Methods of Treating Hyperalgesia

Abstract

This application describes compounds and methods that can be used to treat, reverse, or avoid hyperalgesia.

1 . A method of treating or reversing hyperalgesia in a subject comprising administering to the subject a compound of Formula I, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 A 1  is selected from the group consisting of null, CH 2 , CHR 1 , CR 1 R 2 , CH, CR 1 , O, S, SO, SO 2 , NH and NR 1 ; 
 A 2  is selected from the group consisting of null, CH 2 , CHR 5 , CR 5 R 6 , CH, CR 5 , O, S, SO, SO 2 , NH and NR 5 ; 
 A 3  is selected from the group consisting of null, CH 2 , CHR 7 , CR 7 R 8 , O, S, SO, SO 2 , NH, NR 7 , CH and CR 7 ; 
 A 4  selected from the group consisting of is null, CH 2 , cycle of the formula C(CH 2 ) n , where n=2-5, CHR 9 , CR 9 R 10 , O, S, SO, SO 2 , NH, NR 9 , CH and CR 9 ; 
 A 5  is selected from the group consisting of null, CH 2 , CHR 11 , CR 11 R 12 , CH 2 CH 2 , CHR 11 CH 2 , CH 2 CHR 11 , CHR 11 CHR 12 , O, S, SO, SO 2 , NH, NR 11 , CH and CR 11 ; 
 B 1  is selected from the group consisting of CH 2 , CHR 13 , CR 13 R 14 , O, S, SO, SO 2 , NH, NR 13 , CR 13  and CO; 
 B 2  is selected from the group consisting of CH 2 , CHR 15 , CR 15 R 16 , CR 15  and CO; 
 B 3  is selected from the group consisting of H, alkyl, branched alkyl, halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, and alkylsulfonyl; 
 B 4  is selected from the group consisting of null, C 1 -C 6  alkyl, CH 2 , CH 2 CH 2 , CHR 19 , CR 19 R 20  and CO; 
 B 5  is selected from the group consisting of alkyl, branched alkyl, halogenated alkyl, carbocycle-substituted alkyl, aryl, carbocycle and arylalkyl; 
 D 1  is an aryl group or a cycle; 
 R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 19 , and R 20  are independently selected from the group consisting of cyano, halogen, hydroxyl, alkyloxy, alkyl, branched alkyl, halogenated alkyl, branched halogenated alkyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl, alkylcarbonyl, branched alkylcarbonyl, halogenated alkylcarbonyl, branched halogenated alkylcarbonyl, arylcarbonyl and alkoxycarbonyl; 
 wherein no more than 2 out of 5 of Au, A 2 , A 3 , A 4 , and A 5  can be null at the same time, 
 wherein the number of heteroatoms in Au, A 2 , A 3 , A 4 , A 5  cannot exceed 2 at the same time; 
 wherein the bonds between Au, A 2 , A 3 , A 4  and A 5  cannot be S—O, S—S, or S—N; and 
 wherein alkyl is a linear carbon chain having from 1 to 10 carbon atoms; wherein the cycle is not aromatic; 
 
       wherein each aryl group is a monocyclic aromatic group or a bicyclic aromatic group; wherein each cycle is a monocyclic or a bicyclic non-aromatic ring system. 
     
     
         2 . The method of  claim 1 , wherein the hyperalgesia is opioid induced hyperalgesia. 
     
     
         3 - 4 . (canceled) 
     
