Use of trpa1 antagonists to prevent or treat infections caused by biological-warfare agents

Abstract

Provided are methods for preventing and treating injuries caused by exposure to biological warfare agents. The methods include administering to a subject in need thereof an effective amount of a TRPA1 antagonist or a pharmaceutically acceptable salt thereof. In an embodiment the TRPA1 antagonist is selected from the group consisting of compounds of formula I and compounds of formula II as described herein.

1 . A method of preventing or treating an injury resulting from exposure to a biological warfare agent, comprising administering to a subject in need thereof an effective amount of a TRPA1 antagonist or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein the TRPA1 antagonist is selected from the group consisting of compounds of formula I 
       
         
           
           
               
               
           
         
         wherein, 
         R is hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halo, hydroxyl, alkoxy, amino, alkylamino, thiol, alkylthiol, nitro, or cyano, each of which is optionally substituted with one or two R 11 ; 
         X is 
       
       
         
           
           
               
               
           
         
         R 1  and R 2  are each independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl, each of which is optionally substituted with one to four R 5 ; 
         L is NR 6 SO 2 , SO 2 NR 6 , C(O)NR 6 , NR 6 C(O), C(S)NR 6 , NR 6 C(S), OC(O)NR 6 , NR 6 C(O)O, NR6C(O)NR 6 , S, S(O), S(O) 2 , NR 6 , CH 2 , O, C(O), C(O)NR 6 SO 2 , SO 2 NR 6 C(O), heteroarylene, or carbocyclylene; 
         R 3  is carbocyclyl, heterocyclyl, aryl, heteroaryl, or R 3a , each of which is optionally substituted with one to four R 7 ; 
         R 3a  is carbocyclylene, heterocyclylene, arylene, heteroarylene, each of which is substituted with one R 3b ; 
         R 3b  is carbocyclyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one to four R 7 ; 
         each R 5  is independently halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, cyano, nitro, amido, alkylamido, dialkylamido, thioyl, sulfonyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; 
         each R 6  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, hydroxy-C 1 -C 6  alkyl, alkoxy-C 1 -C 6  alkyl, cyanoalkyl, haloalkyl, arylalkyl, —S(O)alkyl, acyl, amino, amidyl, —S(O)H, —S(O) 2 H, —S(O) 2 OH, aryl, or alkoxyaryl; 
         each R 7  is independently C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  haloalkenyl, C 2 -C 6  alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, halo, hydroxyl, alkoxy, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, thioyl, alkylthioyl, sulfonyl, sulfonamidyl (e.g., where the nitrogen of the sulfonamide is substituted with an alkyl, or where the nitrogen of the sulfonamide together with two carbons to which it is attached, forms a heterocyclyl), amido (e.g., where the nitrogen of the amide is substituted with an alkyl, or where the nitrogen of the amide together with two carbons to which it is attached, forms a heterocyclyl), urea, sulfonylurea, acyl, —C(O)aryl, —NHC(O)aryl, —C(O)NHaryl, —C(O)OH, —C(O)Oalkyl, nitro, or cyano, each of which is optionally substituted with one to three R 8 ; 
         each R 8  is independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halo, C 1 -C 6  haloalkyl, hydroxyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, thioyl, sulfonyl, sulfonamidyl, amido, —C(O)OH, —C(O)Oalkyl, urea, sulfonylurea, acyl, nitro, cyano, carbocyclyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one to three C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or halo; 
         R 9  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halo, C 1 -C 6  haloalkyl, hydroxyl, alkoxy, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, thioyl, alkylthioyl, sulfonyl, sulfonamidyl, amido, urea, sulfonylurea, acyl, nitro, or cyano, each of which is optionally substituted with one to three R 8 ; 
         each R 11  is independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halo, hydroxyl, alkoxy, oxo, aryloxy, amino, alkylamino, dialkylamino, C(O)OH, —C(O)Oalkyl, thioyl, sulfonyl, sulfonamidyl, amido, urea, sulfonylurea, acyl, nitro, cyano, cyclyl, heterocyclyl, aryl, or heteroaryl; and 
         each of m and n is independently 0, 1, 2, 3, 4, 5 or 6; 
         compounds of formula II 
       
       
         
           
           
               
               
