Compositions and methods for treating colitis

1. A method for treating a subject for an inflammatory epithelial disease, comprising administering to a subject an effective amount of one or more compounds having the formula:

wherein L is chosen from CH 2 or SO 2 ;

R represents from 0 to 5 substitutions for hydrogen;

the index n is an integer from 0 to 5;

R 1 and R 2 are each independently chosen from:

i) hydrogen;

ii) substituted or unsubstituted C 1 -C 10 linear, branched, or cyclic alkyl;

iii) substituted or unsubstituted C 2 -C 10 linear, branched, or cyclic alkenyl;

iv) substituted or unsubstituted C 2 -C 10 linear or branched alkynyl;

v) substituted or unsubstituted C 6 or C 10 aryl;

vi) substituted or unsubstituted C 1 -C 9 heterocyclic;

vii) substituted or unsubstituted C 1 -C 9 heteroaryl; or

viii) R 1 and R 2 can be taken together to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring having from form 2 to 20 carbon atoms and from 1 to 7 heteroatoms; or

a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein the one or more compounds are in the form of a pharmaceutically acceptable salt chosen from hydrochloride salt, hydrogen sulfate salt, sulfate salt, p-toluenesulfonyl salt, methansulfonyl salt and mixtures thereof.

3. The method according to claim 1 , wherein the inflammatory epithelial disease is a disease affecting intestinal epithelial tissue.

4. The method according to claim 3 , wherein the disease is Crohn's disease.

5. The method according to claim 3 , wherein the disease is ulcerative colitis.

6. The method according to claim 3 , wherein the disease is collagenous colitis.

7. The method according to claim 3 , wherein the disease is lymphocytic colitis.

8. The method according to claim 3 , wherein the disease is ischemic colitis.

9. The method according to claim 3 , wherein the disease is diversion colitis.

10. The method according to claim 3 , wherein the disease is Behçet's syndrome.

11. The method according to claim 3 , wherein the disease is indeterminate colitis.

12. The method according to claim 1 , wherein the inflammatory epithelial disease is chosen from a disease affecting the respiratory tract, mucosa, skin, GI tract, lining of major organs and endocrine glands, vascular tissue, and combinations thereof.

13. The method according to claim 1 , wherein L is CH 2 .

14. The method according to claim 1 , wherein L is SO 2 .

15. The method according to claim 1 , wherein each R is a substitution for hydrogen independently chosen from:

i) substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl;

ii) substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkenyl;

iii) substituted or unsubstituted C 2 -C 12 linear or C 3 -C 12 branched alkynyl;

iv) C 6 or C 10 substituted or unsubstituted aryl;

v) C 1 -C 9 substituted or unsubstituted heterocyclic;

vi) C 1 -C 11 substituted or unsubstituted heteroaryl;

vii) halogen;

viii) —[C(R 23a )(R 23b )] x OR 10 ;

R 10 is chosen from:

a) —H;

b) substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl;

c) C 6 or C 10 substituted or unsubstituted aryl or alkylenearyl;

d) C 1 -C 9 substituted or unsubstituted heterocyclic;

e) C 1 -C 11 substituted or unsubstituted heteroaryl;

ix) —[C(R 23a )(R 23b )] x N(R 11a )(R 11b );

R 11a and R 11b are each independently chosen from:

a) —H;

b) —OR 12 ;

R 12 is hydrogen or C 1 -C 4 linear alkyl;

c) substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl;

d) C 6 or C 10 substituted or unsubstituted aryl;

e) C 1 -C 9 substituted or unsubstituted heterocyclic;

f) C 1 -C 11 substituted or unsubstituted heteroaryl; or

g) R 11a and R 11b can be taken together to form a substituted or unsubstituted ring having from 3 to 10 carbon atoms and from 0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;

x) —[C(R 23a )(R 23b )] x C(O)R 13 ;

R 13 is:

a) substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl;

b) —OR 14 ;

R 14 is hydrogen, substituted or unsubstituted C 1 -C 4 linear alkyl, C 6 or C 10 substituted or unsubstituted aryl, C 1 -C 9 substituted or unsubstituted heterocyclic, C 1 -C 11 substituted or unsubstituted heteroaryl;

c) —N(R 15a )(R 15b );

R 15a and R 15b are each independently hydrogen, substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl; C 6 or C 10 substituted or unsubstituted aryl; C 1 -C 9 substituted or unsubstituted heterocyclic; C 1 -C 11 substituted or unsubstituted heteroaryl; or R 15a and R 15b can be taken together to form a substituted or unsubstituted ring having from 3 to 10 carbon atoms and from 0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;

xi) —[C(R 23a )(R 23b )] x OC(O)R 16 ;

