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Title:  Monoamine oxidase (MAO) inhibitors and uses thereof

United States Patent:  6,569,470

Issued:  May 27, 2003

Inventors:  Williams; Jonnie R. (Manakin-Sabot, VA); DeLorenzo; Robert J. (Richmond, VA); Burton; Harold R. (Lexington, KY)

Assignee:  Regent Court Technologies, LLC (Town and Country, MO)

Appl. No.:  042164

Filed:  January 11, 2002

Abstract

The present invention provides a group of tobacco alkaloids, tobacco extract, Yerbamate extract, and an extract of chewing gum and lozenges which are modulators of monoamine oxidase (MAO) activity (i.e., compounds and substances which inhibit MAO enzyme and prevent its biological activity). The MAO inhibitors of the present invention can cause an increase in the level of norepinephrine, dopamine, and serotonin in the brain and other tissues, and thus can cause a wide variety of pharmacological effects mediated by their effects on these compounds. The MAO inhibitors of the present invention are useful for a variety of therapeutic applications, such as the treatment of depression, disorders of attention and focus, mood and emotional disorders, Parkinson's disease, extrapyramidal disorders, hypertension, substance abuse, smoking substitution, anti-depression therapy, eating disorders, withdrawal syndromes, and the cessation of smoking.

SUMMARY OF THE INVENTION

The present invention relates to the discovery that certain tobacco alkaloids or extracts, a certain tea plant extract, and a certain extract of tobacco extract-containing chewing gum and lozenges provide MAO-inhibiting effects. The present invention also relates to the use of these compounds or substances in the treatment of certain conditions and disorders in mammals, including humans.

The compounds and substances of the present invention are capable of inhibiting MAO activity in mammalian brain and peripheral tissue. These compounds and substances act by increasing the concentration of monoamine compounds (norepinephrine, dopamine, and serotonin) in the body and brain.

The present invention provides a method of treating certain medical, psychiatric and/or neurological conditions or disorders. In a first embodiment of the invention, the method comprises administering a MAO-inhibiting effective amount of anabasine, anatabine or nornicotine to a mammal, particularly a human, for the treatment of medical, psychiatric and/or neurological conditions and disorders such as, but not limited to, Alzheimer's disease, Parkinson's disease, major depression, minor depression, atypical depression, dysthymia, attention deficit disorder, hyperactivity, conduct disorder, narcolepsy, social phobia, obsessive-compulsive disorder, atypical facial pain, eating disorders, drug withdrawal syndromes and drug dependence disorders, including dependence from alcohol, opioids, amphetamines, cocaine, tobacco, and cannabis (marijuana), melancholia, panic disorder, bulimia, anergic depression, treatment-resistant depression, headache, chronic pain syndrome, generalized anxiety disorder, and other conditions in which alteration of MAO activity could be of therapeutic value.

In a second embodiment of the invention, the method comprises administering a MAO-inhibiting effective amount of an extract of Yerbamate (Ilex paraguariensis) tea plant to a mammal, particularly a human, for the treatment of medical, psychiatric and/or neurological conditions and disorders such as, but not limited to, Alzheimer's disease, Parkinson's disease, major depression, minor depression, atypical depression, dysthymia, attention deficit disorder, hyperactivity, conduct disorder, narcolepsy, social phobia, obsessive-compulsive disorder, atypical facial pain, eating disorders, drug withdrawal syndromes and drug dependence disorders, including dependence from alcohol, opioids, amphetamines, cocaine, tobacco, and cannabis (marijuana), melancholia, panic disorder, bulimia, anergic depression, treatment-resistant depression, headache, chronic pain syndrome, generalized anxiety disorder, and other conditions in which alteration of MAO activity could be of therapeutic value.

In a third embodiment of the invention, the method comprises administering a MAO-inhibiting effective amount of a tobacco extract to a mammal, particularly a human, for the treatment of medical, psychiatric and/or neurological conditions and disorders such as, but not limited to, Alzheimer's disease, Parkinson's disease, major depression, minor depression, atypical depression, dysthymia, attention deficit disorder, hyperactivity, conduct disorder, narcolepsy, social phobia, obsessive-compulsive disorder, atypical facial pain, eating disorders, drug withdrawal syndromes and drug dependence disorders, including dependence from alcohol, opioids, amphetamines, cocaine, tobacco, and cannabis (marijuana), melancholia, panic disorder, bulimia, anergic depression, treatment-resistant depression, headache, chronic pain syndrome, generalized anxiety disorder, and other conditions in which alteration of MAO activity could be of therapeutic value.

