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

Bis-pyridino containing compounds for the use in the treatment of cns pathologies description/claims

This application claims priority to U.S. Provisional Application Ser. No. 60/533,213, filed Dec. 31, 2003, which is incorporated herein in its entirety.

Considerable effort has focused on the development of neuronal nicotinic receptor (nAChR) agonists as therapeutic agents. However, relatively few studies have focused on the therapeutic development of nAChR antagonists. As a result, only a few subtype-selective antagonists are currently available for use as pharmacological tools to investigate the physiological roles of specific nAChR subtypes.

It has been found that nicotine stimulates all known nAChR subtypes, and that N-quaternization of nicotine converts it from an agonist into an antagonist with enhanced nAChR subtype selectivity. Several classical nAChR antagonists are bis-quaternary ammonium structures. Hexamethonium chloride and decamethonium bromide, both bis-quaternary ammonium salts, are considered simplified analogs of d-tubocurarine. The latter drugs have been used to distinguish between peripheral nAChR subtypes, specifically neuromuscular and ganglionic nAChRs. More recently, quaternary ammonium N-n-alkyl analogs of nicotine have been reported to be nAChR subtype-selective antagonists. However, it is generally believed that quaternary ammonium compounds do not easily access the brain due to their charge and polarity. Thus, there remains a need for compounds that are bioavailable in the brain and effective in treatment of nicotine addiction and dopamine mediated disease states.

The present invention is directed to the development and therapeutic use of nAChR subtype-selective and brain-bioavailable antagonists. The compounds are made via modification of the nicotine molecule by (1) quaternization of the pyridine-N atom with a lipophillic substituent to afford N-substituted analogs, and (2) modifying the structure of the nicotinium cationic head group. The compounds of the invention are nicotine antagonists 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.

The nicotine antagonists of the invention are useful for the treatment of dopamine related conditions and dopamine-mediated disease states such as myasthenia gravis, Parkinson's disease, Alzheimer's disease, schizophrenia, eating disorders, and drug addiction. These compounds are also useful when used as substitutes for psycho-stimulant self-administration. The nicotine antagonists of the invention are particularly useful for treating drug addiction due to nicotinic agonists, cocaine, amphetamines, caffeine, phencyclidine, opiates, barbituates, benzodiazepines, cannabinoids, hallucinogens and alcohol.

The invention further includes a method of treating nicotine addiction by administering a formulation containing one or more compounds of the invention to the patient. The compounds and compositions of the invention may be administered by applying the formulation to a medical patch which is then attached or adhered to the skin of the patient; providing an oral formulation which is taken orally; providing a formulation which is injected into the patient with a syringe or similar device; providing a formulation which is applied to the nasal cavity; providing a formulation which is applied to the rectum; providing a formulation which is inhaled; providing a formulation which is applied sublingual; and any other means of applying the formulation to the patient.

In another aspect of the invention the nicotine antagonists of the invention are administered to a patient in order to inhibit dopamine release from presynaptic terminals in neuronal dopamine tissue in a stereoselective and receptor-mediated manner.

• Provisional Patent
• Utility Patent

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