Other

R.j. Reynolds Tobacco Company

Targacept, Inc.

Wake Forest University

Patrick Michael Lippiello

William Scott Caldwell

Merouane Bencherif

Gary Maurice Dull

Peter Anthony Crooks

Balwinder Singh Bhatti

Jared Miller Wagner

Srishailkumar Basawannappa Hadimani

Haeil Park

Thomas A Perfetti

Huw M Davies

Jerry W Redding

Robert L Suber, Sr

William S Caldwel

Carr J Smith

The present invention generally relates to nicotinic compounds, in the form of aryl substituted olefinic compounds, as well as pro-drug, N-oxide, metabolite and pharmaceutically acceptable salt forms thereof. Methods of modulating neurotransmitter release via administration of the compounds, pro-drugs, N-oxides and/or pharmaceutically acceptable salts are also disclosed.

Compounds capable of activating cholinergic receptors

Patients susceptible to or suffering from disorders, such as central nervous system disorders, which are characterized by an alteration in normal neurotransmitter release, such as dopamine release (e.g., Parkinsonism, Parkinson's Disease, Tourette's Syndrome, attention deficient disorder, or schizophrenia) are treated by administering an endo or exo form of a 1-aza-2-(3-pyridyl)bicyclo&lsqb;2.2.1&rsqb;heptane, a 1-aza-2-(3-pyridyl)bicyclo&lsqb;2.2.2&rsqb;octane, a 1-aza-2-(3-pyridyl)bicyclo&lsqb;3.2.2&rsqb;nonane, a 1-aza-7-(3-pyridyl)bicyclo&lsqb;2.2.1&rsqb;heptane, a 1-aza-3-(3-pyridyl)bicyclo&lsqb;3.2.2&rsqb;nonane, or a 1-aza-7-(3-pyridyl)bicyclo&lsqb;3.2.2&rsqb;nonane.

Pharmaceutical compositions and methods for effecting dopamine release

Patients susceptible to or suffering from central nervous system disorders (e.g., Alzheimer's disease, Parkinson's disease, Tourette's syndrome, attention deficit disorder or schizophrenia) are treated by administering an effective amount of an aryl substituted olefinic amine compound. Exemplary compounds include, (E)-N-methyl-4-&lsqb;3-(5-isopropoxypyridin)yl&rsqb;-3-buten-1-amine, and (E)-N-methyl-4-&lsqb;3-(5-methoxymethylpyridin)yl&rsqb;-3-buten-1-amine.

Methods of treating central nervous system disorders with aryl substituted olefinic amine compounds

Pharmaceutical compositions incorporate aryl substituted olefinic amine compounds. Representative compounds are (4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine, (4E)-N-methyl-5-(5-pyrimidinyl)-4-penten-2-amine, (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine, (4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine, (2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine, (2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine, (4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine, (4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine, (2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine, (4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine and (2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.

Methods for treatment of CNS disorders

Patients susceptible to or suffering from Tourette's syndrome or schizophrenia are treated by administering an effective amount of an aryl substituted aliphatic compound, an aryl substituted olefinic amine compound or an aryl substituted acetylenic compound. Exemplary compounds are (E)-4-(5-pyrimidinyl)-3-butene-1-amine, (E)-4-[3-(5-methoxypyridin)yl]-3-butene-1-amine, (E)-N-methyly-4-(5-pyrimidinyl)-3-butene-1-amine, (E)-N-methyl-4-[3-(5-methoxypyrindin)yl]-3-butene-1-amine, (Z)-metanicotine, (E)-metanicotine, N-methyl-(3-pyridinyl)-butane-1-amine, N-methyl-4-(3-pyridinyl)-3-butyne-1-amine and (E)-N-methyl-4-[3-(6-methylpyrindin)yl]-3-butene-1-amine.

Methods for prevention and treatment of Tourette's syndrome and

Patients susceptible to or suffering from central nervous system disorders (e.g., neurodegenerative diseases including presenile dementia, senile dementia of the Alzheimer's type, and Parkinsonism including Parkinson's disease, and other CNS disorders including attention deficit disorder, schizophrenia and Tourette's syndrome) are treated by administering an effective amount of 2-azabicyclo [2.2.1] heptane and 2-azabicyclo [2.2.2] octane compounds.

Pharmaceutical compositions for prevention and treatment of central

A pharmaceutical composition incorporating a nicotinic antagonist is provided. The composition is an effective amount of a compound of the formula: wherein X' is nitrogen or carbon bonded to a substituent species characterized as having a sigma m value greater than 0, less than 0 or 0; X is nitrogen or carbon bonded to a substituent species characterized as having a sigma m value greater than 0, less than 0 or 0; A, A' and A' are individually substituent species characterized as having a sigma m value greater than 0, less than 0 or 0; Z' is a substituent other than hydrogen; j is an integer from 0 to 5; and the wavy line in the structure indicates that the compound can exist in the form of an enantiomer or a diasteromer; Z' is hydrogen or a substituent other than hydrogen; Y is C.dbd.O, C(OH)R' or C--A, where R' is hydrogen or lower alkyl.

Pharmaceutical compositions and methods of using nicotinic antagonists

Patients susceptible to or suffering from central nervous system disorders (e.g., neurodegenerative diseases including presenile dementia, senile dementia of the Alzheimer's type, and Parkinsonism including Parkinson's disease, and other CNS disorders including attention deficit disorder, schizophrenia and Tourette's syndrome) are treated by administering an effective amount of 2-azabicyclo �2.2.1! hept-5-ene and 2-azabicyclo �2.2.2! oct-5-ene compounds.

