Bis-pyridino containing compounds for the use in the treatment of CNS pathologies

A composition for treating nicotine addiction comprising at least one nicotine antagonist having the formula:

• wherein:
• R2, R3, R4, R5, R6 are each independently selected from hydrogen;
• alkyl;
• substituted alkyl;
• cycloalkyl;
• substituted cycloalkyl, pyrrolidine;
• N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• unsaturated pyrrolidine;
• unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• aziridine;
• N-methyl aziridine;
• azetidine;
• N-methyl azetidine;
• unsaturated azetidine;
• unsaturated N-methyl azetidine;
• piperidine;
• N-methyl piperidine;
• unsaturated piperidine;
• unsaturated N-methyl piperidine;
• azepane;
• N-methyl azepane;
• unsaturated azepane;
• unsaturated N-methyl azepane;
• azocane;
• N-methyl azocane;
• unsaturated azocane;
• unsaturated N-methyl azocane;
• 1-aza-bicyclo[3.2.1]octane;
• 1-aza-bicyclo[2.2.1]heptane;
• 8-methyl-8-aza-bicyclo[3.2.1]octane;
• 1-aza-tricyclo[3.3.1.1]decane;
• methyl cycloalkyl;
• methyl substituted cycloalkyl, methylpyrrolidine;
• methyl N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• methyl unsaturated pyrrolidine;
• methyl unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• methyl aziridine;
• methyl N-methyl aziridine;
• methyl azetidine;
• methyl N-methyl azetidine;
• methyl unsaturated azetidine;
• methyl unsaturated N-methyl azetidine;
• methyl piperidine;
• methyl N-methyl piperidine;
• methyl unsaturated piperidine;
• methyl unsaturated N-methyl piperidine;
• methyl azepane;
• methyl N-methyl azepane;
• methyl unsaturated azepane;
• methyl unsaturated N-methyl azepane;
• methyl azocane;
• methyl N-methyl azocane;
• methyl unsaturated azocane;
• methyl unsaturated N-methyl azocane;
• methyl 1-aza-bicyclo[3.2.1]octane;
• methyl 1-aza-bicyclo[2.2.1]heptane;
• 8-methyl-8-aza-bicyclo[3.2.1]octane;
• methyl 1-aza-tricyclo[3.3.1.1]decane;
• R1 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, alkoxy, alkylamine, and thioalkyl, with the proviso that rings 1 and 2 are not isoquinolinium or quinolinium rings when R1 is alkyl with the proviso that the substituted alkyl or substituted alkenyl does not include a carbonyl group;
• and
• X is selected from Cl, Br, I, HSO4, ½SO2, CH3SO3, p-TsO, CF3SO3 and any ion that completes the salt form of the nicotine antagonist;
• and enantomers, diastereomers and racemic mixes thereof.

A method of treating nicotine addiction comprising administering to a patient a composition comprising an effective amount of at least one nicotine antagonist having the formula