In a fourth embodiment of the invention, the method comprises administering a MAO-inhibiting effective amount of an extract of gum and lozenges formulated with tobacco extract to a mammal, particularly a human, for the treatment of medical, psychiatric and/or neurological conditions and disorders such as, but not limited to, Alzheimer's disease, Parkinson's disease, major depression, minor depression, atypical depression, dysthymia, attention deficit disorder, hyperactivity, conduct disorder, narcolepsy, social phobia, obsessive-compulsive disorder, atypical facial pain, eating disorders, drug withdrawal syndromes and drug dependence disorders, including dependence from alcohol, opioids, amphetamines, cocaine, tobacco, and cannabis (marijuana), melancholia, panic disorder, bulimia, anergic depression, treatment-resistant depression, headache, chronic pain syndrome, generalized anxiety disorder, and other conditions in which alteration of MAO activity could be of therapeutic value.

DETAILED DESCRIPTION OF THE INVENTION

MAO is an important enzyme that plays a major role in the metabolic transformation of catecholamines and serotonin. Neurotransmitters from this group are metabolized by MAO, and thus their effect is decreased at their receptor cites. MAO is important for the regulation of the levels of dopamine, norepinephrine and serotonin.

Accordingly, inhibition of this major enzyme system will have major effects on the functions regulated by this compound.

In a first embodiment of the invention, the method comprises administering a MAO-inhibiting effective amount of anabasine, anatabine or nornicotine to a mammal, particularly a human, for the treatment of medical, psychiatric and/or neurological conditions and disorders such as, but not limited to, Alzheimer's disease, Parkinson's disease, major depression, minor depression, atypical depression, dysthymia, attention deficit disorder, hyperactivity, conduct disorder, narcolepsy, social phobia, obsessive compulsive disorder, atypical facial pain, eating disorders, drug withdrawal syndromes and drug dependence disorders, including dependence from alcohol, opioids, amphetamines, cocaine, tobacco, and cannabis (marijuana), melancholia, panic disorder, bulimia, anergic depression, treatment-resistant depression, headache, chronic pain syndrome, generalized anxiety disorder, and other conditions in which alteration of MAO activity could be of therapeutic value.

Anabasine, anatabine and nornicotine are minor tobacco alkaloids. These compounds are commercially available. However, they may be synthesized according to known techniques or extracted directly from tobacco itself.

Preferably, anatabine is synthesized according to the method disclosed by N. M. Deo and P. A. Crooks, "Regioselective Alkylation of N-(diphenylmethylidine)-3-(aminomethylpyridine: A Simple Route to Minor Tobacco Alkaloids and Related Compounds," 1137-1141 (Dec. 11, 1995), which is incorporated herein by reference.

In addition, nornicotine is preferably synthesized according to the method disclosed by S. Brandange and L. Lindblom, "N-Vinyl as N--H Protecting Group: A Convenient Synthesis of Myosmine," Acta Chem. Scand., B30, No. 1, p. 93 (1976), which is also incorporated herein by reference.

In a second embodiment of the invention, the method comprises administering a MAO-inhibiting effective amount of an extract of Yerbamate (Ilex paraguariensis) tea plant to a mammal, particularly a human, for the treatment of medical, psychiatric and/or neurological conditions and disorders such as, but not limited to, Alzheimer's disease, Parkinson's disease, major depression, minor depression, atypical depression, dysthymia, attention deficit disorder, hyperactivity, conduct disorder, narcolepsy, social phobia, obsessive-compulsive disorder, atypical facial pain, eating disorders, drug withdrawal syndromes and drug dependence disorders, including dependence from alcohol, opioids, amphetamines, cocaine, tobacco, and cannabis (marijuana), melancholia, panic disorder, bulimia, anergic depression, treatment-resistant depression, headache, chronic pain syndrome, generalized anxiety disorder, and other conditions in which alteration of MAO activity could be of therapeutic value.

