The Scripps Research Institute

University of California

The Hong Kong University of Science and Technology

Valery Fokin

K Barry Sharpless

Luke Green

Fahmi Himo

Palmer Taylor

Vsevold A Rostovtsev

Jiajia Dong

Zoran Radic

Larisa Krasnova

Luke R Kwisnek

Vsevold V Rostovtsev

James S Oakdale

M G Finn

Rakesh Sit

Jonathan Clive Tripp

Guocheng Jia

Malin Andersson

Robert Epple

Guochen Jia

Gisela-Andrea Camacho-Hernandez

Jason E Hein

Larissa Krasnova

Vsevolod Rostovsev

Barry K Sharpless

In alternative embodiments, the invention provides nucleophilic hydroxyimino-acetamido alkylamine antidotes that cross the blood-brain barrier (BBB) to catalyze the hydrolysis of organophosphate (OP)-inhibited human acetylcholinesterase (hAChE) in the central nerve system (CNS). The hydroxyimino-acetamido alkylamines of the invention are designed to fit within AChE active center gorge dimensions, bind with reasonable affinity, and react with the conjugated phosphate atom in the gorge. The hydroxyimino-acetamido alkylamines of the invention are also designed to possess ionization states that govern affinity and reactivity for the two linked hAChE re-activation steps. In alternative embodiments, the invention provides pumps, devices, subcutaneous infusion devices, continuous subcutaneous infusion devices, infusion pens, needles, reservoirs, ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump, a syringe, a cartridge or a pen or a jet injector, comprising a compound of the invention.

Centrally active and orally bioavailable antidotes for organophosphate exposure and methods for making and using them

In alternative embodiments, provided are selective agonists having a high affinity for the alpha7 nicotinic acetylcholine receptor (&#x3b1;7 nAChR), assays for selectivity of nicotinic receptor subtype and ligand-gated ion channel subtype based on receptor occupation and response, behavioral assessments for reversing cognitive impairment after scopolamine treatment, enhancing memory retention over time, pharmaceutical compositions and formulations and devices comprising them, and methods for making and using them, including characterizing and efficiently assaying them for receptor subtype selectivity. In alternative embodiments, provided are substituted anti 1,2,3-triazoles compounds with high affinity, and selective binding, for the alpha7 nicotine acetylcholine receptor (&#x3b1;7 nAChR), as exemplified by 5-(1-(2-(Piperidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)-1H-indole ('IND1'), 5-((quinuclid-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indole ('IND8') and 3-(4-hydroxyphenyl-1,2,3-triazol-1-yl) quinuclidine (&#x201c;QND8&#x201d;). In alternative embodiments, provided are products of manufacture such as pumps, devices, syringes and the like comprising a compound, pharmaceutical composition or formulation as provided herein.

Selective alpha-7 nicotinic receptor agonists and methods for making and using them

Provided are N-alkyl imidazole 2-aldoximes, including cationic imidazolium and uncharged tertiary imidazole aldoximes, and compositions and methods for making and using them, including methods for reactivating human butyrylcholinesterase (hBChE) or acetylcholinesterase (hAChE) inhibited by organophosphate (OP). By administration of a composition of the invention, the inactive or conjugated hBChE-OP or hAChE-OP is reactivated and the catalytic cycle of turnover and inactivation of the OP is completed; and in alternative embodiments, secondary mechanisms of reversible protection of hBChE and hAChE from irreversible inactivation by OPs and reactivation of tissue AChE also contribute to overall efficacy.

Catalytic scavengers of organophosphates to potentiate butyrylcholinesterase (hBChE) as a catalytic bioscavenger and methods for making and using them

Condensation of fluoro-substituted and silyl-substituted monomers provides polymers suitable for use, e.g., as engineering polymers. A monomer composition is condensed in the presence of a basic catalyst. The monomer composition contains a compound of formula F&#x2014;X&#x2014;F and a compound of formula (R)Si&#x2014;Z&#x2014;Si(R), and forms an alternating X&#x2014;Z polymer chain and a silyl fluoride byproduct. X has the formula -A(&#x2014;R-A)n-; each A is SO, C(&#x2550;O), or Het; Ris an organic moiety; n is 0 or 1; Het is an aromatic nitrogen heterocycle; Z has the formula -L-R-L; each L is O, S, or N(R); and each Ris an organic moiety, and Rcomprises H or an organic moiety.