R 16 is:

a) substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl;

b) —N(R 17a )(R 17b )

R 17a and R 17b are each independently hydrogen, substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl; C 6 or C 10 substituted or unsubstituted aryl; C 1 -C 9 substituted or unsubstituted heterocyclic; C 1 -C 11 substituted or unsubstituted heteroaryl; or R 17a and R 17b can be taken together to form a substituted or unsubstituted ring having from 3 to 10 carbon atoms and from 0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;

xii) —[C(R 23a )(R 23b )] x NR 18 C(O)R 19 ;

R 18 is:

a) —H; or

b) substituted or unsubstituted C 1 -C 4 linear, C 3 -C 4 branched, or C 3 -C 4 cyclic alkyl;

R 19 is:

a) substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl;

b) —N(R 20a )(R 20b );

R 20a and R 20b are each independently hydrogen, substituted or unsubstituted C 1 -C 4 linear or C 2 -C 4 branched alkyl; C 6 or C 10 substituted or unsubstituted aryl; C 1 -C 9 substituted or unsubstituted heterocyclic; C 1 -C 11 substituted or unsubstituted heteroaryl; or R 20a and R 20b can be taken together to form a substituted or unsubstituted ring having from 3 to 10 carbon atoms and from 0 to 3 heteroatoms chosen from oxygen, nitrogen, and sulfur;

xiii) —[C(R 23a )(R 23b )] x CN;

xiv) —[C(R 23a )(R 23b )] x NO 2 ;

xv) —[C(R 23a )(R 23b )] x R 21 ;

R 21 is C 1 -C 10 linear, branched, or cyclic alkyl substituted by from 1 to 21 halogen atoms chosen from —F, —Cl, —Br, or —I;

xvi) —[C(R 23a )(R 23b )] x SO 2 R 22 ;

R 22 is hydrogen, hydroxyl, substituted or unsubstituted C 1 -C 4 linear or C 2 -C 4 branched alkyl; substituted or unsubstituted C 6 , C 10 , or C 14 aryl; C 7 -C 15 alkylenearyl; C 1 -C 9 substituted or unsubstituted heterocyclic; or C 1 -C 11 substituted or unsubstituted heteroaryl;

R 23a and R 23b are each independently hydrogen or C 1 -C 4 alkyl; and

the index x is an integer from 0 to 5.

16. The method according to claim 1 , wherein R 1 and R 2 are taken together to form a 5-member substituted or unsubstituted C 1 -C 4 heterocyclic or a substituted or unsubstituted C 1 -C 4 heteroaryl ring.

17. The method according to claim 16 , wherein R 1 and R 2 are taken together to form a ring having the formula:

18. The method according to claim 1 , wherein R 1 and R 2 are taken together to form a substituted or unsubstituted C 4 -C 11 heterocyclic or a substituted or unsubstituted C 4 -C 11 heteroaryl ring.

19. The method according to claim 18 , wherein R 1 and R 2 are taken together to form a ring having the formula:

20. The method according to claim 1 , wherein R 1 and R 2 are taken together to form a ring chosen from pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 2-(pyrdin-2-yl)pyrrolidin-1-yl, 2-methylcarboxypyrrolidin-1-yl, 2-(methoxymethyl)pyrrolidin-1-yl, thiazolidin-3-yl, 1H-imidazol-1-yl, piperidin-1-yl, 4-benzylpiperidin-1-yl, 1,4′-bipiperidinyl-1′-yl, piperazin-1-yl, 4-benzylpiperazin-1-yl, 4-(2-methoxyphenyl)-piperazin-1-ylmethyl, 4-(6-chloropyridazin-3-yl)piperazin-1-yl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, morpholin-4-yl, thiomorpholin-4-yl, azepan-1-yl, azocan-1-yl, and 3,4-dihydroquinolin-1(2H)-yl.

21. The method according to claim 1 , wherein R 2 is hydrogen and R 1 is chosen from benzyl, 4-methoxybenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-methylbenzyl, 2-(pyridin-2-yl)ethyl, [1,3]dioxolan-2-ylmethyl, tetrahydrofuran-2-ylmethyl, 2-methoxyethyl, 1-hydroxy-2-methylpropan-2-yl, pyridin-4-ylmethyl, furan-2-ylmethyl, 2-(methylthio)ethyl, 1-phenylethyl, 3-imidazol-1-ylpropyl, cycloheptyl, 4-methylcyclohexyl, 1-benzylpiperidin-4-yl, azepan-2-on-3-yl, and 1-benzyl-pyrrolidin-3-yl.

