Prodrugs of fumarates and their use in treating various diseases
The present invention provides compounds of formula (I), wherein: R 1 is unsubstituted C 1 -C 6 alkyl; L a is substituted or unsubstituted C 1 -C 6 alkyl linker, substituted or unsubstituted C 3 -C 10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; and R 2 and R 3 are each, independently, H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 6 -C 10 aryl; or alternatively, R 2 and R 3 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. The invention also provides pharmaceutical compositions and methods for treating neurological diseases, such as multiple sclerosis.
1. A method of treating a multiple sclerosis or psoriasis comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (Ib):
wherein:
A − is a pharmaceutically acceptable anion;
R 1 is unsubstituted C 1 -C 6 alkyl;
L a is unsubstituted C 1 -C 6 alkyl linker,
R 3 ′ is unsubstituted C 1 -C 6 alkyl; and
R 2 and R 3 are each, independently, H, unsubstituted C 1 -C 6 alkyl, unsubstituted C 2 -C 6 alkenyl, or unsubstituted C 2 -C 6 alkynyl.
2. The method of claim 1 , wherein R 1 is methyl.
3. The method of claim 2 , wherein L a is unsubstituted C 1 -C 3 alkyl.
4. The method of claim 2 , wherein L a is unsubstituted C 2 alkyl.
5. The method of claim 4 , wherein R 2 and R 3 are each, independently, unsubstituted C 1 C 6 alkyl.
6. The method of claim 5 , wherein R 3 ′ is methyl.
7. The method of claim 1 , wherein the compound is:
wherein A − is a pharmaceutically acceptable anion.
8. The method of claim 1 , wherein the multiple sclerosis is further selected from the group consisting of relapsing remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, and progressive relapsing multiple sclerosis.
9. The method of claim 2 , wherein the multiple sclerosis is further selected from the group consisting of relapsing remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, and progressive relapsing multiple sclerosis.
10. The method of claim 3 , wherein the multiple sclerosis is further selected from the group consisting of relapsing remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, and progressive relapsing multiple sclerosis.
11. The method of claim 4 , wherein the multiple sclerosis is further selected from the group consisting of relapsing remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, and progressive relapsing multiple sclerosis.
12. The method of claim 5 , wherein the multiple sclerosis is further selected from the group consisting of relapsing remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, and progressive relapsing multiple sclerosis.
13. The method of claim 6 , wherein the multiple sclerosis is further selected from the group consisting of relapsing remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, and progressive relapsing multiple sclerosis.
14. The method of claim 7 , wherein the multiple sclerosis is further selected from the group consisting of relapsing remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, and progressive relapsing multiple sclerosis.