Lanthionine-related compounds for the treatment of inflammatory diseases
The present invention provides compositions comprising lanthionine ketimine derivatives and thiomorpholine dicarboxylic acid derivatives, as well as processes for the preparation of such compounds. The invention also concerns the use of lanthionine, lanthionine ketimine (LK), LK derivatives, thiomorpholine dicarboxylic acid (TMDCA), and TMDCA derivatives. It concerns the use of these compounds for the treatment and/or prevention diseases, including diseases affecting the central nervous system. The invention provides for compounds and methods having anti-oxidant, anti-neuroinflammatory and neuroprotective activities. It also provides for compounds having the ability to pass through and/or be transported through cellular membranes, such the blood-brain barrier.
1. A compound having the structure:
wherein R 1 is —OH, —NH 2 , —OCH 3 , —OCH 2 CH 2 CH 3 , —OCH(CH 3 ) 2 , —OCH(CH 2 ) 2 , or heteroatom substituted or unsubstituted versions of C 2 -C 10 -alkenyloxy, C 2 -C 10 -alkynyloxy, C 1 -C 10 -aryloxy, C 2 -C 10 -aralkoxy, C 1 -C 10 -acyloxy, C 1 -C 10 -alkylamino, C 2 -C 10 -alkenylamino, C 2 -C 10 -alkynylamino, C 1 -C 10 -arylamino, C 2 -C 10 -aralkylamino, or C 1 -C 10 -amido;
wherein R 2 is —OH, —NH 2 , or heteroatom substituted or unsubstituted versions of C 2 -C 10 -alkoxy, C 2 -C 10 -alkenyloxy, C 2 -C 10 -alkynyloxy, C 1 -C 10 -aryloxy, C 2 -C 10 -aralkoxy, C 1 -C 10 -acyloxy, C 1 -C 10 -alkylamino, C 2 -C 10 -alkenylamino, C 2 -C 10 -alkynylamino, C 1 -C 10 -arylamino, C 2 -C 10 -aralkylamino, or C 1 -C 10 -amido;
provided that R 1 and R 2 are not both —OH;
is —OCH 3 and R 1 is —OH, then the compound is predominantly one enantiomer, and
pharmaceutically acceptable salts and optical isomers thereof.
2. The compound of claim 1 , wherein R 1 is —OCH 3 , —OCH 2 CH 2 CH 3 , —OCH(CH 3 ) 2 or —OCH(CH 2 ) 2 .
3. The compound of claim 1 , wherein R 2 is a heteroatom substituted or unsubstituted C 2 -C 10 -alkoxy.
4. The compound of claim 1 , wherein R 1 is a heteroatom substituted or unsubstituted C 2 -C 10 -alkenyloxy.
5. The compound of claim 1 , wherein R 2 is a heteroatom substituted or unsubstituted C 2 -C 10 -alkenyloxy.
6. The compound of claim 1 , wherein R 1 is a heteroatom substituted or unsubstituted C 1 -C 10 -aryloxy.
7. The compound of claim 1 , wherein R 2 is a heteroatom substituted or unsubstituted C 1 -C 10 -aryloxy.
8. The compound of claim 1 , wherein R 1 or R 2 is —NH 2.
9. The compound of claim 1 , wherein R 1 is a heteroatom substituted or unsubstituted C 1 -C 10 -alkylamino.
10. The compound of claim 1 , wherein R 2 is a heteroatom substituted or unsubstituted C 1 -C 10 -alkylamino.
11. The compound of claim 1 , wherein R 1 is selected from the group consisting of ascorbyl, dehydroascorbate, glycinyl, and serinyl.
12. The compound of claim 1 , wherein R 2 is selected from the group consisting of ascorbyl, dehydroascorbate, glycinyl, and serinyl.
13. The compound of claim 1 , further defined as:
substantially free from other optical isomers, and pharmaceutically acceptable salts thereof.
14. The compound of claim 1 , further defined as:
substantially free from other optical isomers, and pharmaceutically acceptable salts thereof.
15. The compound of claim 13 , further defined as
substantially free from other optical isomers, and pharmaceutically acceptable salts thereof.
16. The compound of claim 14 , further defined as
substantially free from other optical isomers, and pharmaceutically acceptable salts thereof.
17. The compound of claim 12 , further defined as:
substantially free from other optical isomers, and pharmaceutically acceptable salts thereof.