Patients susceptible to or suffering from attention deficit disorder are treated by administering an effective amount of an aryl subsistituted aliphatic compound, an aryl substituted olefinic amine compound or an aryl substituted acetylenic compound. Exemplary compounds are (E)-4-(5-pyrimidinyl)-3-butene-1-amine, (E)-4-�3-(5-methoxypyridin)yl!-3-butene-1-amine, (E)-N-methyl-4-(5-pyrimidinyl)-3-butene-1-amine, (E)-N-methyl-4-�3-(5-methoxypyrindin)yl!-3-butene-1-amine, (Z)-metanicotine, (E)-metanicotine, N-methyl-(3-pyridinyl)-butane-1-amine, N-methyl-4-(3-pyridinyl)-3-butyne-1-amine and (E)-N-methyl-4-�3-(6-methylpyrindin)yl!-3-butene-1-amine.

Methods for prevention and treatment of attention deficit disorder

Patients susceptible to or suffering from central nervous system disorders (e.g., Alzheimer's disease, Parkinson's disease, Tourette's syndrome, attention deficit disorder or schizophrenia) are treated by administering an effective amount of an aryl substituted olefinic amine compound. Exemplary compounds include (E)-N-methyl-4-�3-(5-benzyloxypyridin)yl!-3-buten-1-amine, (E)-N-methyl-4-�3-(5-phenoxypyridin)yl!-3-buten-1-amine, and (E)-N-methyl-4-�3-(5-phenylpyridin)yl!-3-buten-1-amine.

Pharmaceutical compositions incorporating aryl substituted olefinic

Patients susceptible to or suffering from central nervous system disorders (e.g., neurodegenerative diseases including presenile dementia, senile dementia of the Alzeimer's type, and Parkinsonism including Parkinson's disease) are treated by administering an effective amount of an aryl substituted aliphatic compound, an aryl substituted olefinic amine compound or an aryl substituted acetylenic compound. Exemplary compounds are (E)-4-(5-pyrimidinyl)-3-butene-1-amine, (E)-4-�3-(5-methoxypyridin)yl!-3-butene-1-amine, (E)-N-methyl-4-(5-pyrimidinyl)-3-butene-1-amine, (E)-N-methyl-4-�3-(5-methoxypyrindin)yl!-3-butene-1-amine, (Z)-metanicotine, N-methyl-(3-pyridinyl)-butane-1-amine, N-methyl-4-(3-pyridinyl)-3-butyne-1-amine and (E)-N-methyl-4-�3-(6-methylpyrindin)yl!-3-butene-1-amine.

Patients suffering from or susceptible to conditions of the vascular or circulatory system, particularly the microvasculature, which conditions are associated with decreased blood flow in regions of microcirculation (e.g., Raynaud's disease and Raynaud's phenomenon) are treated with pharmaceutical compositions incorporating an effective amount of an aryl substituted olefinic amine compound. The compounds incorporated into the pharmaceutical compositions of the present invention exhibit selective activity of to the .beta.2-containing nicotinic acetylcholine receptors and thereby yield beneficial therapeutic effects increasing vascular blood flow in regions of microcirculation.

Pharmaceutical compositions for the treatment of conditions associated

Patients susceptible to or suffering from Tourette's syndrome are treated by administering an effective amount of an aryl substituted aliphatic compound, an aryl substituted olefinic amine compound or an aryl substituted acetylenic compound. Exemplary compounds are (E)-4-(5-pyrimidinyl)-3-butene-1-amine, (E)-4-�3-(5-methoxypyridin)yl!-3-butene-1-amine, (E)-N-methyl-4-(5-pyrimidinyl)-3-butene-1-amine, (E)-N-methyl-4-�3-(5-methoxypyrindin)yl!-3-butene-1-amine, (Z)-metanicotine, (E)-metanicotine, N-methyl-(3-pyridinyl)-butane-1-amine, N-methyl-4-(3-pyridinyl)-3-butyne-1-amine and (E)-N-methyl-4-�3-(6-methylpyrindin)yl!-3-butene-1-amine.

Pharamceutical compositions for prevention and treatment of tourette's

Patients suffering from or susceptible to an idiopathic chronic inflammatory bowel disease (e.g., ulcerative colitis) are treated with pharmaceutical compositions. Those patients are treated by administration of an effective amount of aryl substituted aliphatic compound, an aryl substituted olefinic amine compound or an aryl substituted acetylenic compound. Exemplary compounds are (E)-4-(5-pyrimidinyl)-3-butene-1-amine, (E)-4-[3-(5-methoxypyridin)yl]-3-butene-1-amine, (E)-N-methyl-4-(5-pyrimidinyl)-3-butene-1-amine, (E)-N-methyl-4-[3-(5-methoxypyridin)yl]-3-butene-1-amine, (E)-metanicotine, (Z)-metanicotine, N-methyl-(3-pyridinyl)-butane-1-amine, N-methyl-4-(3-pyridinyl)-3-butyne-1-amine and (E)-N-methyl-4 -[3-(6-methylpyrindin)yl]-3-butone-1-amine.

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Lewisville, NC, United States of America

Patrick Michael Lippiello