TREATMENT OF INFLAMMATION USING ALPHA 7 RECEPTOR-BINDING CHOLINERGIC AGONISTS
A method of treating a patient suffering from pancreatitis comprising treating said patient with a therapeutically effective amount of a cholinergic agonist selective for an α7 nicotinic receptor in an amount sufficient to decrease the amount of the proinflammatory cytokine that is released from a macrophage wherein said condition is acute pancreatitis. The compounds of the present invention include 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), a compound of formula (II), a compound of formula (III), a compound of formula (IV), and an oligonucleotide or mimetic capable of attenuating the symptoms of acute pancreatitis wherein the oligonucleotide or mimetic consists essentially of a sequence greater than 5 nucleotides long that is complementary to an mRNA of an α7 cholinergic receptor. The variables of formulae (I), (II), (III) and (IV) are described herein.
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.