Compositions and methods for reactivating cholinesterases
The invention relates to compounds, compositions and methods for activating, reactivating, reversing or preventing the deactivation of cholinesterases, such as acetylcholinesterase and butyrylcholinesterase.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein
is a 5- or 6-membered substituted or unsubstituted aromatic ring or a 5- or 6-membered substituted or unsubstituted cycloalkyl;
R 1 is R 5 —C(R 6 )(OH)—R 7 —C(R 8 )(NH 2 )—R 9 ;
R 2 is NH 2 ;
R 3 is NH 2 ; wherein R 3 is ortho to R 1 and R 1 is ortho to R 2 ;
R 4 is selected from the group consisting of H, CN, OR 10 , S(O) 0-2 R 10 , C 1-6 alkyl, C 1-6 alkene, NR 11 R 12 and C(O)NR 13 R 14 ;
R 5 is selected from the group consisting of a bond, C 1-4 alkylene and C 1-4 alkenylene;
R 6 is selected from the group consisting of H and C 1-3 alkyl;
R 7 is selected from the group consisting of a bond, substituted or unsubstituted C 1-3 alkylene and substituted or unsubstituted C 1-3 alkenylene;
R 8 is selected from the group consisting of H, C(O)NHR 15 and C(O)OR 15 ;
R 9 is selected from the group consisting of H, CN, —C(R 6 ) 2 OH, OR 8 , NR 11 R 12 , C(O)NR 11 R 12 , C 1-6 alkyl and C 1-6 alkene;
R 10 is selected from the group consisting of H, C 1-3 alkyl and C 6-12 aryl;
R 11 , R 12 , R 13 , and R 14 are independently selected from the group consisting of H, C 1-4 alkyl and C 1-4 alkene, wherein at least one of R 11 and R 12 is H; and
R 15 is selected from the group consisting of H and C 1-3 alkyl.
2. A compound selected from:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 , wherein the compound is
4. A method of reactivating an inactivated acetylcholinesterase (AChE) or preventing inactivation of an AChE in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I of claim 1 , or a pharmaceutically acceptable salt thereof.
5. A method of reactivating an inactivated acetylcholinesterase (AChE) or preventing inactivation of an AChE in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 2 , or a pharmaceutically acceptable salt thereof.
6. The method of claim 5 , wherein the compound is
7. The method of claim 4 , wherein the method is directed to reactivating an inactivated AChE and the inactivated AChE is an aged AChE.
8. The method of claim 4 , wherein the method is directed to preventing inactivation of an AChE and the subject was exposed to an inactivating agent.
9. The method of claim 8 , wherein the compound of Formula I is co-administered with an oxime.
10. The method of claim 8 , wherein the subject was exposed to sarin, soman or cyclosarin prior to administration of the compound of Formula I.
11. The method of claim 5 , wherein the method is directed to reactivating an inactivated AChE and the inactivated AChE is an aged AChE.
12. The method of claim 5 , wherein the method is directed to preventing inactivation of an AChE and the subject was exposed to an inactivating agent.
13. The method of claim 12 , wherein the compound is co-administered with an oxime.
14. The method of claim 12 , wherein the subject was exposed to sarin, soman or cyclosarin prior to administration of the compound.