US2022204472A1PendingUtilityA1
Heteroaromatic electrophiles and methods of using thereof
Assignee: OHIO STATE INNOVATION FOUNDATIONPriority: Feb 15, 2017Filed: Mar 10, 2022Published: Jun 30, 2022
Est. expiryFeb 15, 2037(~10.6 yrs left)· nominal 20-yr term from priority
Inventors:Christopher HadadChristopher CallamJeremy BeckQinggeng ZhuangAndrew FranjesevicThomas CorriganCraig Mcelroy
A61P 29/00C07D 213/61A61K 45/06C07D 401/06A61K 31/4427C07D 213/65A61K 31/44A61K 31/4545C07D 215/20A61K 31/445A61K 31/496C07D 317/58C07D 213/64A61K 31/47A61K 31/5377A61K 31/4709C07D 213/38A61K 31/4439C07D 215/227C07D 295/096C07D 413/06A61K 31/55C07D 401/14
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Claims
Abstract
Disclosed herein are compounds, compositions, and methods for reactivating or realkylating aged acetylcholinesterase inhibited by or conjugated to the organophosphorus compound. The organophosphorus compound can be a nerve agent. The acetylcholinesterase can be in the central nerve system (CNS) and/or the peripheral nervous system (PNS) of a subject. Accordingly, methods for ameliorating, diminishing, reversing, treating or preventing the toxic effects of an organophosphorus compound in a subject are provided herein. Methods for prophylactic or therapeutic treatment of exposure to an organophosphorus nerve agent are also provided.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method for ameliorating, diminishing, reversing, treating or preventing the toxic effects of an organophosphorus compound in a subject, the method comprising administering a composition comprising a therapeutically effective amount of a compound having a structure represented by Formula I:
wherein
X 1 -X 5 are independently selected from N, NR′, and CR′,
R′ is, independently for each occurrence, selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, hydroxyl, halogen, amine, alkylamine, alkylammonium, or where two R′ groups combine to form a substituted or unsubstituted fused C 5 -C 7 cyclic moiety;
R 1 and R 2 are independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, or R 1 and R 2 combine to form a 3 to 7 membered aliphatic ring, and wherein R 1 and R 2 are optionally substituted with alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, alkyl halide, halogen, alkoxy, amine, alkylamine, and alkylammonium; and
R 2′ is optionally present and selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, and C 1 -C 6 alkyl amine, or R 1 and R 2′ or R 2 and R 2′ combine to form a 5 to 7 membered aliphatic ring; and
wherein at least one of X 1 -X 5 is N or NR′, and at least one of X 1 -X 5 is C—OH.
2 . The method of claim 1 , wherein the organophosphorus compound is a nerve agent.
3 . The method of claim 1 or 2 , wherein the compound reverses inhibition of acetylcholinesterase by the organophosphorus compound.
4 . The method of any one of claims 1 - 3 , wherein the compound reactivates aged acetylcholinesterase inhibited by or conjugated to the organophosphorus compound.
5 . The method of any one of claims 1 - 4 , wherein the acetylcholinesterase (AChE) is in the central nerve system (CNS).
6 . The method of any one of claims 1 - 5 , wherein the compound is represented by a structure having the Formula II-A to II-G:
wherein
R 3 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, alkylamine;
R 4 is selected from C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, nitrile, amine, alkylamine, and alkylammonium; and
wherein R 2′ , R 3 and R 4 are optionally present.
7 . The method of any one of claims 1 - 6 , wherein R 2′ is present and represents a C 1 -C 4 alkyl group.
8 . The method of any one of claims 1 - 7 , wherein R 2′ is absent.
9 . The method of any one of claims 1 - 8 , wherein the compound is represented by a structure having the Formula II-A-1:
wherein
R 4′ , R 4 ″, R 4′ ″, and R 5 are independently selected from C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, nitrile, amine, alkylamine, and alkylammonium.
10 . The method of claim 9 , wherein the compound is represented by a structure having the Formula II-A-2:
wherein
R 4″ and R 5 are independently selected from C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, nitrile, amine, alkylamine, and alkylammonium.
11 . The method of any one of claims 1 - 10 , wherein the compound is represented by a structure having the Formula:
wherein R is C 1 -C 6 alkyl and X is OH, OR, NH 2 , NHR, OR NR 2 .
12 . The method of any one of claims 1 - 9 , wherein the compound is represented by a structure having the Formula II-H to II-Q:
wherein R 3 , R 4 , and R 4b are optionally present, and
wherein R 4b when present is selected from C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, nitrile, amine, alkylamine, and alkylammonium.
