independently selected from H or lower alkyl,
Z is selected from H, —CO 2 R, —OR, —SR, —NR 2 ,
a, c and e are independently selected from values from 0 to 10;
b and d are independently selected from 0 and 1, provided that when a=0 then b=0, and when c=0 then d=0;
or R 3 may occupy two adjacent positions to form a fused aromatic ring,
n is selected from values between 0 and 4;
R 5 is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aralkyl, aryl, thioalkyl, thioaryl, and thioaralkyl,
each of which may be unsubstituted or substituted with one or more substituents selected from halogen, lower alkyl, and lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide; or R 5 may be a group of the formula
wherein
R 2 is selected from
an unsubstituted or substituted aromatic group, wherein the substituted aromatic group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
a substituted or unsubstituted aralkyl group, wherein the substituted aralkyl group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
an unsubstituted or substituted alkyl group, wherein the substituted alkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy; and
an unsubstituted or substituted cycloalkyl group, wherein the substituted cycloalkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy;
R 4 is selected from halogen, hydroxy, amino, lower alkyl, lower alkoxy, lower alkenyl, and lower alkynyl, wherein the lower alkyl, lower alkoxy, lower alkenyl and lower alkynyl may be unsubstituted or may be substituted with one or more of halogen, hydroxy, and lower alkoxy; or R 4 is a group of the formula
Z-(CH 2 ) a —Y b —(CH 2 ) c -Q d -(CH 2 ) e —
wherein Y and Q are independently selected from an aromatic group, O, S, —CR═CR—,
each R is independently selected from H or lower alkyl,
Z is selected from H, —CO 2 R, —OR, —SR, —NR 2 ,
a, c and e are independently selected from values from 0 to 10;
b and d are independently selected from 0 and 1, provided that when a=0 then b=0, and when c=0 then d=0;
or R 4 may occupy two adjacent positions to form a fused aromatic ring,
and, m is selected from values between 0 and 4,
in a pharmaceutically acceptable carrier.
21. The pharmaceutical composition of claim 20 , comprising a compound of the formula II,
wherein
R 1 and R 2 are independently selected from
an unsubstituted or substituted aromatic group, wherein the substituted aromatic group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
a substituted or unsubstituted aralkyl group, wherein the substituted aralkyl group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide;
an unsubstituted or substituted alkyl group, wherein the substituted alkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy; and
an unsubstituted or substituted cycloalkyl group, wherein the substituted cycloalkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy; and
each R 3 and R 4 is independently selected from halogen, hydroxy, amino, lower alkyl, lower alkoxy, lower alkenyl, and lower alkynyl, wherein the lower alkyl, lower alkoxy, lower alkenyl and lower alkynyl may be unsubstituted or may be substituted with one or more of halogen, hydroxy, and lower alkoxy; or is a group of the formula
Z-(CH 2 ) a —Y b —(CH 2 ) c -Q d -(CH 2 ) e —
wherein Y and Q are independently selected from an aromatic group, O, S, —CR═CR—,
each R is independently selected from H or lower alkyl,
Z is selected from H, —CO 2 R, —OR, —SR, —NR 2 ,
a, c and e are independently selected from values from 0 to 10;
b and d are independently selected from 0 and 1, provided that when a=0 then b=0, and when c=0 then d=0;
or or may occupy two adjacent positions to form a fused aromatic ring, and
n and m are independently selected from values between 0 and 4.
22. The pharmaceutical composition of claim 20 , comprising a compound of the Formula III
wherein R 1 , R 3 and n are as described for the compound of Formula I.
23. The pharmaceutical composition of claim 22 , wherein
R 1 is selected from an unsubstituted or substituted aromatic group, wherein the substituted aromatic group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C 1 –C 8 acyl, lower alkyl ester, amide, and lower alkyl amide.
24. The pharmaceutical composition of claim 23 , wherein the unsubstituted or substituted aromatic group is an unsubstituted or substituted phenyl group.
25. The pharmaceutical composition of claim 23 , comprising a compound having the formula
26. The pharmaceutical composition of claim 23 , comprising a compound having the formula
27. A pharmaceutical composition for the treatment of HCV infection comprising a therapeutically effective amount of a compound according to claim 1 in a pharmaceutically acceptable carrier.
28. A pharmaceutical composition for the treatment of HCV infection comprising a therapeutically effective amount of a compound according to claim 2 in a pharmaceutically acceptable carrier.
29. The pharmaceutical composition of claim 28 , comprising a compound having the formula
30. The pharmaceutical composition of claim 28 , comprising a compound having the formula
31. The pharmaceutical composition of claim 28 , comprising a compound having the formula