Treatment of inflammation using alpha 7 receptor-binding cholinergic agonists

1 . A method of treating a subject suffering from pancreatitis, comprising: treating said subject with a therapeutically effective amount of a cholinergic agonist selective for an α7 nicotinic receptor. 
     
     
         2 . The method of  claim 1  wherein said acute pancreatitis is acute edematous pancreatitis. 
     
     
         3 . The method of  claim 1  wherein said acute pancreatitis is acute hemorrhaging pancreatitis. 
     
     
         4 . The method of  claim 1  wherein said acute pancreatitis is acute necrotizing pancreatitis. 
     
     
         5 . The method of  claim 1  wherein said acute pancreatitis is infected acute pancreatitis. 
     
     
         6 . The method of  claim 1  wherein said subject is treated prophylactically for acute pancreatitis. 
     
     
         7 . The method of  claim 1 , wherein the cholinergic agonist is selected
 from the group consisting of
 a quaternary analog of cocaine; 
 (1-aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid 1-(2-fluorophenyl)-ethyl ester; 
 a compound of formula I: 
   
       
         
           
           
               
               
           
         
         wherein, R represents hydrogen or methyl, and 
         n represents 0 or 1;
 a pharmaceutically acceptable salt of a compound of formula I; 
 a compound of formula II: 
 
       
       
         
           
           
               
               
           
         
         wherein: 
         m is 1 or 2, 
         n is 0 or 1, 
         Y is CH, N or NO, 
         X is oxygen or sulfur, 
         W is oxygen, H 2  or F 2 , 
         A is N or C(R 2 ), 
         G is N or C(R 3 ), 
         D is N or C(R 4 ), 
         with the proviso that no more than one of A, G and D is nitrogen but at least one of Y, A, G and D is nitrogen or NO, 
         R 1  is hydrogen or C 1 -C 4  alkyl, 
         R 2 , R 3  and R 4  are independently hydrogen, halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, aryl, heteroaryl, OH, OC 1 -C 4  alkyl, CO 2 R 1 , —CN, —NO 2 , —NR 5 R 6 , —CF 3  or —OSO 2 CF 3 , or R 2  and R 3 , R 3  and R 4 , respectively, may together form another six membered aromatic or heteroaromatic ring sharing A and G, or G and D, respectively, containing between zero and two nitrogen atoms, and substituted with one to two of the following substitutents: independently hydrogen, halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, aryl, heteroaryl, OH, OC 1 -C 4  alkyl, CO 2 R 1 , —CN, —NO 2 , —NR 5 R 6 , —CF 3  or —OSO 2 CF 3 , R 5  and R 6  are independently hydrogen, C 1 -C 4  alkyl, C(O)R 7 , C(O)NHR 8 , C(O)OR 9 , SO 2 R 10  or may together be (CH 2 ) j Q(CH 2 ) k  where Q is O, S, NR 11 , or a bond, 
         j is 2 to 7, 
         k is 0 to 2, 
         R 7 , R 8 , R 9 , R 10  and R 11  are independently C 1 -C 4  alkyl, aryl, or heteroaryl, or 
         an enantiomer thereof;
 a pharmaceutically acceptable salt of a compound of formula II; 
 a compound of formula III: 
 
       
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen; R 6  and R 7  are hydrogen or C 1 -C 4  alkyl or are absent, and R 2  is selected from a 
         group of 
       
       
         
           
           
               
               
           
         
         wherein, R 3 , R 4  and R 5  are selected from the group consisting of hydrogen, C 1 -C 4  alkyl optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, C 1 -C 6  alkoxy optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, carboalkoxy having 1 to 4 carbons in the alkoxy, amino, amido having 1 to 4 carbons in the acyl, cyano, and N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, halo, hydroxyl or nitro; and
 a compound of formula IV: 
 
       
       
         
           
           
               
               
           
         
         wherein X is O or S, and R is selected from the group consisting of H, OR 1 , NHC(O)R 1 , and a halogen, wherein R 1  is a C 1 -C 4  alkyl. 
       
     
     
         8 . The method of  claim 1 , wherein the cholinergic agonist is a compound of formula I: 
       
         
           
           
               
               
           
         
         wherein, R represents hydrogen or methyl, and 
         n represents 0 or 1; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . The method of  claim 8 , wherein the cholinergic agonist is (−)-spiro[1-azabicyclo[2.2.2]octane-3,5′-oxazolidin-2′-one] 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 1 , wherein the cholinergic agonist is a compound of formula II: 
       
         
           
           
               
               
           
         
         wherein:
 m is 1 or 2; 
 n is 0 or 1; 
 Y is CH, N or NO; 
 X is oxygen or sulfur; 
 W is oxygen, H 2  or F 2 ; 
 A is N or C(R 2 ); 
 G is N or C(R 3 ); 
 D is N or C(R 4 ); 
 