     
         5 . A method of decreasing nociceptive sensitization in a subject comprising administering to the subject a compound of Formula I, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 A 1  is selected from the group consisting of null, CH 2 , CHR 1 , CR 1 R 2 , CH, CR 1 , O, S, SO, SO 2 , NH and NR 1 ; 
 A 2  is selected from the group consisting of null, CH 2 , CHR 5 , CR 5 R 6 , CH, CR 5 , O, S, SO, SO 2 , NH and NR 5 ; 
 A 3  is selected from the group consisting of null, CH 2 , CHR 7 , CR 7 R 8 , O, S, SO, SO 2 , NH, NR S , CH and CR 7 ; 
 A 4  selected from the group consisting of is null, CH 2 , cycle of the formula C(CH 2 ) n , where n=2-5, CHR 9 , CR 9 R 10 , O, S, SO, SO 2 , NH, NR 9 , CH and CR 9 ; 
 A 5  is selected from the group consisting of null, CH 2 , CHR 1 , CR 11 R 12 , CH 2 CH 2 , CHR 11 CH 2 , CH 2 CHR 1 , CHR 11 CHR 12 , O, S, SO, SO 2 , NH, NR 1 , CH and CR 11 ; 
 B 1  is selected from the group consisting of CH 2 , CHR 13 , CR 13 R 14 , O, S, SO, SO 2 , NH, NR 13 , CR 13  and CO; 
 B 2  is selected from the group consisting of CH 2 , CHR 15 , CR 15 R 16 , CR 15  and CO; 
 B 3  is selected from the group consisting of H, alkyl, branched alkyl, halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, and alkylsulfonyl; 
 B 4  is selected from the group consisting of null, C 1 -C 6  alkyl, CH 2 , CH 2 CH 2 , CHR 19 , CR 19 R 20  and CO; 
 B 5  is selected from the group consisting of alkyl, branched alkyl, halogenated alkyl, carbocycle-substituted alkyl, aryl, carbocycle and arylalkyl; 
 D 1  is an aryl group or a cycle; 
 R 1 , R 2 , R 5 , R 6 , R 7 , R 5 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 19 , and R 20  are independently selected from the group consisting of cyano, halogen, hydroxyl, alkyloxy, alkyl, branched alkyl, halogenated alkyl, branched halogenated alkyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl, alkylcarbonyl, branched alkylcarbonyl, halogenated alkylcarbonyl, branched halogenated alkylcarbonyl, arylcarbonyl and alkoxycarbonyl; 
 wherein no more than 2 out of 5 of Au, A 2 , A 3 , A 4 , and A 5  can be null at the same time, 
 wherein the number of heteroatoms in Au, A 2 , A 3 , A 4 , A 5  cannot exceed 2 at the same time; 
 wherein the bonds between Au, A 2 , A 3 , A 4  and A 5  cannot be S—O, S—S, or S—N; and 
 wherein alkyl is a linear carbon chain having from 1 to 10 carbon atoms; wherein the cycle is not aromatic; 
 
       wherein each aryl group is a monocyclic aromatic group or a bicyclic aromatic group; wherein each cycle is a monocyclic or a bicyclic non-aromatic ring system. 
     
     
         6 - 27 . (canceled) 
     
     
         28 . The method of  claim 1 , wherein the compound has a formula of Formula II-1, Formula II-2, or Formula III, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         A 2  is selected from the group consisting of CH 2 , CHR 5  and CR 5 R 6 ; 
         A 4  is elected from the group consisting of CH 2 , CHR 9 , CR 9 R 10  and a cycle of the formula C(CH 2 ) n , where n=2-5; 
         R 5 , R 6 , R 9  and R 10  are independently selected from the group consisting of CH 3 , CH 2 CH 3 , CH 2 F, CHF 2 , CF 3 , n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu and phenyl; 
         B 3  is selected from the group consisting of H, alkyl, branched alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl and alkylsulfonyl; 
         B 4  is selected from the group consisting of null, CH 2 , CHR 19 , CR 19 R 20  and CO; 
         B 5  is selected from the group consisting of alkyl, branched alkyl, carbocycle, carbocycle-substituted alkyl, aryl and arylalkyl; and 
         D 1  is aryl. 
       
     
     
         29 - 44 . (canceled) 
     
     
         45 . The method of  claim 1 , wherein the compound has a formula of Formula IV-1, IV-2, or IV-3, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 21  and R 22  are independently H or CH 3 ; 
         A 4  is selected from the group consisting of CH 2 , CR 9 R 10  and a cycle of the formula C(CH 2 ) n , where n=2-5; 
         R 9  and R 10  are independently CH 3  or CH 2 CH 3 ; 
         B 3  is H, CH 3 , or —(CH 2 ) n CH 3 , where n=2-3; 
         B 4  is selected from the group consisting of null, CH 2 , C 1 -C 6  alkyl, CH 2 CH 2  or —CHCH 3 ; 
         B 5  is selected from the group consisting of —(CH 2 ) n CH 3 , where n=2-3, —C(CH 3 ) 3 , cyclohexyl, cyclopentyl, aryl and arylalkyl; 
         D 1  is a phenyl or 2-pyridyl, wherein the phenyl or 2-pyridyl can be independently mono or multiply substituted with a member of the group consisting of F, Cl, Br, CF 3 , OCF 3  and CH 3 ; and 
         wherein the aryl group is selected from group consisting of 
       