13 . The method of claim 12 , wherein the compound is represented by a structure having the Formula II-H-1
wherein R 3 , R 4′ , R 4b′ , R 4b″ , R 4b″′ and R 4b″″ are optionally present, and
when present, R 4′ , R 4b′ , R 4b″ , R 4b″′ are independently selected from C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, nitrile, amine, alkylamine, and alkylammonium.
14 . The method of claim 12 or 13 , wherein the compound is represented by a structure having the Formula:
15 . The method of any one of claims 1 - 6 , wherein the compound is represented by a structure having the Formula IV:
wherein
X 1 -X 5 are independently selected from N, NR′, C, and CR′, wherein R′ is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, hydroxyl, halogen, amine, alkylamine, and alkylammonium;
R 1 and R 2 combine to form a 3 to 7 membered aliphatic ring, wherein the 3 to 7 membered aliphatic ring is substituted with C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, hydroxyl, halogen, amine, alkylamine, and alkylammonium;
R 2′ is optionally present and selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, and C 1 -C 6 alkyl amine, or R 1 and R 2′ or R 2 and R 2′ combine to form a 5 to 7 membered aliphatic ring;
L is a bond or a linker; and
Z is an acetylcholinesterase inhibitor;
wherein at least one of X 1 -X 5 is N or NR′, and at least one of X 1 -X 5 is C—OH.
16 . The method of claim 15 , wherein the compound is represented by a structure having the Formula IV-A:
17 . The method of claim 15 or 16 , wherein the acetylcholinesterase inhibitor is donepezil.
18 . The method of claim 15 , wherein the compound is represented by a structure having the Formula IV-B:
19 . A method of prophylactic or therapeutic treatment of exposure to an organophosphorus nerve agent comprising administering a composition to a subject requiring such treatment in an amount effective to prophylactically or therapeutically treat exposure to the organophosphorus nerve agent,
wherein the composition comprises a compound having a structure represented by Formula I:
wherein
X 1 -X 5 are independently selected from N, NR′, and CR′,
R′ is, independently for each occurrence, selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, hydroxyl, halogen, amine, alkylamine, alkylammonium, or where two R′ groups combine to form a substituted or unsubstituted fused C 5 -C 7 cyclic moiety;
R 1 and R 2 are independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, or R 1 and R 2 combine to form a 3 to 7 membered aliphatic ring, and wherein R 1 and R 2 are optionally substituted with alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, alkyl halide, halogen, alkoxy, amine, alkylamine, and alkylammonium; and
R 2′ is optionally present and selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, and C 1 -C 6 alkyl amine, or R 1 and R 2′ or R 2 and R 2′ combine to form a 5 to 7 membered aliphatic ring, and
wherein at least one of X 1 -X 5 is N or NR′, and at least one of X 1 -X 5 is C—OH.
20 . A method for ameliorating, diminishing, reversing, treating or preventing the toxic effects of an organophosphorus compound in the central nervous system of a subject, the method comprising administering a composition comprising a therapeutically effective amount of a compound having a structure represented by Formula I:
wherein
X 1 -X 5 are independently selected from N, NR′, and CR′,
R′ is, independently for each occurrence, selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, hydroxyl, halogen, amine, alkylamine, alkylammonium, or where two R′ groups combine to form a substituted or unsubstituted fused C 5 -C 7 cyclic moiety;
R 1 and R 2 are independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, or R 1 and R 2 combine to form a 3 to 7 membered aliphatic ring, and wherein R 1 and R 2 are optionally substituted with alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, alkyl halide, halogen, alkoxy, amine, alkylamine, and alkylammonium; and
R 2′ is optionally present and selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, and C 1 -C 6 alkyl amine, or R 1 and R 2′ or R 2 and R 2′ combine to form a 5 to 7 membered aliphatic ring; and
wherein at least one of X 1 -X 5 is N or NR′, and at least one of X 1 -X 5 is C—OH.
21 . The method of claim 20 , wherein the compound is represented by a structure having the Formula II-A-1 or Formula II-H-1:
wherein R 3 , R 4′ , R 4b′ , R 4b″ , R 4b″′ and R 4b″″ are optionally present, and when present, R 4′ , R 4b′ , R 4b″ , R 4b″′ are independently selected from C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, nitrile, amine, alkylamine, and alkylammonium.
22 . The method of claim 21 , wherein the compound is represented by a structure having the Formula II-A-2:
wherein
R 4″ and R 5 are independently selected from C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, nitrile, amine, alkylamine, and alkylammonium.
23 . The method of any one of claims 20 - 22 , wherein the compound of Formula I is administered in combination with a second compound that reverses inhibition of acetylcholinesterase by the organophosphorus compound.
24 . The method of claim 23 , wherein the second compound does not cross the blood brain barrier.
