Compounds for reactivation of acetylcholinesterase and related compositions methods and systems
Described herein are oxime compounds capable of inactivating a nerve agent, blood brain barrier (BBB)-penetration, and/or reactivation of nerve agent-inhibited acetylcholinesterase (AChE) and related methods, systems and compositions for inactivation of one or more nerve agents, therapeutic and/or prophylactic treatment of an individual, and/or decomposition of nerve agent for decontamination.
1. A compound, wherein the compound has Formula (IV)
wherein R1=H, CH3, and
wherein R11, R12, R13, and R21 are independently H, a linear or branched, alkyl, alkenyl, alkynyl, aryl, arylalkyl or alkylaryl group having equal to or less than 18 carbon atoms and optionally containing additional one to six heteroatoms or one to three substituents.
2. A compound having a Formula (IIId)
wherein
X is N or C—R102,
R1=H, CH3, and
R102, R125, R135, and R165 are independently H, a linear or branched, alkyl, alkenyl, alkynyl, aryl, arylalkyl or alkylaryl groups having equal to or less than 18 carbon atoms, optionally containing additional one to six heteroatoms or one to three substituents, and
wherein m5 and n5 are independent 0-5.
3. A compound of Formula (VI),
wherein R1=H, CH3, and
R11=H, a linear or branched, optionally additional one to six heteroatoms or one to three substituents containing, alkyl, alkenyl, alkynyl, aryl, arylalkyl or alkylaryl carbon atom or a heteroatom having equal to or less than 18 carbon atoms,
p1=0 to 5, p2=0 to 5 and p1+p2 is 1 to 5,
Z1 is N or C—R20, wherein R20=H, a linear or branched, optionally one to three substituents containing, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl or heteroalkylaryl, each having 12 or less carbon atoms and 0-6 heteroatoms,
Y1=H, a linear or branched, optionally one to three substituents containing, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl or heteroalkylaryl, each having 12 or less carbon atoms and 0-6 heteroatoms, and
wherein R9 has a Formulas R9a, R9b, R9c, R9d, R9e and R9f,
4. The compound of claim 1 , wherein the compound has a c log P in the range of 2.0 to 4.5.
5. The compound of claim 1 , wherein the compound has a c log P in the range of 0 to 2.
6. The compound of claim 1 , wherein the compound has a pKa between 7 to 9.
7. A method to reactivate a nerve agent inhibited acetylcholinesterase in an individual, the method comprising:
administering to the individual an effective amount of at least one compound of claim 1 for a time and under a condition to allow contact between the at least one compound and a nerve agent inhibited acetylcholinesterase in the individual thus resulting in a reactivated acetylcholinesterase.
8. A method of treating and/or preventing a condition of an individual, the condition associated with exposure of the individual to a nerve agent, the method comprising:
administering to the individual a therapeutically effective amount of at least one compound of claim 1 for a time and under a condition to allow contact between the at least one compound and a nervous system of the individual.
9. A method of preventing a condition of an individual, the condition associated with exposure of the individual to a nerve agent, the method comprising:
administering to the individual a therapeutically effective amount of at least one compound of claim 1 capable of inactivating one or more nerve agent, the administering performed for a time and under a condition to allow contact between the at least one compound and a nervous system and/or vascular system of the individual.
10. A method for decontaminating an environment contaminated with at least one nerve agent, the method comprising:
contacting the environment with at least one compound of claim 1 to allow contact of the at least one compound with the at least one nerve agent and inactivation of the at least one nerve agent by the at least one compound.
11. The method of claim 7 , wherein the nerve agent comprises the compound of Formula (VIII),
wherein Z is O or S,
J is hydrogen, a C1-C6 alkyl group, a methyl, ethyl, n-propyl, isopropyl, or an amino group NR71R72, wherein R71 and R72 are independently a C1 to C4 alkyl or heteroalkyl group,
K is selected from F, Cl, Br, I, CN and SCH2CH2N[CH(CH3)2]2, and
L is a C1 to C8 linear or branched alkoxy, a O-cyclohexyl, or a 3,3-dimethylbutan-2-yl group.
12. The method of claim 7 , wherein the nerve agent comprises a compound of Formula (X),
wherein L2 is a C1 to C8 linear or branched alkoxy group.
13. The method of claim 7 , wherein the nerve agent comprises a compound of Formula (XI),
wherein
J3 is a N(CH3)2, N(CH3)(C2H5) or N(CH2CH3)2 group,
K3 is a thiolate group SR75, wherein R75 is a alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl or heteroalkylaryl, each having 12 or less carbon atoms and 0-3 heteroatoms, and
L3 is selected from the group consisting of O—CH3, O—CH2CH3, O—CH2CH2CH3, O—CH(CH3)2, O-cyclohexyl, and 3,3-dimethylbutan-2-yl group.
14. A pharmaceutical composition to treat a condition associated with exposure of an individual to a nerve agent, the composition comprising at least one compound of claim 1 in a therapeutically effective amount and a pharmaceutically acceptable vehicle.
15. A composition for decomposing a nerve agent, the composition comprising at least one compound of claim 1 in an acceptable vehicle.
16. The composition of claim 15 , further comprising at least one metal ion selected from the group consisting of Cu 2+ , Pt 2+ , Pd 2+ , Zn 2+ , Y 3+ , Sc 3+ , Ce 3+ , La 3+ , Pr 3+ , Nd 3+ , Sm 3+ , Eu 3+ , Gd 3+ , Tb 3+ , Dy 3+ , Ho 3+ , Er 3+ , Tm 3+ , and Yb 3+ , or combinations thereof.
17. The compound of claim 1 , wherein at least 20% of the compound is in the un-protonated form at pH 7.4.
18. The compound of claim 2 , wherein at least 20% of the compound is in the un-protonated form at pH 7.4.
19. The compound of claim 2 , wherein the compound has a c log P in the range of 2.0 to 4.5.
20. The compound of claim 2 , wherein the compound has a c log P in the range of 0 to 2.
21. The compound of claim 2 , wherein the compound has a pKa between 7 to 9.
22. A pharmaceutical composition to treat a condition associated with exposure of an individual to a nerve agent, the composition comprising at least one compound of claim 2 in a therapeutically effective amount and a pharmaceutically acceptable vehicle.
23. A composition for decomposing a nerve agent, the composition comprising at least one compound of claim 2 in an acceptable vehicle.
24. The composition of claim 23 , further comprising at least one metal ion selected from the group consisting of Cu 2+ , Pt 2+ , Pd 2+ , Zn 2+ , Y 3+ , Sc 3+ , Ce 3+ , La 3+ , Pr 3+ , Nd 3+ , Sm 3+ , Eu 3+ , Gd 3+ , Tb 3+ , Dy 3+ , Ho 3+ , Er 3+ , Tm 3+ , and Yb 3+ , or combinations thereof.
25. The compound of claim 3 , wherein at least 20% of the compound is in the un-protonated form at pH 7.4.
26. The compound of claim 3 , wherein the compound has a c log P in the range of 2.0 to 4.5.
27. The compound of claim 3 , wherein the compound has a c log P in the range of 0 to 2.
28. The compound of claim 3 , wherein the compound has a pKa between 7 to 9.
29. A pharmaceutical composition to treat a condition associated with exposure of an individual to a nerve agent, the composition comprising at least one compound of claim 3 in a therapeutically effective amount and a pharmaceutically acceptable vehicle.
30. A composition for decomposing a nerve agent, the composition comprising at least one compound of claim 3 in an acceptable vehicle.