       
         
           
           
               
               
           
         
       
     
     
         46 . (canceled) 
     
     
         47 . The method of  claim 1 , wherein the compound has a formula of Formula V-1, V-2, V-3, VI-1, VI-2, or VI-3, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein D 1  is an optionally mono or multiply substituted aryl; 
         B 5  is an optionally mono or multiply substituted aryl or carbocycle; 
         wherein aryl is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         and 
         wherein the carbocycle is cyclohexyl, cyclohexenyl or cyclopentyl. 
       
     
     
         48 - 54 . (canceled) 
     
     
         55 . The method of  claim 1 , wherein the compound has a formula of Formula IV-1, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 21  and R 22  are independently H or CH 3 ; 
         A 4  is an optionally substituted cycle of the formula C(CH 2 ) n , where n=2-5; 
         B 3  is H or an optionally substituted alkyl; 
         B 4  is C 1 -C 6  alkyl; 
         D 1  is an optionally substituted aryl; and 
         B 5  is an optionally substituted aryl. 
       
     
     
         56 . The method of  claim 55 , having the structure of Formula VII-1: 
       
         
           
           
               
               
           
         
         wherein R 26  and R 27  are independently H or an isotope thereof. 
       
     
     
         57 . The method of  claim 56 , wherein the compound has the structure of Formula IX, Formula VII-1, or Formula X, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         58 - 63 . (canceled) 
     
     
         64 . The method of  claim 55 , wherein B 5  is an optionally substituted aryl selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein
 R 23 , R 24 , and R 30  are each independently null, H, OH, cycle, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amine, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, alkylsulfanyl; or, R 23  and R 24  together form a aryl or cycle that is attached to one or more of the atoms of B 5 ; and R 25  is H or an optionally substituted branched or unbranched alkyl. 
 
     
     
         65 . The method of  claim 64 , wherein R 23 , R 24 , and R 30  are each independently H, NH 2 , OH, Cl, Br, F, I, OMe, CN, CH 3 , phenyl, C 3 -C 6  carbocycle, methanesulfonyl, CF 3 , 
       
         
           
           
               
               
           
         
       
       wherein R 29  is H or an optionally substituted branched or unbranched alkyl. 
     
     
         66 . The method of  claim 64 , wherein B 5  is 
       
         
           
           
               
               
           
         
       
     
     
         67 . The method of  claim 64 , wherein B 5  is 
       
         
           
           
               
               
           
         
       
     
     
         68 . The method of  claim 66 , wherein R 23  is alkoxy. 
     
     
         69 . (canceled) 
     
     
         70 . The method of  claim 66 , wherein R 23  is methoxy. 
     
     
         71 . (canceled) 
     
     
         72 . The method of any one of  claim 1 , wherein the compound has a formula of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein: 
 D 1  is an optionally substituted aryl; and 
 B 5  is an optionally substituted pyridyl. 
 
     
     
         73 - 83 . (canceled) 
     
     
         84 . The method of  claim 72 , wherein the compound, has the formula of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         85 . (canceled) 
     
     
         86 . The method of  claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition. 
     
     
         87 - 89 . (canceled) 
     
     
         90 . The compound of  claim 1 , wherein the pharmaceutically acceptable salt is formed from non-toxic inorganic or organic acid. 
     
     
         91 . The compound of  claim 90 , wherein the acid is 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, or toluene sulfonic acid. 
     
     
         92 . The compound of  claim 90 , wherein the pharmaceutically acceptable salt is a fumaric acid salt. 
     
     
         93 . The compound of  claim 92 , wherein the fumaric acid salt of a compound of Formula I is a fumaric acid salt of a compound having the formula of