25 . The method of any one of claims 20 - 24 , wherein the composition is administered enterally or parenterally
26 . A method for reactivating acetylcholinesterase inhibited by or conjugated to an organophosphorus compound comprising contacting the acetylcholinesterase with a composition comprising an effective amount of a compound having a structure represented by Formula I:
wherein
X 1 -X 5 are independently selected from N, NR′, and CR′,
R′ is, independently for each occurrence, selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, hydroxyl, halogen, amine, alkylamine, alkylammonium, or where two R′ groups combine to form a substituted or unsubstituted fused C 5 -C 7 cyclic moiety;
R 1 and R 2 are independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, or R 1 and R 2 combine to form a 3 to 7 membered aliphatic ring, and wherein R 1 and R 2 are optionally substituted with alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, alkyl halide, halogen, alkoxy, amine, alkylamine, and alkylammonium; and
R 2′ is optionally present and selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, and C 1 -C 6 alkyl amine, or R 1 and R 2′ or R 2 and R 2′ combine to form a 5 to 7 membered aliphatic ring; and
wherein at least one of X 1 -X 5 is N or NR′, and at least one of X 1 -X 5 is C—OH.
27 . A method for realkylating aged acetylcholinesterase inhibited by or conjugated to the organophosphorus compound comprising contacting the aged acetylcholinesterase with a composition comprising an effective amount of a compound having a structure represented by Formula I:
wherein
X 1 -X 5 are independently selected from N, NR′, and CR′,
R′ is, independently for each occurrence, selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, hydroxyl, halogen, amine, alkylamine, alkylammonium, or where two R′ groups combine to form a substituted or unsubstituted fused C 5 -C 7 cyclic moiety;
R 1 and R 2 are independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, or R 1 and R 2 combine to form a 3 to 7 membered aliphatic ring, and wherein R 1 and R 2 are optionally substituted with alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, alkyl halide, halogen, alkoxy, amine, alkylamine, and alkylammonium; and
R 2′ is optionally present and selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, and C 1 -C 6 alkyl amine, or R 1 and R 2′ or R 2 and R 2′ combine to form a 5 to 7 membered aliphatic ring; and
wherein at least one of X 1 -X 5 is N or NR′, and at least one of X 1 -X 5 is C—OH.
28 . A compound represented by a structure having the Formula II-A to II-G:
wherein
R 1 and R 2 are independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, or R 1 and R 2 combine to form a 3 to 7 membered aliphatic ring, and wherein R 1 and R 2 are optionally substituted with alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, alkyl halide, halogen, alkoxy, amine, alkylamine, and alkyl ammonium;
R 2′ is optionally present and selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, and C 1 -C 6 alkyl amine, or R 1 and R 2′ or R 2 and R 2′ combine to form a 5 to 7 membered aliphatic ring;
R 3 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, alkylamine; and
R 4 is selected from C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, nitrile, amine, alkylamine, and alkylammonium; and
wherein R 2′ , R 3 and R 4 are optionally present.
29 . The compound of claim 28 , wherein the compound is represented by a structure having the Formula II-A-1:
wherein
R 4′ , R 4″ , R 4″′ , and R 5 are independently selected from C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, nitrile, amine, alkylamine, and alkylammonium.
30 . The compound of claim 29 , wherein the compound is represented by a structure having the Formula II-A-1′:
31 . The compound of any one of claims 28 - 30 , wherein the compound is represented by a structure having the Formula II-A-2:
wherein
R 4″ and R 5 are independently selected from C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, nitrile, amine, alkylamine, and alkylammonium.
32 . A compound represented by a structure having the Formula II-H to II-Q:
wherein
R 1 and R 2 are independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, or R 1 and R 2 combine to form a 3 to 7 membered aliphatic ring, and wherein R 1 and R 2 are optionally substituted with alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, alkyl halide, halogen, alkoxy, amine, alkylamine, and alkylammonium; and
R 3 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, alkylamine;
R 4 and R 4b , are independently for each occurrence, selected from C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, nitrile, amine, alkylamine, and alkylammonium; and
wherein R 3 , R 4 , and R 4b are optionally present.
33 . The compound of claim 32 , wherein the compound is represented by a structure having the Formula II-H-1:
wherein R 3 , R 4′ , R 4b′ , R 4b″ , R 4b″′ and R 4b″″ are optionally present, and
when present, R 4′ , R 4b′ , R 4b″ , R 4b″′ and R 4b″″ are independently selected from C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, nitrile, amine, alkylamine, and alkylammonium.
