# US 8,772,345 B2 · Oximes for treatment of peripheral and central nervous system exposure to acetyl cholinesterase inhibitors

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- Number: US 8,772,345 B2
- Document ID: US8772345B2
- Status: Granted
- Kind: B2
- Application number: 13/197,550
- Filed: 2011-08-03
- Published: 2013-02-07
- Granted: 2014-07-08
- Earliest claimed: 2011-08-03
- Assignees: Southwest Research Institute
- Applicants: Stanton F. McHardy; Richard M. Corbett; Donald M. Maxwell; Michael W. Tidwell; Bismarck Campos; Christopher J. Bemben
- Inventors: Stanton F. McHardy; Richard M. Corbett; Donald M. Maxwell; Michael W. Tidwell; Bismarck Campos; Christopher J. Bemben
- Web page: https://patentgrep.com/patent/US8772345B2

## CPC

- C07D 251/38: Sulfur atoms
- A61K 31/15: Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) {; Imines (C—N=C)}
- A61K 31/16: Amides, e.g. hydroxamic acids
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K 31/4453: only substituted in position 1, e.g. propipocaine, diperodon
- A61K 31/4468: having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/473: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07C 251/38: to carbon atoms of a saturated carbon skeleton
- C07D 211/26: with hydrocarbon radicals, substituted by nitrogen atoms
- C07D 211/34: with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 211/58: attached in position 4
- C07D 213/64: attached in position 2 or 6
- C07D 219/12: Amino-alkylamino radicals attached in position 9
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention relates to non-charged oxime compounds which are acetyl cholinesterase (AChE) reactivators of inhibited AChE and which protect against organophosphate poisoning both peripherally and in the central nervous system. Also disclosed are pharmaceutical compositions and methods for preparing the reactivator compounds and associated intermediates.

## Claims

### Claim 1

A pharmaceutical composition comprising:
(a) an acetyl cholinesterase reactivator compound of a formula:
or a pharmaceutically acceptable salt thereof, in an amount ranging from 1.0 mg to 2,000 mg,
wherein V is independently a hydrogen, an alkyl (C1 to C5) group, or a benzyl or substituted benzyl group;
Z is independently an optionally substituted methylene or methine group from 1 to 8 carbon atoms in length, and wherein in the case of optionally substituted methylene or methine, Z can also be connected to R1 to form a heterocyclic or bicyclic heteratom ring from 3 to 10 atoms;
R1 can independently be H or optionally substituted alkyl (C1 to C7), or can be connected to Z to form a heterocyclic or bicyclic heteratom ring from 3 to 10 atoms;
R2 is independently H or optionally substituted alkyl (C1 to C7), benzyl or optionally substituted benzyl, phenyl, optionally substituted phenyl, heterocyclic, heteroaryl and optionally substituted heterocyclic or optionally substituted heteroaryl; and
X is independently H, cyano (CN) or COR, wherein said R group is alkyl (C1 to C3); and
(b) a pharmaceutically acceptable buffered aqueous carrier solution,
wherein the pH of the pharmaceutical composition is greater than 8 and wherein the pharmaceutical composition is sterile.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the acetyl cholinesterase reactivator compound is present as the E or Z isomer with respect to the oxime moiety.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein said pharmaceutically acceptable salt is selected from the group consisting of acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, citrate, formate, fumarate, gluconate, glucuronate, hexafluorophosphate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, lactate, malate, maleate, malonate, mandelates, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate, di hydrogen phosphate, pyroglutamate, salicylate, saccharate, stearate, succinate, sulfonate, stannate, tartrate, tosylate, and trifluoroacetate.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, wherein said pharmaceutically acceptable salt is selected from the group consisting of aluminum, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, and zinc.

### Claim 5 (depends on 1)

The pharmaceutical composition of claim 1, wherein said acetyl cholinesterase reactivator compound is isotopically labeled.

### Claim 6 (depends on 5)

The acetyl cholinesterase reactivator compound of claim 5 wherein said isotopic labeling comprises labeling with one or more of the following: 2H, 3H, 11C, 13C, 14C, 36Cl, 18F, 123I , 125I, 13N, 15N, 15O, 17O, 18O, 32P, and 35S.

### Claim 7 (depends on 1)

A method for reactivating acetyl cholinesterase in a mammal comprising administering to said mammal an effective amount of a pharmaceutical composition according to claim 1.