Thienyl- and furanyl-isoquinolinones and methods for using them

1. A method of treating tissue damage due to ischemia and reperfusion, of inhibiting neuronal cell death due to ischemia and reperfusion, or both, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula I:

wherein:

X is C 1 -C 9 alkylene, C 2 -C 9 alkenylene, or C 2 -C 9 alkynylene;

Y is S or O;

R 1 is halogen, hydroxy, NH 2 , C 1 -C 6 alkoxy, CN, or C 1 -C 6 perfluoroalkyl;

R 2 , R 3 , and R 4 are each, independently, selected from hydrogen, C 1 -C 6 alkyl, halogen, hydroxy, NH 2 , CN, C 1 -C 6 perfluoroalkyl, CO 2 H, OR 8 , COOR 8 , and NHR 8 ;

R 5 and R 6 are each, independently, selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 3 -C 7 cycloalkyl, phenyl, and benzyl, wherein the alkyl, alkenyl and rings of the cycloalkyl, phenyl and benzyl groups are optionally substituted with one or more groups independently selected from hydroxy, C 1 -C 4 alkoxy, —CO 2 H, C 1 -C 6 alkoxycarbonyl, NH 2 , C 1 -C 6 mono- or dialkylamino, and halogen; or

R 5 and R 6 together with the nitrogen to which they are attached form a saturated, partially unsaturated, or unsaturated 3 to 12 membered monocyclic or bicyclic heterocyclic ring optionally comprising from one to three additional ring heteroatoms independently selected from N, O, and S, the remaining ring atoms are carbon atoms;

R 7 is hydrogen, halogen, hydroxy, NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy or NO 2 ;

R 8 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 3 -C 7 cycloalkyl wherein the alkyl, alkenyl, and rings of the cycloalkyl are optionally substituted with one or more groups independently selected from hydroxy, C 1 -C 4 alkoxy, —CO 2 H, C 1 -C 6 alkoxycarbonyl, NH 2 , C 1 -C 6 mono- or dialkylamino, and halogen;

or a pharmaceutically acceptable salt or zwitterionic form thereof.

2. The method according to claim 1 , wherein

X is C 1 -C 9 alkylene, C 2 -C 9 alkenylene, or C 2 -C 9 alkynylene;

Y is S or O;

R 1 is halogen, hydroxy, NH 2 , C 1 -C 6 alkoxy, CN, or C 1 -C 6 perfluoroalkyl;

R 2 , R 3 , and R 4 are each, independently, selected from hydrogen, halogen, hydroxy, NH 2 , C 1 -C 6 alkoxy, CN, and C 1 -C 6 perfluoroalkyl;

R 5 and R 6 are each, independently, selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 3 -C 7 cycloalkyl, phenyl, and benzyl; or

R 5 and R 6 together with the nitrogen to which they are attached form a saturated, partially unsaturated, or unsaturated 3 to 12 membered monocyclic or bicyclic heterocyclic ring optionally comprising from one to three additional ring heteroatoms selected from N, O, and S, the remaining ring atoms are carbon atoms; and

R 7 is hydrogen, halogen, hydroxy, NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy or NO 2 ; or a pharmaceutically acceptable salt or zwitterionic form thereof.

3. The method according to claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt or zwitterionic form thereof.

4. The method according to claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt or zwitterionic form thereof.

5. The method according to claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt or zwitterionic form thereof.

6. The method according to claim 5 , wherein R 3 is halogen or hydrogen.

7. The method according to claim 6 , wherein R 3 is hydrogen.

8. The method according to claim 1 , wherein Y is S.

9. The method according to claim 1 , wherein Y is O.

10. The method according to claim 1 , wherein R 5 and R 6 are each, independently, C 1 -C 6 alkyl.

11. The method according to claim 1 , wherein R 5 and R 6 together with the nitrogen to which they are attached form a saturated monocyclic heterocyclic ring optionally comprising from one to three additional ring heteroatoms selected from N, O, and S, the remaining ring atoms are carbon atoms.

12. The method according to claim 11 , wherein R 5 and R 6 are taken together to form piperidine, morpholine, pyrrolidine, homopiperidine, aziridine, or azetidine.

13. The method according to claim 1 , wherein X is C 1 -C 3 alkylene.

14. The method according to claim 1 , wherein X is C 1 -C 3 alkylene and R 5 and R 6 are each, independently, C 1 -C 6 alkyl.

15. The method according to claim 1 , wherein X is methyl.

16. The method according to claim 1 , wherein X is methyl and R 5 and R 6 are each, independently, methyl.

17. The method according to claim 1 , wherein:

Y is S;

X is C 1 -C 3 alkylene; and

R 5 and R 6 are each, independently, C 1 -C 6 alkyl.