• wherein:
• R2, R3, R4, R5, R6 are each independently selected from hydrogen;
• alkyl;
• substituted alkyl;
• cycloalkyl;
• substituted cycloalkyl, pyrrolidine;
• N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• unsaturated pyrrolidine;
• unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• aziridine;
• N-methyl aziridine;
• azetidine;
• N-methyl azetidine;
• unsaturated azetidine;
• unsaturated N-methyl azetidine;
• piperidine;
• N-methyl piperidine;
• unsaturated piperidine;
• unsaturated N-methyl piperidine;
• azepane;
• N-methyl azepane;
• unsaturated azepane;
• unsaturated N-methyl azepane;
• azocane;
• N-methyl azocane;
• unsaturated azocane;
• unsaturated N-methyl azocane;
• 1-aza-bicyclo[3.2.1]octane;
• 1-aza-bicyclo[2.2.1]heptane;
• 8-methyl-8-aza-bicyclo[3.2.1]octane;
• 1-aza-tricyclo[3.3.1.1]decane;
• methyl cycloalkyl;
• methyl substituted cycloalkyl, methylpyrrolidine;
• methyl N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• methyl unsaturated pyrrolidine;
• methyl unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• methyl aziridine;
• methyl N-methyl aziridine;
• methyl azetidine;
• methyl N-methyl azetidine;
• methyl unsaturated azetidine;
• methyl unsaturated N-methyl azetidine;
• methyl piperidine;
• methyl N-methyl piperidine;
• methyl unsaturated piperidine;
• methyl unsaturated N-methyl piperidine;
• methyl azepane;
• methyl N-methyl azepane;
• methyl unsaturated azepane;
• methyl unsaturated N-methyl azepane;
• methyl azocane;
• methyl N-methyl azocane;
• methyl unsaturated azocane;
• methyl unsaturated N-methyl azocane;
• methyl 1-aza-bicyclo [3.2.1]octane;
• methyl 1-aza-bicyclo[2.2.1]heptane;
• 8-methyl-8-aza-bicyclo[3.2.1]octane;
• methyl 1-aza-tricyclo[3.3.1.1]decane;
• R1 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, alkoxy, alkylamine, thioalkyl;
• and
• X is selected from Cl, Br, I, HSO4, ½SO2, CH3SO3, p-TsO, CF3SO3 and any ion that completes the salt form of the nicotine antagonist;
• and enantomers, diastereomers and racemic mixes thereof.

A method of treating a dopamine mediated disease state comprising administering to an individual an effective amount of a composition comprising at least one nicotine antagonist having the formula

• wherein:
• R2, R3, R4, R5, R6 are each independently selected from hydrogen;
• alkyl;
• substituted alkyl;
• cycloalkyl;
• substituted cycloalkyl, pyrrolidine;
• N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• unsaturated pyrrolidine;
• unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• aziridine;
• N-methyl aziridine;
• azetidine;
• N-methyl azetidine;
• unsaturated azetidine;
• unsaturated N-methyl azetidine;
• piperidine;
• N-methyl piperidine;
• unsaturated piperidine;
• unsaturated N-methyl piperidine;
• azepane;
• N-methyl azepane;
• unsaturated azepane;
• unsaturated N-methyl azepane;
• azocane;
• N-methyl azocane;
• unsaturated azocane;
• unsaturated N-methyl azocane;
• 1-aza-bicyclo[3.2.1]octane;
• 1-aza-bicyclo[2.2.1]heptane;
• 8-methyl-8-aza-bicyclo[3.2.1]octane;
• 1-aza-tricyclo[3.3.1.1]decane;
• methyl cycloalkyl;
• methyl substituted cycloalkyl, methylpyrrolidine;
• methyl N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• methyl unsaturated pyrrolidine;
• methyl unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• methyl aziridine;
• methyl N-methyl aziridine;
• methyl azetidine;
• methyl N-methyl azetidine;
• methyl unsaturated azetidine;
• methyl unsaturated N-methyl azetidine;
• methyl piperidine;
• methyl N-methyl piperidine;
• methyl unsaturated piperidine;
• methyl unsaturated N-methyl piperidine;
• methyl azepane;
• methyl N-methyl azepane;
• methyl unsaturated azepane;
• methyl unsaturated N-methyl azepane;
• methyl azocane;
• methyl N-methyl azocane;
• methyl unsaturated azocane;
• methyl unsaturated N-methyl azocane;
• methyl 1-aza-bicyclo[3.2.1]octane;
• methyl 1-aza-bicyclo[2.2.1]heptane;
• 8-methyl-8-aza-bicyclo[3.2.1]octane;
• methyl 1-aza-tricyclo[3.3.1.1]decane;
• R1 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, alkoxy, alkylamine, thioalkyl;
• and
• X is selected from Cl, Br, I, HSO4, ½SO2, CH3SO3, p-TsO, CF3SO3 and any ion that completes the salt form of the nicotine antagonist;
• and enantomers, diastereomers and racemic mixes thereof.