18. The compound of claim 12 , further defined as:
substantially free from other optical isomers, and pharmaceutically acceptable salts thereof.
19. A compound having the structure:
wherein:
R 1 is —OH, —NH 2 , or heteroatom substituted or unsubstituted versions of C 1 -C 10 -alkoxy, C 2 -C 10 -alkenyloxy, C 2 -C 10 -alkynyloxy, C 1 -C 10 -aryloxy, C 2 -C 10 -aralkoxy, C 1 -C 10 -acyloxy, C 1 -C 10 -alkylamino, C 2 -C 10 -alkenylamino, C 2 -C 10 -alkynylamino, C 1 -C 10 -arylamino, C 2 -C 10 -aralkylamino, or C 1 -C 10 -amido;
R 2 is —OH, or heteroatom substituted or unsubstituted versions of C 2 -C 10 -alkenyloxy, C 1 -C 10 -alkynyloxy, C 1 -C 10 -aryloxy, C 2 -C 10 -aralkoxy, C 1 -C 10 -acyloxy, C 1 -C 10 -alkylamino, C 2 -C 10 -alkenylamino, C 2 -C 10 -alkynylamino, C 1 -C 10 -arylamino, C 2 -C 10 -aralkylamino, or C 1 -C 10 -amido; provided that R 1 and R 2 are not both —OH;
or pharmaceutically acceptable salts, and optical isomers thereof.
20. The compound of claim 19 , wherein R 1 is a heteroatom substituted or unsubstituted C 2 -C 10 -alkoxy.
21. The compound of claim 19 , wherein R 1 is a heteroatom substituted or unsubstituted C 2 -C 10 -alkenyloxy.
22. The compound of claim 19 , wherein R 1 is a heteroatom substituted or unsubstituted C 1 -C 10 -aryloxy.
23. The compound of claim 19 , wherein R 2 is a heteroatom substituted or unsubstituted C 1 -C 10 -aryloxy.
24. The compound of claim 19 , wherein R 1 is —NH 2 .
25. The compound of claim 19 , wherein R 1 or R 2 is a heteroatom substituted or unsubstituted C 1 -C 10 -alkylamino.
26. The compound of claim 19 , wherein R 1 is selected from the group consisting of ascorbyl, dehydroascorbate, glycinyl, and serinyl.
27. The compound of claim 19 , wherein R 2 is selected from the group consisting of ascorbyl, dehydroascorbate, glycinyl, and serinyl.
28. The compound of claim 19 , further defined as:
substantially free from other optical isomers, and pharmaceutically acceptable salts thereof.
29. The compound of claim 19 , further defined as:
substantially free from other optical isomers, and pharmaceutically acceptable salts thereof.
30. The compound of claim 28 , further defined as
substantially free from other optical isomers, and pharmaceutically acceptable salts thereof.
31. The compound of claim 29 , further defined as
substantially free from other optical isomers, and pharmaceutically acceptable salts thereof.
32. A method of treating a disease in a subject, wherein the disease is sepsis, Parkinson's disease, Huntington's disease, multiple sclerosis, macular degeneration, atherosclerosis, rheumatoid arthritis, inflammatory bowel disease (IBD), hypertension, attention deficit disorder, major depression, anxiety disorder, stroke, brain cancer, lung cancer, liver cancer, spleen cancer, kidney cancer, lymph node cancer, small intestinal cancer, pancreatic cancer, colon cancer, stomach cancer, prostate cancer, testicular cancer, ovarian cancer, or esophageal cancer, comprising administering to a subject a pharmacologically effective amount of a compound of claim 1 .
33. The method of claim 32 , wherein the subject is a mammal.
34. The method of claim 32 , wherein the subject is a human.
35. The method of claim 32 , wherein the disease is sepsis.
36. The method of claim 32 , wherein the disease is Parkinson's disease, Huntington's disease, multiple sclerosis, macular degeneration, atherosclerosis, rheumatoid arthritis or inflammatory bowel disease (IBD).
37. The method of claim 32 , wherein said subject had a stroke.
38. The method of claim 32 , wherein the disease is brain cancer, lung cancer, liver cancer, spleen cancer, kidney cancer, lymph node cancer, small intestinal cancer, pancreatic cancer, colon cancer, stomach cancer, prostate cancer, testicular cancer, ovarian cancer, or esophageal cancer.