Chain-modified pyridino-N substituted nicotine compounds for use in the treatment of CNS pathologies
View Patent ↗Compounds for treating abuse of nicotinic receptor agonists, addiction to psychostimulant drugs, addiction to opiates, addiction to alcohol, addiction to tobacco products, addiction to nicotine, schizophrenia and related diseases, depression and related conditions, Alzheimer's disease, Parkinson's disease, irritable bowel syndrome, and colitis. The compounds competitively inhibit central nervous system acting nicotinic receptor agonists and act at the putative α3β2* and α4β2 neuronal nicotinic receptors in the central nervous system.
1. A compound including resolved enantiomers and diastereoisomers thereof selected from a formula consisting of formula (VI):
wherein
Q is methylene;
R 1 is selected from the group consisting of hydrogen, lower straight chain or branched alkyl, cycloalkyl, substituted cycloalkyl, aryl and aralkyl;
R 2 , Z 1 and Z 4 are each independently selected from the group consisting of hydrogen, lower alkyl, lower branched alkyl, lower alkenyl, and lower branched alkenyl;
A and B are carbon;
R 3 , R 4 , Z 2 and Z 3 are each independently selected from the group consisting of hydrogen; alkyl; substituted alkyl; cycloalkyl; substituted cycloalkyl; substituted alkenyl; substituted alkenyl; alkynyl; substituted alkynyl; aryl; substituted aryl; alkylaryl; substituted alkylaryl; arylalkyl; substituted arylalkyl; arylalkenyl; substituted arylalkenyl; arylalkynyl; substituted arylalkynyl;
R 5 is selected from the group consisting of alkyl; substituted alkyl; cycloalkyl; substituted cycloalkyl; alkenyl; substituted alkenyl; alkynyl; substituted alkynyl; aryl; substituted aryl; arylalkyl; substituted arylalkyl; arylalkenyl; substituted arylalkenyl; arylalkynyl; substituted arylalkynyl, with the proviso that R 5 of R optical isomer of Formula (VI) is not —CH 2 OH when A and B are carbon, and R 5 of the S optical isomer of Formula (VI) is not hydrogen, —CH 2 NH 2 or —CH 2 Ph when A and B are carbon;
R 6 is hydrogen; and
Y is selected from the group consisting of 2Cl, 2Br, 2I, 2HSO 4 , SO 2 , 2CH 3 SO 3 , 2p-TsO and 2CF 3 SO 3 .
2. The compound according to claim 1 , wherein said compound is (S)-trans-3-(1-methyl-pyrrolidin-2-yl)-1-oct-3-enyl-pyridinium bromide hydrobromide salt.
3. The compound according to claim 1 , wherein said compound is (S)-trans-1-dec-4-enyl-3-(1-methyl-pyrrolidin-2-yl)-pyridinium bromide.
4. The compound according to claim 1 , wherein said compound is (S)-cis-3-(1-methyl-pyrrolidin-2-yl)-1-oct-3-enyl-pyridinium bromide hydrobromide salt.
5. The compound according to claim 1 , wherein said compound is (S)-cis-1-dec-4-enyl-3-(1-methyl-pyrrolidin-2-yl)-pyridinium bromide hydrobromide salt.
6. The compound according to claim 1 , wherein said compound is (S)-1-dec-9-enyl-3-(1-methyl-pyrrolidin-2-yl)-pyridinium bromide.
7. The compound according to claim 1 , wherein said compound is (S)-1-(6-cyclobutyl-hexyl)-3-(1-methyl-pyrrolidin-2-yl)-pyridinium bromide hydrobromide salt.
8. The compound according to claim 1 , wherein said compound is (S)-1-(6-cyclopentyl-hexyl)-3-(1-methyl-pyrrolidin-2-yl)-pyridinium bromide hydrobromide salt.
9. The compound according to claim 1 , wherein said compound is (S)-1-(6-cyclohexyl-hexyl)-3-(1-methyl-pyrrolidin-2-yl)-pyridinium bromide hydrobromide salt.
10. The compound according to claim 1 , wherein said compound is (S)-1-(7-methyl-oct-6-enyl)-3-(1-methyl-pyrrolidin-2-yl)-pyridinium bromide hydrobromide.
11. The compound according to claim 1 , wherein said compound is (S)-1-(7-methyl-octyl)-3-(1-methyl-pyrrolidin-2-yl)-pyridinium bromide hydrobromide salt.
12. The compound according to claim 1 , wherein R 1 is hydrogen or straight chain or branched alkyl having 1–10 carbons, R 5 is a branched or non-branched C 4 –C 19 alkyl having 4–19 carbons, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl or arylalkynyl; and Y is 2Br or 2I.
13. The compound according to claim 1 , wherein R 1 is methyl, ethyl, isopropyl or isobutyl; R 2 is hydrogen; and R 3 and R 4 are individually hydrogen, halogen, alkyl or alkyol, R 5 is a branched or non-branched C 4 –C 19 alkyl having 4–19 carbons, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl or arylalkynyl; Z 1 , Z 2 , Z 3 and Z 4 hydrogen; Y is 2Br or 2I.
14. The compound according to claim 1 , wherein R 1 is methyl; R 2 is hydrogen; and R 3 and R 4 are individually hydrogen, halogen, alkyl or alkyol, R 5 is a branched or non-branched C 4 –C 19 alkyl having 4–19 carbons, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl or arylalkynyl; Z 1 , Z 2 , Z 3 and Z 4 are hydrogen; and Y is 2Br or 2I.
15. The compound according to claim 1 , wherein said compound is substantially optically pure.