A method of displacing nicotine from nicotinic receptor sites in the brain comprising administering to an individual in need of such treatment an effective amount of a composition comprising at least one nicotine antagonist having the formula

• wherein:
• R2, R3, R4, R5, R6 are each independently selected from hydrogen;
• alkyl;
• substituted alkyl;
• cycloalkyl;
• substituted cycloalkyl, pyrrolidine;
• N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• unsaturated pyrrolidine;
• unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• aziridine;
• N-methyl aziridine;
• azetidine;
• N-methyl azetidine;
• unsaturated azetidine;
• unsaturated N-methyl azetidine;
• piperidine;
• N-methyl piperidine;
• unsaturated piperidine;
• unsaturated N-methyl piperidine;
• azepane;
• N-methyl azepane;
• unsaturated azepane;
• unsaturated N-methyl azepane;
• azocane;
• N-methyl azocane;
• unsaturated azocane;
• unsaturated N-methyl azocane;
• 1-aza-bicyclo[3.2.1]octane;
• 1-aza-bicyclo[2.2.1]heptane;
• 8-methyl-8-aza-bicyclo[3.2.1]octane;
• 1-aza-tricyclo[3.3.1.1]decane;
• methyl cycloalkyl;
• methyl substituted cycloalkyl, methylpyrrolidine;
• methyl N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• methyl unsaturated pyrrolidine;
• methyl unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• methyl aziridine;
• methyl N-methyl aziridine;
• methyl azetidine;
• methyl N-methyl azetidine;
• methyl unsaturated azetidine;
• methyl unsaturated N-methyl azetidine;
• methyl piperidine;
• methyl N-methyl piperidine;
• methyl unsaturated piperidine;
• methyl unsaturated N-methyl piperidine;
• methyl azepane;
• methyl N-methyl azepane;
• methyl unsaturated azepane;
• methyl unsaturated N-methyl azepane;
• methyl azocane;
• methyl N-methyl azocane;
• methyl unsaturated azocane;
• methyl unsaturated N-methyl azocane;
• methyl 1-aza-bicyclo[3.2.1]octane;
• methyl 1-aza-bicyclo[2.2.1]heptane;
• 8-methyl-8-aza-bicyclo[3.2.1]octane;
• methyl 1-aza-tricyclo[3.3.1.1]decane;
• R1 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, alkoxy, alkylamine, thioalkyl;
• and
• X is selected from Cl, Br, I, HSO4, ½SO2, CH3SO3, p-TsO, CF3SO3 and any ion that completes the salt form of the nicotine antagonist;
• and enantomers, diastereomers and racemic mixes thereof;
• wherein said composition is administered outside the central nervous system and in an amount sufficient to cross the blood-brain barrier.

A method of obtaining dopamine release from presynaptic terminals in neuronal dopamine tissue in a stereoselective and receptor-mediated manner comprising administering to an individual in need of such treatment an effective amount of a composition comprising at least one nicotine antagonist having the formula