Polymerization method and polymers formed therewith

Condensation of fluoro-substituted and silyl-substituted monomers provides polymers suitable for use, e.g., as engineering polymers. A monomer composition is condensed in the presence of a basic catalyst. The monomer composition contains a compound of formula F&#x2014;X&#x2014;F and a compound of formula (R)Si&#x2014;Z&#x2014;Si(R), and forms an alternating X&#x2014;Z polymer chain and a silyl fluoride byproduct. X has the formula -A(-R-A)n-; each A is SO, C(&#x2550;O) or Het; Ris an organic moiety; n is 0 or 1; Het is an aromatic nitrogen heterocycle; Z has the formula -L-R-L-; each L is O, S, or N(R); and each Ris an organic moiety, and Rcomprises H or an organic moiety.

Condensation of fluoro-substituted and silyl-substituted monomers provides polymers suitable for use, e.g., as engineering polymers. A monomer composition is condensed in the presence of a basic catalyst. The monomer composition contains a compound of formula F&#x2014;X&#x2014;F and a compound of formula (R)3Si&#x2014;Z&#x2014;Si(R)3, and forms an alternating X&#x2014;Z polymer chain and a silyl fluoride byproduct. X has the formula -A(-R-A)n-; each A is SO, C(&#x2550;O), or Het; Ris an organic moiety; n is 0 or 1; Het is an aromatic nitrogen heterocycle; Z has the formula -L-R-L-; each L is O, S, or N(R); and each Ris an organic moiety, and Rcomprises H or an organic moiety.

A copper catalyzed click chemistry ligation process is employed to bind azides and terminal acetylenes to provide 1,4-disubstituted 1,2,3-triazole triazoles. The process comprises contacting a solution of an organic azide and a terminal alkyne with a source of catalytic Cu(I) ion to form a 1,4-disubstituted 1,2,3-triazole, wherein the source of Cu(I) ion comprises Cu(II) and a metal capable of reducing Cu(II) to Cu(I). In some embodiments, the metal capable of reducing Cu(II) to Cu(I) is selected from the group consisting of Al, Be, Co, Cr, Fe, Mg, Mn, Ni, and Zn.

Copper-catalysed ligation of azides and acetylenes

A copper catalyzed click chemistry ligation process is employed to bind azides and terminal acetylenes to provide 1,4-disubstituted 1,2,3-triazole triazoles. The process comprises contacting an organic azide and a terminal alkyne with a source of reactive Cu(I) ion in human blood plasma to form by cycloaddition a 1,4-disubstituted 1,2,3-triazole. The source of reactive Cu(I) ion can be, for example, a Cu(I) salt, Cu(II) ion in the presence of a reducing agent, or copper metal.

This invention provides a method for preparing a 1,2,3-triazole compound comprising contacting an organic azide with a 2-substituted-1-haloalkyne, in the presence of a copper catalyst and a copper-coordinating ligand (preferably a tertiary amine) in a liquid reaction medium, thereby forming a 1,4,5-substituted-1,2,3-triazole compound including a halo substituent at the 5-position of the triazole, the organic portion of the organic azide at the 1-position of the triazole, and the substituent of the 1-iodoalkyne at the 4-position of the triazole. A method for preparing 1-iodoalkynes is also provided.

Copper catalyzed cycloaddition of organic azides and 1-haloalkynes

A copper catalyzed click chemistry ligation process is employed to bind azides and terminal acetylenes to provide 1,4-disubstituted 1,2,3-triazole triazoles. The process comprises contacting an organic azide and a terminal alkyne with a source of reactive Cu(I) ion for a time sufficient to form by cycloaddition a 1,4-disubstituted 1,2,3-triazole. The source of reactive Cu(I) ion can be, for example, a Cu(I) salt or copper metal. The process is preferably carried out in a solvent, such as an aqueous alcohol. Optionally, the process can be performed in a solvent that comprises a ligand for Cu(I) and an amine.

A convenient process for the regioselective synthesis of 1,5-disubstituted 1,2,3-triazoles and 1,4,5-trisubstituted 1,2,3-triazoles from organic azides and alkynes employs catalytic ruthenium.

Ruthenium-catalyzed cycloaddition of alkynes and organic azides

Adhesive polymers are formed when polyvalent azides and alkynes are assembled into crosslinked polymer networks by copper-catalyzed 1,3-dipolar cycloaddition. The condensation polymerization is efficiently promoted by Cu ions either leached from the metal surface or added to the monomer mixture, and strong interactions with metal surfaces are provided by the multiple triazole binding elements produced. The adhesive polymers may be formed either as adhesive polymer coatings or as adhesive polymer cement.

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Oceanside, CA, United States of America

Valery Fokin