22. The method according to claim 1 , wherein the one or more compounds have the formula:

wherein Z is phenyl substituted with from 1 to 5 halogens chosen from fluorine and chlorine;

R 4 is C 1 -C 4 linear alkyl or C 3 -C 4 branched alkyl; or

a pharmaceutically acceptable salt thereof.

23. The method according to claim 22 , wherein R 4 is methyl.

24. The method according to claim 22 , wherein R 4 is ethyl.

25. The method according to claim 22 , wherein R 4 is tert-butyl.

26. The method according to claim 22 , wherein Z is 4-chlorophenyl.

27. The method according to claim 22 , wherein Z is chosen from 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl.

28. The method according to claim 22 , wherein Z is chosen from 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, and 2,6-dichlorophenyl.

29. The method according to claim 1 , wherein the one or more compounds is tert-butyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate or a pharmaceutically acceptable salt chosen from hydrochloride salt, hydrogen sulfate salt, sulfate salt, p-toluenesulfonyl salt, methansulfonyl salt and mixtures thereof.

30. The method according to claim 1 , wherein the one or more compounds is chosen from:

Methyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;

tert-Butyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;

tert-Butyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;

Methyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;

Ethyl 4-{([1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;

Ethyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;

tert-Butyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate;

tert-Butyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; and

tert-Butyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate.

31. A composition for treating a subject for an inflammatory epithelial disease, comprising

a) an effective amount of one or more compounds having the formula:

wherein L is chosen from CH 2 or SO 2 ;

R represents from 0 to 5 substitutions for hydrogen;

the index n is an integer from 0 to 5;

R 1 and R 2 are each independently chosen from:

i) hydrogen;

ii) substituted or unsubstituted C 1 -C 10 linear, branched, or cyclic alkyl;

iii) substituted or unsubstituted C 2 -C 10 linear, branched, or cyclic alkenyl;

iv) substituted or unsubstituted C 2 -C 10 linear or branched alkynyl;

v) substituted or unsubstituted C 6 or C 10 aryl;

vi) substituted or unsubstituted C 1 -C 9 heterocyclic;

vii) substituted or unsubstituted C 1 -C 9 heteroaryl; or

i) R 1 and R 2 can be taken together to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring having from form 2 to 20 carbon atoms and from 1 to 7 heteroatoms;

R 4 is C 1 -C 4 linear or C 3 -C 4 branched alkyl; or

a pharmaceutically acceptable salt thereof; and

b) one or more excipients.

32. The composition according to claim 31 , wherein the one or more compounds are in the form of a pharmaceutically acceptable salt chosen from hydrochloride salt, hydrogen sulfate salt, sulfate salt, p-toluenesulfonyl salt, methansulfonyl salt and mixtures thereof.

33. The composition according to claim 31 , wherein the one or more compounds have the formula:

wherein Z is phenyl substituted with from 1 to 5 halogens chosen from fluorine and chlorine;

R 4 is C 1 -C 4 linear alkyl or C 3 -C 4 branched alkyl; or

a pharmaceutically acceptable salt thereof.

34. The composition according to claim 33 , wherein R 4 is methyl.

35. The composition according to claim 33 , wherein R 4 is ethyl.

36. The composition according to claim 33 , wherein R 4 is tert-butyl.

37. The composition according to claim 33 , wherein Z is 4-chlorophenyl.

38. The composition according to claim 33 , wherein Z is chosen from 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl.

39. The composition according to claim 31 , wherein the one or more compounds is tert-butyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}-piperazine-1-carboxylate or a pharmaceutically acceptable salt hydrochloride salt, hydrogen sulfate salt, sulfate salt, p-toluenesulfonyl salt, methansulfonyl salt and mixtures thereof.

40. The composition according to claim 31 , further comprising one or more chemotherapeutic compounds.

41. The composition according to claim 40 , wherein the one or more chemotherapeutic compounds are chosen from 6-hydroxymethylacylfulvene, cyclophosphamide, dacarbazine, carmustine, doxorubicin, and methotrexate.

42. The composition according to claim 31 , wherein the inflammatory epithelial disease is chosen from Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behçet's syndrome, and indeterminate colitis.