         with the proviso that no more than one of A, G and D is nitrogen but at least one of Y, A, G and D is nitrogen or NO;
 R 1  is hydrogen or C 1 -C 4  alkyl; 
 R 2 , R 3  and R 4  are independently hydrogen, halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, aryl, heteroaryl, OH, OC 1 -C 4  alkyl, CO 2 R 1 , —CN, —NO 2 , —NR 5 R 6 , —CF 3  or —OSO 2 CF 3 , or R 2  and R 3 , R 3  and R 4 , respectively, may together form another six membered aromatic or heteroaromatic ring sharing A and G, or G and D, respectively, containing between zero and two nitrogen atoms, and substituted with one to two of the following substitutents: independently hydrogen, halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, aryl, heteroaryl, OH, OC 1 -C 4  alkyl, CO 2 R 1 , —CN, —NO 2 , —NR 5 R 6 , —CF 3  or —OSO 2 CF 3 ; 
 R 5  and R 6  are independently hydrogen, C 1 -C 4  alkyl, C(O)R 7 , C(O)NHR 8 , C(O)OR 9 , SO 2 R 10  or may together be (CH 2 ) j Q(CH 2 ) k  where Q is O, S, NR 11 , or a bond; 
 j is 2 to 7; 
 k is 0 to 2; 
 R 7 , R 8 , R 9 , R 10  and R 11  are independently C 1 -C 4  alkyl, aryl, or heteroaryl, or an enantiomer thereof, or a pharmaceutically acceptable salts thereof. 
 
       
     
     
         11 . The method of  claim 10 , wherein the cholinergic agonist is a compound of formula II wherein m is 1; n is 0; p is 0; x is oxygen; A is C(R 2 ); G is C(R 3 ); and D is C(R 4 ). 
     
     
         12 . The method of  claim 10 , wherein the cholinergic agonist is 5′-phenylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridin]. 
     
     
         13 . The method of  claim 1 , wherein the cholinergic agonist is a compound of formula III: 
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen; R 6  and R 7  are hydrogen or C 1 -C 4  alkyl or are absent; and R 2  is selected from a group of 
       
       
         
           
           
               
               
           
         
       
       wherein, R 3 , R 4  and R 5  are selected from the group consisting of hydrogen, C 1 -C 4  alkyl optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, C 1 -C 6  alkoxy optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, carboalkoxy having 1 to 4 carbons in the alkoxy, amino, amido having 1 to 4 carbons in the acyl, cyano, and N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, halo, hydroxyl or nitro. 
     
     
         14 . The method of  claim 12 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 13 , wherein the cholinergic agonist is a compound of formula III, wherein R 2  is attached to the 3-position of the tetrahydropyridine ring, and further wherein R 3 , which is attached to the 4- or the 2-position of the phenyl ring, is selected from the group consisting of amino, hydroxyl, chloro, cyano, dimethylamino, methyl, methoxy, acetylamino, acetoxy, and nitro. 
     
     
         16 . The method of  claim 13 , wherein the cholinergic agonist is a compound selected from the group consisting of formula III, wherein R 3  is hydroxyl, and wherein R 1 , R 4 , and R 5  are hydrogen; formula III, wherein R 3  is acetylamino and wherein R 1 , R 4 , and R 5  are hydrogen; formula III, wherein R 3  is acetoxy and wherein R 1 , R 4 , and R 5  are hydrogen; formula III, wherein R 3  is methoxy, and wherein R 1 , R 4 , and R 5  are hydrogen; formula III, wherein R 3  is methoxy and wherein R 1  and R 4  are hydrogen, and further wherein R 3  is attached to the 2-position of the phenyl ring, and R 5 , which is attached to the 4-position of the phenyl ring, is methoxy or hydroxy. 
     
     
         17 . The method of  claim 13 , wherein the cholinergic agonist is selected from the group consisting of 3-2,4-dimethoxybenzylidine anabaseine (DMXB-A), 3-(4-hydroxybenzylidene)anabaseine, 3-(4-methoxybenzylidene)anabaseine, 3-(4-aminobenzylidene)anabaseine, 3-(4-hyrdoxy-2-methoxybenzylidene)anabaseine, 3-(4-methoxy-2-hydroxybenzylidene)anabaseine, trans-3-cinnamylidene anabaseine, trans-3-(2-methoxy-cinnamylidene)anabaseine and trans-3-(4-methoxycinnamylidene)anabaseine. 
     
     
         18 . The method of  claim 13 , wherein the cholinergic agonist is 3-(4-hydroxy-2-methoxybenzylidene)anabasine 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 13 , wherein the cholinergic agonist is 3-(2,4-dimethoxybenzylidene)anabaseine. 
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 13 , wherein the cholinergic agonist is trans-3-cinnamylidene anabaseine. 
     
     
         21 . The method of  claim 13 , wherein the cholinergic agonist is trans-3-(2-methoxy-cinnamylidene)anabaseine. 
     
     
         22 . The method of  claim 13 , wherein the cholinergic agonist is trans-3-(4-methoxycinnamylidene)anabaseine. 
     
     
         23 . The method of  claim 1 , wherein the cholinergic agonist is a compound of formula IV: 
       
         
           
           
               
               
           
         
         wherein X is O or S; and 
         R is selected from the group consisting of H, OR 1 , NHC(O)R 1 , and a halogen, wherein R 1  is a C 1 -C 4  alkyl. 
       
     
     
         24 . The method of  claim 19 , wherein the cholinergic agonist is selected from a group consisting of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-hydroxyphenoxy)benzamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-acetamidophenoxy)benzamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(phenylsulfanyl)benzamide, and N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenylsulphonyl)benzamide. 
     
     
         25 . The method of  claim 19 , wherein the cholinergic agonist is N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(phenylsulfanyl)benzamide. 
     
     
         26 . The method of  claim 1 , wherein the cholinergic agonist is cocaine methiodide.