34 . The compound of claim 32 or 33 , wherein the compound is represented by a structure having the Formula:
35 . A compound represented by a structure having the Formula IV:
wherein
X 1 -X 5 are independently selected from N, NR′, and CR′,
R′ is, independently for each occurrence, selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, hydroxyl, halogen, amine, alkylamine, alkylammonium, or where two R′ groups combine to form a substituted or unsubstituted fused C 5 -C 7 cyclic moiety;
R 1 and R 2 are independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, or R 1 and R 2 combine to form a 3 to 7 membered aliphatic ring, and wherein R 1 and R 2 are optionally substituted with alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, alkyl halide, halogen, alkoxy, amine, alkylamine, and alkylammonium;
R 2′ is optionally present and selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, and C 1 -C 6 alkyl amine, or R 1 and R 2′ or R 2 and R 2′ combine to form a 5 to 7 membered aliphatic ring;
L is a bond or a linker; and
Z is an acetylcholinesterase inhibitor;
wherein at least one of X 1 -X 5 is N or NR′, and at least one of X 1 -X 5 is C—OH.
36 . The compound of claim 35 , wherein the compound is represented by a structure having the Formula IV-A:
37 . The compound of claim 35 or 36 , wherein the acetylcholinesterase inhibitor is donepezil.
38 . The compound of claim 35 , wherein the compound is represented by a structure having the Formula IV-B:
39 . A pharmaceutical composition or formulation comprising a compound represented by a structure having the Formula I and a pharmaceutically acceptable excipient, wherein the compound is present in a therapeutically effective amount to reverse inhibition of acetylcholinesterase by at least one organophosphorus nerve agent:
wherein
X 1 -X 5 are independently selected from N, NR′, and CR′,
R′ is, independently for each occurrence, selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, hydroxyl, halogen, amine, alkylamine, alkylammonium, or where two R′ groups combine to form a substituted or unsubstituted fused C 5 -C 7 cyclic moiety;
R 1 and R 2 are independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, or R 1 and R 2 combine to form a 3 to 7 membered aliphatic ring, and wherein R 1 and R 2 are optionally substituted with alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, alkyl halide, halogen, alkoxy, amine, alkylamine, and alkylammonium; and
R 2′ is optionally present and selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, and C 1 -C 6 alkyl amine, or R 1 and R 2′ or R 2 and R 2′ combine to form a 5 to 7 membered aliphatic ring; and
wherein at least one of X 1 -X 5 is N or NR′, and at least one of X 1 -X 5 is C—OH.
40 . A composition comprising a realkylated phosphyl adduct, the realkylated phosphyl adduct produced from a method comprising contacting aged acetylcholinesterase with a compound of Formula I, and allowing the compound to react with the aged acetylcholinesterase to produce the realkylated phosphyl adduct:
wherein
X 1 -X 5 are independently selected from N, NR′, and CR′,
R′ is, independently for each occurrence, selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, hydroxyl, halogen, amine, alkylamine, alkylammonium, or where two R′ groups combine to form a substituted or unsubstituted fused C 5 -C 7 cyclic moiety;
R 1 and R 2 are independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, or R 1 and R 2 combine to form a 3 to 7 membered aliphatic ring, and wherein R 1 and R 2 are optionally substituted with alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, alkyl halide, halogen, alkoxy, amine, alkylamine, and alkylammonium; and
R 2′ is optionally present and selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, and C 1 -C 6 alkyl amine, or R 1 and R 2′ or R 2 and R 2′ , combine to form a 5 to 7 membered aliphatic ring; and
wherein at least one of X 1 -X 5 is N or NR′, and at least one of X 1 -X 5 is C—OH.
41 . A composition comprising a realkylated phosphyl adduct, the realkylated phosphyl adduct produced from a method comprising contacting a phosphonate anion with a compound of Formula I, and allowing the compound to react with the phosphonate anion to produce the realkylated phosphyl adduct:
wherein
X 1 -X 5 are independently selected from N, NR′, and CR′,
R′ is, independently for each occurrence, selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, hydroxyl, halogen, amine, alkylamine, alkylammonium, or where two R′ groups combine to form a substituted or unsubstituted fused C 5 -C 7 cyclic moiety;
R 1 and R 2 are independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, or R 1 and R 2 combine to form a 3 to 7 membered aliphatic ring, and wherein R 1 and R 2 are optionally substituted with alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, alkyl halide, halogen, alkoxy, amine, alkylamine, and alkylammonium; and
R 2′ is optionally present and selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl halide, C 1 -C 6 alkoxy, and C 1 -C 6 alkyl amine, or R 1 and R 2′ or R 2 and R 2′ combine to form a 5 to 7 membered aliphatic ring; and
wherein at least one of X 1 -X 5 is N or NR′, and at least one of X 1 -X 5 is C—OH.Join the waitlist — get patent alerts
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