           
         
         wherein, independently for each occurrence, 
         each W is O or S; 
         each R is hydrogen or lower alkyl; 
         R′ is alkyl or aryl, each optionally substituted with one to five substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, fluoroalkyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluoroalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluoroalkoxysulfonyl, alkenyloxysulfonyl, alkynyloxysulfony, aminosulfonyl, sulfinic acid, alkylsulfinyl, haloalkylsulfinyl, fluoroalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl, fluoroalkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfinyl, aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, fluoroalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluoroalkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfinyloxy, alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy, fluoroalkoxysulfinyloxy, alkenyloxysulfinyloxy, alkynyloxysulfinyloxy, aminosulfinyloxy, amino, amido, aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl, phosphoryl, silyl, silyloxy, and any of said substituents bound to the alkyl or aryl group through an alkylene moiety; 
         X is O or NR″; 
         R″ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, or carbocyclylalkyl, each optionally substituted with one to five substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, fluoroalkyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, carbocycloxy, heterocycloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluoroalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluoroalkoxysulfonyl, alkenyloxysulfonyl, alkynyloxysulfonyl, aminosulfonyl, sulfinic acid, alkylsulfinyl, haloalkylsulfinyl, fluoroalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl, fluoroalkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfinyl, aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, fluoroalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluoroalkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfinylkoxy, alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy, fluoroalkoxysulfinyloxy, alkenyloxysulfinyloxy, alkynyloxysulfinyloxy, aminosulfinyloxy, amino, amido, aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl, phosphoryl, silyl, silyloxy, and any of said substituents bound to the alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, or carbocyclylalkyl group through an alkylene moiety; and 
         Ar is aryl, optionally substituted with one to five substituents selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycl, carbocycl, aralkyl, heteroaralkyl, heterocycylalkyl, or carbocyclalkyl, each optionally substituted with one to five substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, fluoroalkyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluoroalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, fluoroalkoxysulfonyl, alkenyloxysulfonyl, alkynyloxysulfony, aminosulfonyl, sulfinic acid, alkylsulfinyl, haloalkylsulfinyl, fluoroalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinul, haloalkoxysulfinyl, fluoroalkoxysulfinyl, alkenyloxyaulfinyl, alkynyloxysulfiny, aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, fluoroalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluoroalkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfinylkoxy, alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy, fluoroalkoxysulfinyloxy, alkenyloxysulfinyloxy, alkynyloxysulfinyloxy, aminosulfinyloxy, amino, amido, aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl, phosphoryl, silyl, silyloxy, and any of said substituents bound to the alkyl or aryl group through an alkylene moiety; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         3 . The method of  claim 1 , wherein the TRPA1 antagonist is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         4 . The method of  claim 2 , wherein the TRPA1 antagonist is administered orally. 
     
     
         5 . The method of  claim 2 , wherein the TRPA1 antagonist is administered via intramuscular injection. 
     
     
         6 . The method of  claim 2 , wherein the TRPA1 antagonist is administered topically. 
     
     
         7 . The method of  claim 2 , wherein the TRPA1 antagonist is administered by topical ocular administration. 
     
     
         8 . The method of  claim 2 , wherein the TRPA1 antagonist is administered prior to the exposure to the biological-warfare agent. 
     
     
         9 . The method of  claim 2 , wherein the TRPA1 antagonist is administered after exposure to the biological-warfare agent. 
     
     
         10 . The method of  claim 2 , wherein the biological warfare agent comprises Brucellosis, Cholera,  Clostridium perfringens  toxin, saxitoxin, smallpox, staphylococcal enterotoxin B, trichothecene mycotoxins, tularemia, Dengue virus, Nipah virus, hantaviruses, or tuberculosis. 
     
     
         11 . The method of  claim 10 , wherein the biological-warfare agent is Cholera. 
     
     
         12 . The method of  claim 10 , wherein the biological-warfare agent is staphylococcal enterotoxin B. 
     
     
         13 . The method of  claim 1 , wherein the subject is human. 
     
     
         14 . The method of  claim 1 , further comprising co-administering an antibiotic to the subject in need thereof. 
     
     
         15 . The method of  claim 14 , wherein the antibiotic is doxycycline. 
     
     
         16 . The method of  claim 2 , wherein X is 
       
         
           
           
               
               
           
         
       
       R is hydrogen, L is NR 6 C(O) or C(O)NR 6 ; and n is 2, 3, 4, 5, or 6. 
     
     
         17 . The method of  claim 2 , wherein X 
       
         
           
           
               
               
           
         
       
       R is hydrogen, L is C(O)NR 6 ; R6 is hydrogen, C 1 -C 6  alkyl, arylalkyl, —S(O)alkyl, acetyl, —S(O)H, —S(O) 2 H, — or S(O) 2 OH; and n is 0. 
     
     
         18 . The method of  claim 1 , wherein the TRPA1 antagonist is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof.