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

Abstract

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.

1 . A compound having one of the following structures or compositions having one or more compounds of the following structures, or equivalents thereof, or a stereoisomer thereof, or an analog thereof, or a pharmaceutically acceptable salt thereof, or a bioisostere thereof; or
 a composition comprising an isolated compound consisting essentially of, or consisting of:   (a) a compound having the formula:   
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of: —H, -alkyl, and -aryl; 
 R 2  is selected from the group consisting of: —H, -alkyl, and -aryl; 
 R 3  is selected from the group consisting of: —(CH 2 ) n —, and (CH 2 ) n —CH(CH 3 )—, 
 
       wherein n is the integer 0, 1, 2, 3, 4 or 5;
 R 4  is selected from the group consisting of: —H, -alkyl, 
 wherein optionally:
 the alkyl is selected from the group consisting of: -methyl, -ethyl, -propyl, -butyl, -i-propyl, and -i-butyl), -cycloalkyl, 
 the cycloalkyl is selected from the group consisting of: -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and -cyclooctyl), -aryl, 
 the aryl is selected from the group consisting of: -phenyl, -naphthyl, -thienyl, and -indolyl), -saturated and nonsaturated heterocyclics, 
 the saturated or nonsaturated heterocyclic is selected from the group consisting of: -aziridine, -oxirane-thiirane, -azirine, -oxirene, -thiirene, -azetidine, -oxetane, -thietane, -azete, -oxete, -thiete, -pyrrolidine, -oxolane, -thiolane, -pyrrole, -furan, -thiophene, -piperidine, -oxane, -thiane, -pyridine, -pyran, -thiopyran, -azepane, -oxepane, -thiepane, -azepine, -oxepine, -thiepine, -azocane, -azocine, and bridged compounds 
 the bridged compound is selected from the group consisting of: -adamantanes, -amantadines, -biperidenes, -memantines, -methenamines, -rimantadines, -norbornanes, and -triazoles; 
 
 (b) a compound having the formula: 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of: —(CH 2 ) n —, and (CH 2 ) n —CH(CH 3 )—, 
 
       wherein n is the integer 0, 1, 2, 3, 4 or 5;
 R 2  is selected from the group consisting of: —H, -alkyl-, 
 wherein optionally:
 the alkyl is selected from the group consisting of: -methyl, -ethyl, -propyl, -butyl, -i-propyl, and -i-butyl), -cycloalkyl, 
 the cycloalkyl is selected from the group consisting of: -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and -cyclooctyl), -aryl, 
 the aryl is selected from the group consisting of: -phenyl, -naphthyl, -thienyl, and -indolyl), -saturated and nonsaturated heterocyclics, 
 the saturated or nonsaturated heterocyclic is selected from the group consisting of: -aziridine, -oxirane-thiirane, -azirine, -oxirene, -thiirene, -azetidine, -oxetane, -thietane, -azete, -oxete, -thiete, -pyrrolidine, -oxolane, -thiolane, -pyrrole, -furan, -thiophene, -piperidine, -oxane, -thiane, -pyridine, -pyran, -thiopyran, -azepane, -oxepane, -thiepane, -azepine, -oxepine, -thiepine, -azocane, -azocine), and bridged compounds, 
 the bridged compound is selected from the group consisting of: -adamantanes, -amantadines, -biperidenes, -memantines, -methenamines, -rimantadines, -norbornanes, and -triazoles; 
 
 (c) a compound having the formula: 
 
       
         
           
           
               
               
           
         
         wherein 
         N is the integer 0, 1, 2, 3, 4 or 5; 
         R is selected from the group consisting of: —H, -alkyl, 
         wherein optionally:
 the alkyl is selected from the group consisting of: -methyl, -ethyl, -propyl, -butyl, -i-propyl, and -i-butyl), -cycloalkyl, 
 the cycloalkyl is selected from the group consisting of: -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and cyclooctyl), -aryl, 
 the aryl is selected from the group consisting of: -phenyl, -naphthyl, -thienyl, and -indolyl), -saturated and nonsaturated heterocyclics, 
 the saturated or nonsaturated heterocyclic is selected from the group consisting of: -aziridine, -oxirane-thiirane, -azirine, -oxirene, -thiirene, -azetidine, -oxetane, -thietane, -azete, -oxete, -thiete, -pyrrolidine, -oxolane, -thiolane, -pyrrole, -furan, -thiophene, -piperidine, -oxane, -thiane, -pyridine, -pyran, -thiopyran, -azepane, -oxepane, -thiepane, -azepine, -oxepine, -thiepine, -azocane, and -azocine), and bridged compounds, 
 the bridged compound is selected from the group consisting of: -adamantanes, -amantadines, -biperidenes, -memantines, -methenamines, -rimantadines, -norbornanes, and -triazoles; 
 
         (d) a compound having the formula: 
       
       
         
           
           
               
               
           
         
         wherein
 R 1  is selected from the group consisting of: —(CH 2 ) n —, and (CH 2 ) n —CH(CH 3 )—, 
 
         wherein N is the integer 0, 1, 2, 3, 4 or 5; 
         R 2  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
          and 
         any combination thereof); 
         (e) a compound having the formula: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
          and 
         any combination thereof; 
         (f) compound having a structure as set forth in Table 1 ( FIG. 3 ) to Table 2 ( FIG. 4 ), or equivalents thereof, or pharmaceutically acceptable salt thereof; 
         or 
         (g) any combination of any of the compounds of (a) to (f). 
       
     
     
         2 . A formulation comprising a compound or composition as set forth in  claim 1 , wherein optionally the formulation is a solid, liquid, aerosol, powder or emulsion formulation. 
     
     
         3 . A pharmaceutical composition comprising a compound or composition as set forth in  claim 1 , wherein optionally the pharmaceutical composition is formulated for enteral or parenteral administration. 
     
     
         4 . A pump, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, an infusion pen, a needles, a reservoir, an 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 as set forth in  claim 1 . 
     
     
         5 . A method for treating, ameliorating or protecting (preventing) an organophosphate toxicity or poisoning or toxic exposure, or for treating, ameliorating or protecting (preventing) organophosphate inhibition of an acetylcholinesterase (AChE), comprising:
 administering to a patient or an individual in need thereof, a compound as set forth in  claim 1 ,   wherein optionally the compound or formulation is administered enterally or parenterally,   wherein optionally the compound or formulation is administered orally, parenterally, by inhalation spray, nasally, topically, intrathecally, intrathecally, intracerebrally, epidurally, intracranially or rectally, or   administering the compound as set forth in  claim 1 , using a pump, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, an infusion pen, a needles, a reservoir, an 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.   
     
     
         6 . The method of  claim 5 , wherein the organophosphate toxicity, poisoning or toxic exposure is caused by exposure of the patient or individual to an alkyl methylphosphonate or related nerve agent, or an alkylphosphorate insecticide. 
     
     
         7 . The method of  claim 5 , wherein the acetylcholinesterase (AChE) is in the central nerve system (CNS), or the acetylcholinesterase (AChE) is a human acetylcholinesterase (hAChE). 
     
     
         8 . A method for treating, preventing or ameliorating excessive acetylcholine stimulation in the brain, comprising:
 administering to a patient or an individual in need thereof, a compound as set forth in  claim 1 ,   wherein optionally the compound or formulation is administered enterally or parenterally,   wherein optionally the compound or formulation is administered orally, parenterally, by inhalation spray, nasally, topically, intrathecally, intrathecally, intracerebrally, epidurally, intracranially or rectally, or   administering the compound as set forth in  claim 1 , using a pump, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, an infusion pen, a needles, a reservoir, an 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.   
     
     
         9 . The method of  claim 8 , wherein the excessive acetylcholine stimulation in the brain, the CNS or the PNS is caused by a drug, a drug overdose, or a poisoning or a toxic exposure to a drug, and optionally the drug overdose causing the excessive acetylcholine stimulation is caused at least in part by physostigmine, neostigmine, pyridostigmine, diisopropylfluorophosphate and/or echothiophate. 
     
     
         10 . The compound of  claim 1 (f), wherein the compound is RS2 138B, RS194B or RS191E; or, the compound is RS251A, RS251B, RS218A, or RS2-57B; or the compound is RS2-148B, RS2-140B, RS3-43D, RS3-36D, RS2-237D, RS2-234D or RS2-245C ( FIG. 4A ). 
     
     
         11 . The compound of  claim 6 , wherein the organophosphate (OP) is or is a component of a toxin, an herbicide, an insecticide, or a nerve gas or nerve agent. 
     
     
         12 . The compound of  claim 11 , wherein the organophosphate (OP) is or comprises a parathion, a malathion, a methyl parathion, a chlorpyrifos, a diazinon, a dichlorvos, a phosmet, a fenitrothion, a tetrachlorvinphos, an azamethiphos or an azinphos methyl, or the nerve agent is a soman (O-Pinacolyl methylphosphonofluoridate), a tabun (Ethyl N,NDimethyl-phosphoramido-cyanidate) or a sarin ((RS)-propan-2-yl methylphosphonofluoridate)