The Yerbamate extract may be prepared by shredding the Yerbamate materials, mixing the shredded materials with a water/ethanol (for example, 1/1 by volume) solution in a mixture of about four leaves per 10 ml of the water/ethanol mixture, extracting with continuous stirring, and then removing the solution from the Yerbamate residue. The residue can then be further extracted two more times with the same volume of water/ethanol mixture, and then the extracts may be combined and filtered to remove the particulate Yerbamate materials. The combined extracts may then be subject to vacuum evaporation to yield the Yerbamate extract.

In a third embodiment of the invention, the method comprises administering a MAO-inhibiting effective amount of a tobacco extract to a mammal, particularly a human, for the treatment of medical, psychiatric and/or neurological conditions and disorders such as, but not limited to, Alzheimer's disease, Parkinson's disease, major depression, minor depression, atypical depression, dysthymia, attention deficit disorder, hyperactivity, conduct disorder, narcolepsy, social phobia, obsessive-compulsive disorder, atypical facial pain, eating disorders, drug withdrawal syndromes and drug dependence disorders, including dependence from alcohol, opioids, amphetamines, cocaine, tobacco, and cannabis (marijuana), melancholia, panic disorder, bulimia, anergic depression, treatment-resistant depression, headache, chronic pain syndrome, generalized anxiety disorder, and other conditions in which alteration of MAO activity could be of therapeutic value.

The tobacco extract may be prepared by shredding tobacco leaves (for example, processed tobacco obtained from STAR TOBACCO, INC.), mixing the shredded leaves with a water/ethanol (for example, 1/1 by volume) solution in a mixture of about four leaves per 10 ml of the water/ethanol mixture, extracting with continuous stirring, and then removing the solution from the tobacco residue. The residue can then be further extracted two more times with the same volume of water/ethanol mixture, and then the extracts may be combined and filtered to remove the particulate tobacco leaf material. The combined extracts may then be subject to vacuum evaporation to yield the tobacco extract.

In a fourth embodiment of the invention, the method comprises administering a MAO-inhibiting effective amount of an extract of chewing gum and lozenges formulated with tobacco extract to a mammal, particularly a human, for the treatment of medical, psychiatric and/or neurological conditions and disorders such as, but not limited to, Alzheimer's disease, Parkinson's disease, major depression, minor depression, atypical depression, dysthymia, attention deficit disorder, hyperactivity, conduct disorder, narcolepsy, social phobia, obsessive-compulsive disorder, atypical facial pain, eating disorders, drug withdrawal syndromes and drug dependence disorders, including dependence from alcohol, opioids, amphetamines, cocaine, tobacco, and cannabis (marijuana), melancholia, panic disorder, bulimia, anergic depression, treatment-resistant depression, headache, chronic pain syndrome, generalized anxiety disorder, and other conditions in which alteration of MAO activity could be of therapeutic value.

The chewing gum and lozenges extract may be prepared by extracting five slices of GUMSMOKE chewing gum and NICOMINT lozenges (obtained from STAR TOBACCO, INC.), which are formulated with tobacco extract, with distilled water (50 ml) at room temperature for 12 hours, and then removing the undissolved gum substance by filtration.

The above compounds and substances were evaluated for their MAO inhibiting activity. Test results surprisingly showed that the compounds and substances of the present invention all provided MAO inhibition. It was also discovered that the MAO inhibiting effects had a different character than for known MAO inhibitors in that they reached an asymptotic or ceiling effect, so that further increases in the dose beyond maximal inhibition did not produce any further increase in the MAO inhibition. This asymptotic effect would provide many benefits. For example, the problems associated with previously known, irreversible MAO inhibitors, such as hypertensive effects, can be avoided. Furthermore, the inventive MAO inhibitors may be provided as an "over the counter" drug or dietary supplement in view of its safety and efficacy.

The MAO inhibitors of the present invention may be provided in forms well known to one skilled in the art. They may be formulated in a pharmaceutically acceptable carrier, diluent or vehicle and administered in effective amounts. They may be provided in the form of a capsule, pill, tablets, lozenge, gum, troches, suppositories, powder packets or the like.

The determination of the effective amounts for a given treatment can be accomplished by routine experimentation and is also well within the ordinary skill in the art.

Claim 1 of 6 Claims

We claim:

1. A method of treating major depression comprising administering to a mammal in need thereof an effective amount of anatabine in an acceptable carrier, diluent or vehicle.
 


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