18. The method according to claim 17 , wherein X is methyl.

19. The method according to claim 1 , wherein:

Y is O;

X is C 1 -C 3 alkylene; and

R 5 and R 6 are each, independently, C 1 -C 6 alkyl.

20. The method according to claim 19 , wherein X is methyl.

21. The method according to claim 1 , wherein the compound is:

2-dimethylaminomethyl-9-methoxythieno[2,3-c]isoquinolin-5(4H)-one;

8-chloro-2-[(dimethylamino)methyl]thieno[2,3-c]isoquinolin-5(4H)-one; or

2-[(dimethylamino)methyl]-8-methoxythieno[2,3-c]isoquinolin-(4H)-one; or

a pharmaceutically salt or zwitterionic form thereof.

22. The method according to claim 1 , wherein the compound is:

2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one or a pharmaceutically acceptable salt or zwitterionic form thereof.

23. The method according to claim 1 , wherein the compound is:

amorphous 2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one or a pharmaceutically acceptable salt or zwitterionic form thereof.

24. The method according to claim 1 , wherein the compound is:

2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one hydrate.

25. The method according to claim 1 , wherein the compound is: 2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one monohydrate.

26. The method according to claim 1 , wherein the compound is:

2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one monohydrate having an endotherm at about 139° C.

27. The method according to claim 1 , wherein the compound is:

2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one anhydrate.

28. The method according to claim 1 , wherein the compound is:

2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5 (4H)-one anhydrate having endotherms at about 210° C. and 270° C.

29. The method according to claim 1 , wherein the compound comprises a crystalline anhydrous form of 2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one thereof having an X-ray powder diffraction containing at least 3 characteristic 20 values measured using CuKα radiation selected from 10.4, 10.6, 14.5, 21.3, 26.8 and 32.1.

30. The method according to claim 1 , wherein the compound comprises a crystalline monohydrate form of 2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one thereof having an X-ray powder diffraction containing at least 3 characteristic 20 values measured using CuKα radiation selected from 8.3, 8.6, 11.7, 18.4, 18.9, 19.4, 25.7 and 28.7.

31. The method according to claim 1 , wherein the compound is:

2-[(dimethylamino)methyl]-7-fluoro-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one; or

a pharmaceutically acceptable salt or zwitterionic form thereof.

32. The method according to claim 1 , wherein the compound is:

2-[(dimethylamino)methyl]-7-fluorothieno[2,3-c]isoquinolin-5(4H)-one;

2-[(dimethylamino)methyl]-9-fluorothieno[2,3-c]isoquinolin-5(4H)-one;

or 2-[(dimethylamino)methyl]furo[2,3-c]isoquinolin-5(4H)-one hydrochloride; or

a pharmaceutically acceptable salt or zwitterionic form thereof.

33. The method according to claim 1 , wherein the compound is:

9-hydroxy-2-(morpholin-4-ylmethyl)thieno[2,3-c]isoquinolin-5(4H)-one;

9-hydroxy-2-(piperidin-1-ylmethyl)thieno[2,3-c]isoquinolin-5 (4H)-one;

9-hydroxy-2-(1,3-thiazolidin-3-ylmethyl)thieno[2,3-c]isoquinolin-5(4H)-one;

9-hydroxy-2-{[(1-methylethyl)amino]methyl}thieno[2,3-c]isoquinolin-5(4H)-one;

9-hydroxy-2-(pyrrolidin-1-ylmethyl)thieno[2,3-c]isoquinolin-5(4H)-one;

2-[(4-bromopiperidin-1-yl)methyl]-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one;

2-[(dibenzylamino)methyl]-9-hydroxythieno[2,3-c]isoquinolin-5 (4H)-one;

2-{[benzyl(methyl)amino]methyl}-9-hydroxythieno[2,3-c]isoquinolin-5 (4H)-one;

or a pharmaceutically acceptable salt or zwitterionic form thereof.

34. The method according to claim 1 , wherein the compound comprises a zwitterion of 2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one.

35. The method according to claim 1 , wherein the compound comprises a crystalline anhydrous form of 2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one with an average particle size of about 5 to 10 μm and more particularly about 7 μm.

36. The method according to claim 1 , wherein the compound comprises a crystalline anhydrous form of 2-dimethylaminomethyl-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one characterized by orthorhombic agglomerations with an average length of about 5 to 10 μm and more particularly about 6 p.m.

37. The method according to claim 1 , wherein the compound is:

2-[(dimethylamino)methyl]thieno[2,3-c]isoquinolin-5(4H)-one or a pharmaceutically acceptable salt or zwitterionic form thereof.