• wherein:
• R2, R3, R4, R5, R6 are each independently selected from hydrogen;
• alkyl;
• substituted alkyl;
• cycloalkyl;
• substituted cycloalkyl, pyrrolidine;
• N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• unsaturated pyrrolidine;
• unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• aziridine;
• N-methyl aziridine;
• azetidine;
• N-methyl azetidine;
• unsaturated azetidine;
• unsaturated N-methyl azetidine;
• piperidine;
• N-methyl piperidine;
• unsaturated piperidine;
• unsaturated N-methyl piperidine;
• azepane;
• N-methyl azepane;
• unsaturated azepane;
• unsaturated N-methyl azepane;
• azocane;
• N-methyl azocane;
• unsaturated azocane;
• unsaturated N-methyl azocane;
• 1-aza-bicyclo[3.2.1]octane;
• 1-aza-bicyclo[2.2.1]heptane;
• 8-methyl-8-aza-bicyclo[3.2.1]octane;
• 1-aza-tricyclo[3.3.1.1]decane;
• methyl cycloalkyl;
• methyl substituted cycloalkyl, methylpyrrolidine;
• methyl N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• methyl unsaturated pyrrolidine;
• methyl unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• methyl aziridine;
• methyl N-methyl aziridine;
• methyl azetidine;
• methyl N-methyl azetidine;
• methyl unsaturated azetidine;
• methyl unsaturated N-methyl azetidine;
• methyl piperidine;
• methyl N-methyl piperidine;
• methyl unsaturated piperidine;
• methyl unsaturated N-methyl piperidine;
• methyl azepane;
• methyl N-methyl azepane;
• methyl unsaturated azepane;
• methyl unsaturated N-methyl azepane;
• methyl azocane;
• methyl N-methyl azocane;
• methyl unsaturated azocane;
• methyl unsaturated N-methyl azocane;
• methyl 1-aza-bicyclo[3.2.1]octane;
• methyl 1-aza-bicyclo[2.2.1]heptane;
• 8-methyl-8-aza-bicyclo[3.2.1]octane;
• methyl 1-aza-tricyclo[3.3.1.1]decane;
• R1 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, alkoxy, alkylamine, thioalkyl;
• and
• X is selected from Cl, Br, I, HSO4, ½SO2, CH3SO3, p-TsO, CF3SO3 and any ion that completes the salt form of the nicotine antagonist;
• and enantomers, diastereomers and racemic mixes thereof, to obtain dopamine release, said composition being administered outside the central nervous system and in an amount sufficient to cross the blood-brain barrier.

A method of activating the mechanism involved in behavioral sensitization to psycho-stimulants which is correlated with craving in humans comprising administering to an individual in need of such treatment a composition comprising at least one nicotine antagonist having the formula

• wherein:
• R2, R3, R4, R5, R6 are each independently selected from hydrogen;
• alkyl;
• substituted alkyl;
• cycloalkyl;
• substituted cycloalkyl, pyrrolidine;
• N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• unsaturated pyrrolidine;
• unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• aziridine;
• N-methyl aziridine;
• azetidine;
• N-methyl azetidine;
• unsaturated azetidine;
• unsaturated N-methyl azetidine;
• piperidine;
• N-methyl piperidine;
• unsaturated piperidine;
• unsaturated N-methyl piperidine;
• azepane;
• N-methyl azepane;
• unsaturated azepane;
• unsaturated N-methyl azepane;
• azocane;
• N-methyl azocane;
• unsaturated azocane;
• unsaturated N-methyl azocane;
• 1-aza-bicyclo[3.2.1]octane;
• 1-aza-bicyclo[2.2.1]heptane;
• 8-methyl-8-aza-bicyclo[3.2.1]octane;
• 1-aza-tricyclo[3.3.1.1]decane;
• methyl cycloalkyl;
• methyl substituted cycloalkyl, methylpyrrolidine;
• methyl N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• methyl unsaturated pyrrolidine;
• methyl unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl;
• methyl aziridine;
• methyl N-methyl aziridine;
• methyl azetidine;
• methyl N-methyl azetidine;
• methyl unsaturated azetidine;
• methyl unsaturated N-methyl azetidine;
• methyl piperidine;
• methyl N-methyl piperidine;
• methyl unsaturated piperidine;
• methyl unsaturated N-methyl piperidine;
• methyl azepane;
• methyl N-methyl azepane;
• methyl unsaturated azepane;
• methyl unsaturated N-methyl azepane;
• methyl azocane;
• methyl N-methyl azocane;
• methyl unsaturated azocane;
• methyl unsaturated N-methyl azocane;
• methyl 1-aza-bicyclo [3.2.1]octane;
• methyl 1-aza-bicyclo[2.2.1]heptane;
• 8-methyl-8-aza-bicyclo[3.2.1]octane;
• methyl 1-aza-tricyclo[3.3.1.1]decane;
• R1 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, alkoxy, alkylamine, thioalkyl;
• and
• X is selected from Cl, Br, I, HSO4, ½SO2, CH3SO3, p-TsO, CF3SO3 and any ion that completes the salt form of the nicotine antagonist;
• and enantomers, diastereomers and racemic mixes thereof, said nornicotine being administered outside the central nervous system and in an amount sufficient to cross the blood-brain barrier.